Adverse
Events
Adverse Effect Category
|
|
Teplizumab
|
|
|
Placebo
|
|
|
|
No. of Events
|
|
|
No.
of Subjects (%)
|
|
|
No. of Events
|
|
|
No.
of Subjects (%)
|
|
Blood/Bone Marrow***
|
|
|
45
|
|
|
|
33 (75)
|
|
|
|
2
|
|
|
|
2 (6.2)
|
|
Dermatology/Skin***
|
|
|
17
|
|
|
|
16 (36.4)
|
|
|
|
1
|
|
|
|
1 (3.1)
|
|
Pain
|
|
|
11
|
|
|
|
5 (11.4)
|
|
|
|
5
|
|
|
|
3 (9.4)
|
|
Infection
|
|
|
8
|
|
|
|
5 (11.4)
|
|
|
|
5
|
|
|
|
3 (9.4)
|
|
Gastrointestinal
|
|
|
5
|
|
|
|
4 (9.1)
|
|
|
|
3
|
|
|
|
3 (9.4)
|
|
Metabolic/Laboratory
|
|
|
7
|
|
|
|
4 (9.1)
|
|
|
|
2
|
|
|
|
2 (6.2)
|
|
Pulmonary/Upper Respiratory
|
|
|
6
|
|
|
|
4 (9.1
|
|
|
|
0
|
|
|
|
0 (0)
|
|
Constitutional Symptoms
|
|
|
3
|
|
|
|
2 (4.5)
|
|
|
|
0
|
|
|
|
0 (0)
|
|
Allergy/Immunology
|
|
|
2
|
|
|
|
2 (4.5)
|
|
|
|
0
|
|
|
|
0 (0)
|
|
Cardiac General
|
|
|
1
|
|
|
|
1 (2.3)
|
|
|
|
1
|
|
|
|
1 (3.1)
|
|
Endocrine
|
|
|
0
|
|
|
|
0 (0)
|
|
|
|
2
|
|
|
|
2 (6.2)
|
|
Vascular
|
|
|
1
|
|
|
|
1 (2.3)
|
|
|
|
1
|
|
|
|
1 (3.1)
|
|
Neurology
|
|
|
1
|
|
|
|
1 (2.3)
|
|
|
|
0
|
|
|
|
0 (0)
|
|
Ocular/Visual
|
|
|
1
|
|
|
|
1 (2.3)
|
|
|
|
0
|
|
|
|
0 (0)
|
|
Musculoskeletal/Soft Tissue
|
|
|
2
|
|
|
|
1 (2.3)
|
|
|
|
0
|
|
|
|
0 (0)
|
|
Hepatobiliary/Pancreas
|
|
|
0
|
|
|
|
0 (0)
|
|
|
|
1
|
|
|
|
1 (3.1)
|
|
Syndromes
|
|
|
1
|
|
|
|
1 (2.3)
|
|
|
|
0
|
|
|
|
0 (0)
|
|
Hemorrhage/Bleeding
|
|
|
1
|
|
|
|
1 (2.3)
|
|
|
|
0
|
|
|
|
0 (0)
|
|
Total Events and Subjects
|
|
|
112
|
|
|
|
44 (100)
|
|
|
|
23
|
|
|
|
32 (100)
|
|
***
p < 0.001 Teplizumab vs placebo
Anti-CD3
mAb treatment has been associated with Epstein Barr virus, or EBV, reactivation. At entry, 30 participants (39%) (16 teplizumab
and 14 placebo) had antibodies against EBV. At weeks 3-6 after study drug treatment, there was quantifiable EBV DNA in whole blood
in eight of the seropositive participants – all in the teplizumab group, one of whom had symptoms of pharyngitis, rhinorrhea,
and cough on day 38. In these participants, the EBV DNA levels were below the level of quantification between day 43 and 134 (average
77 days). At entry, 17 participants (ten teplizumab and seven placebo) had antibodies against cytomegalovirus, or CMV. One teplizumab
participant, who was CMV seropositive, had detectable levels of CMV DNA at day 20 that was undetectable by day 42.
These
results demonstrate that a single course of teplizumab significantly delayed the progression to clinical T1D in high risk Stage
2 non-diabetic relatives who had at least two autoantibodies and dysglycemia. The median delay in the diagnosis of diabetes was
approximately two years, and at the conclusion of the trial, the frequency of diabetes-free subjects was double in the drug (57%)
vs placebo-treated subjects (28%). The relatively rapid rate of progression to clinical diabetes in the placebo group reflects
the very high risk of these individuals and reflects the inevitability of progression from Stage 2 to Stage 3 disease, when two
or more autoantibodies and dysglycemia are found, consistent with observations of high rates of beta cell killing in these subjects.
The rapid development of clinical T1D may reflect the enrichment of pediatric participants (72.4%) in whom the rate of progression
is rapid.
Stage
3 Program
Protégé
Study
Protégé
was a randomized, controlled Phase 3 clinical trial conducted in 83 centers in North America (U.S., Canada, Mexico), India, Israel,
and Europe (Czech Republic, Estonia, Germany, Latvia, Poland, Romania, Spain, Sweden, Ukraine). Patients aged eight to 35 years
with recently diagnosed T1D (≤12 weeks) were followed for 12 months (Protégé) and continued to 24 months (Protégé
Extension). Three dose regimens of PRV-031 were administered to 417 patients as intravenous infusions for six to 14 days; 99 patients
received placebo. At 12 months, the primary efficacy endpoint, the proportion of patients with insulin use <0.5 U/kg per day
and HbA1c <6.5%, ranged from 13.7% to 20.8% patients in the PRV-031 groups, depending on dosing regimen, and 20.4% in the placebo
group. The difference between PRV-031-treated patients and placebo-treated patients was not significant. The change in HbA1c from
baseline also did not show a significant difference between PRV-031 and placebo. However, subgroup analyses indicated the following
findings:
|
●
|
The
primary endpoint could have been achieved if cut-offs were changed to insulin use of <0.25 U/kg per day and HbA1c <7.0%,
not only at 12 months but also at 24 months (figure below).
|
|
●
|
C-peptide
levels significantly improved in the PRV-031 group compared with placebo group in all patients, and further analyses indicated
that this difference was more pronounced in younger patients (aged eight to 11 years) and patients enrolled in U.S. sites.
These findings are consistent with other clinical trials, showing a stronger effect in T1D patients who are younger (<17
years), more recently diagnosed (<10 weeks), and with higher C-peptide levels at baseline.
|
Protégé
Encore Study
Protégé
Encore was a randomized, controlled Phase 3 clinical trial conducted in 125 centers in 16 countries. Patients aged eight to 35
years with recently diagnosed T1D were to be followed for 24 months. Three dose regimens of PRV-031, given as intravenous infusions
for six to 14 days, were compared with placebo. The primary endpoint, the proportion of patients with insulin use <0.5 U/kg
per day and HbA1c <6.5% at 12 months, was not met. Study enrollment was stopped at 254 patients (400 planned) when the Protégé
study showed that the primary endpoint was not met. Efficacy analyses were not conducted in this study.
A
summary of the C-peptide data in the completed Phase 2 clinical trials and Phase 3 Protégé study are shown in the
table below. All these studies have shown consistent and significant C-peptide benefit. Furthermore, subgroup analysis of the
Protégé data indicated that younger patients (aged eight to 17 years) with minimum baseline beta cell function (C-peptide
> 0.2 pmol/mL) along with even more robust data in newly-diagnosed T1D (diagnosis under six 6 weeks, Study 1), informed the
inclusion criteria that will be applied in our planned Phase 3 clinical trial, PROTECT.
*
|
Full
9.0 mg/m
2
/course 14-Day regimen was explored in 205 treated patients and 98 placebos;
|
**
|
Delay
study based on 12-month time-point. All other studies based on 24-month time-points
|
Safety
Data
SUBCUE
was a randomized, controlled Phase 1 clinical trial to evaluate the safety and tolerability, pharmacokinetic, or PK, and pharmacodynamics,
or PD of subcutaneously injected PRV-031. Patients aged 18 to 35 years who were diagnosed with T1D within 12 months were to be
given three dosing regimens of PRV-031 or placebo. Patients were to be followed for 91 days. However, the study was stopped after
one subject was enrolled, upon the Protégé study results.
The
majority of safety data for PRV-031 comes from two completed Phase 3 studies: Protégé and Protégé
Encore. In PRV-031 and placebo-treated subjects, there were no major differences in the overall adverse events, or AEs (99.7%
and 100%), and serious adverse events, or SAEs (13.2% (85 out of 645 subjects), and 9.4% (15 out of 160 subjects)), although there
were more severe adverse events in PRV-031 subjects (63% and 30%). In the Protégé study, 261 of 415 (62.9%) subjects
had severe adverse events compared with placebo, 28 out of 98 subjects (28.6%). In Protégé Encore, 121 of 192 (63%)
subjects had severe adverse events compared with placebo, 16 out of 62 subjects (25.8%).
The
most common AEs were decreased white blood cells including lymphopenia, leukopenia and neutropenia. Leukopenia/lymphopenia and
rash were experienced most frequently by PRV-031-treated subjects. Lymphopenia was expected based on the mechanism of action of
PRV-031 and was observed in approximately 70% of type-1 diabetes patients who received PRV-031; lymphopenia was reported in approximately
14% of placebo subjects. It was commonly mild to moderate and resolved within 14 days. In the Protégé study, approximately
50% and 20% of PRV-031- and placebo-treated patients, respectively, reported rash or pruritus. In PRV-031-treated patients, the
rash was predominantly mild to moderate and usually resolved within one to two weeks. Laboratory abnormalities were also reported
as AEs. The main differences in PRV-031 and placebo subjects were changes in lymphocyte counts (30.1% and 9.4%) and liver function
test (alanine aminotransferase, 30.9% and 14.1%). These abnormalities usually resolved within 14 days of dose completion and did
not cause significant or lasting clinical concern. Cytokine release syndrome, which may include symptoms of rash, headache, nausea,
vomiting, and chills/fever, occurred in fewer than 6% of PRV-031-treated patients and was mild to moderate in severity.
The
most common SAEs reported in the Protégé and Protégé Encore studies were related to diabetes control
including diabetic ketoacidosis, hypoglycemic seizures/unconsciousness, hyperglycemia, hypoglycemia (consistent with the underlying
disorder) and were reported in 6.2% and 2.5% of PRV-031 and placebo subjects, respectively. Three deaths were observed and categorized
by the principal investigator (in accordance with International Conference on Harmonisation/Good Clinical Practice guidelines)
and included in the Investigator Brochure for PRV-031 filed with the FDA. The relationship between each death and PRV-031 is listed
in the Investigator Brochure as follows: one death, “none”; one death “not related”; and one death “unlikely.”
The specific causes of deaths were (1) unknown for which the relationship was listed as “none” in the Investigator
Brochure, (2) anterior myocardial infarction with ventricular tachycardia and cardio-respiratory arrest for which the relationship
was listed as “not related” in the Investigator Brochure and (3) diabetic ketoacidosis for which the relationship
was listed as “unlikely” in the Investigator Brochure. AEs of infections (most commonly gastroenteritis) were reported
in 3.6% and 2.5% of PRV-031 and placebo subjects, respectively. Fifteen of 85 SAEs and five of 15 SAEs were deemed related to
PRV-031 and placebo treatment, respectively.
The
following table reflects all the SAEs reported in the Investigator Brochure for the Protégé and Protégé
Encore studies:
SAE
by Organ System
|
Placebo
N=160
n
(%)
|
Any
PRV-031
N=645
n
(%)
|
At
least one event
|
15
(9.4%)
|
85
(13.2%)*
|
Blood
and Lymphatic disorders
●
Neutropenia
●
Lymphopenia
|
1
(0.6%)
●
1 (0.6%)
|
4
(0.6%)
●
2 (0.3%)
●
2 (0.3%)
|
Cardiac
disorders
●
Acute myocardial infarction
●
Angina pectoris
●
Cardio-respiratory arrest
●
Coronary artery disease
●
Ventricular tachycardia
|
0
|
2
(0.3%)**
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
|
Ear
and Labyrinth disorders
●
Deafness neurosensory
|
0
|
1
(0.2%)
●
1 (0.2%)
|
Eye
disorders
●
Cataract subcapsular
●
Corneal erosion
●
Iritis
|
0
|
3
(0.5%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
|
Gastrointestinal
disorders
●
Gastritis
●
Abdominal pain
●
Abdominal pain upper
●
Intestinal obstruction
●
Nausea
●
Peritonitis
●
Vomiting
|
0
|
10
(1.6%)
●
4 (0.6%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
|
General
disorders and administration site disorders
●
Pyrexia
●
Death***
●
Non-cardiac chest pain
●
Pain
|
2
(1.3%)
●
2 (1.3%)
|
4
(0.6%)
●
2 (0.3%)
●
1 (0.2%)
●
1 (0.2%)
|
Hepatobiliary
disorders
●
Biliary dyskinesia
●
Biloma
●
Chlolecystitis acute
●
Hepatosplenomegaly
|
0
|
3
(0.5%)**
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
|
Immune
system disorders
●
Cytokine release syndrome
●
Hypersensitivity
|
0
|
4
(0.6%)
●
3 (0.5%)
●
1 (0.2%)
|
Infections
and Infestations
●
Gastroenteritis
●
Gastroenteritis viral
●
Anal abscess
●
Appendicitis
●
Appendicitis perforated
●
Bronchitis
●
Dengue fever
●
Gastritis viral
●
Hepatic amoebiasis
●
Hepatitis A
●
Infection
●
Infectious mononucleosis
●
Pharyngotonsillitis
●
Pilonidal cyst
●
Pneumonia
●
Pulmonary tuberculosis
●
Pyelonephritis
●
Renal abscess
●
Sepsis
●
Staphylococcal sepsis
●
Urinary tract infection
●
Varicella
●
Cellulitis
●
Paronychia
●
Tuberculosis
|
4
(2.5%)
●
1 (0.6%)
●
1 (0.6%)
●
1 (0.6%)
●
1 (0.6%)
|
23
(3.6%)**
●
3 (0.5%)
●
2 (0.3%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
|
Injury
poisoning and procedural complications
●
Caustic injury
●
Compression fracture
●
Fall
●
Fibula fracture
●
Foot fracture
●
Splenic rupture
●
Upper limb fracture
●
Facial bones fracture
|
1
(0.6%)
●
1 (0.6%)
|
4
(0.6%)**
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
●
1 (0.2%)
|
Investigations
●
Alanine aminotransferase increased
●
Aspartate aminotransferase increased
●
Nuclear magnetic resonance imaging brain abnormal
|
0
|
3
(0.5%)**
●
2 (0.3%)
●
2 (0.3%)
●
1 (0.2%)
|
Metabolism
and nutrition disorders
●
Diabetic ketoacidosis
●
Hypoglycemic seizures
●
Hyperglycemia
●
Diabetes mellitus out of control
●
Hypoglycemic unconsciousness
●
Hypoglycemia
●
Dehydration
●
Ketoacidosis
●
Ketosis
|
4
(2.5%)
●
3 (1.9%)
●
1 (0.6%)
●
1 (0.6%)
|
40
(6.2%)**
●
21 (3.3%)
●
7 (1.1%)
●
5 (0.8%)
●
4 (0.6%)
●
2 (0.3%)
●
2 (0.3%)
●
1 (0.2%)
●
1 (0.2%)
|
Neoplasms
benign, malignant and unspecified (including cysts and polyps)
●
Metastatic malignant melanoma
|
0
|
1
(0.2%)
●
1 (0.2%)
|
Nervous
system disorders
●
Hypoglycemic coma
|
1
(0.6%)
●
1 (0.6%)
|
1
(0.2%)
●
1 (0.2%)
|
Pregnancy,
puerperium and perinatal conditions
●
Abortion spontaneous
●
Complications of pregnancy
|
1
(0.6%)
●
1 (0.6%)
|
1
(0.2%)
●
1 (0.2%)
|
Psychiatric
disorders
●
Mental disorder
●
Suicide attempt
|
0
|
2
(0.3%)
●
1 (0.2%)
●
1 (0.2%)
|
Renal
and urinary disorders
●
Intercapillary glomerulosclerosis
●
Ketonuria
●
Microalbuminuria
|
1
(0.6%)
●
1 (0.6%)
|
2
(0.3%)
●
1 (0.2%)
●
1 (0.2%)
|
Reproductive
system and breast disorders
●
Epididymitis
|
0
|
1
(0.2%)
●
1 (0.2%)
|
Skin
and subcutaneous tissue disorders
●
Rash
|
0
|
2
(0.3%)
●
2 (0.3%)
|
Vascular
disorders
●
Subclavian vein thrombosis
|
0
|
1
(0.2%)
●
1 (0.2%)
|
*
|
Note:
there are 112 events observed in 85 subjects
|
**
|
Note:
subject may have more than one adverse event
|
***
|
Note:
because the cause of death was unknown, “death” is reported as an adverse event
|
The
most common SAE occurring in at least 10% of subjects in both treatment groups in the Protégé study was decreased
white blood cell counts (lymphopenia/neutropenia) observed in 47% (196 out of 415 subjects) and 10% (ten out of 98 subjects) of
PRV-031 and placebo subjects, respectively. In Protégé Encore, lymphopenia/neutropenia was also the most frequently
observed severe adverse event, occurring in 24% (46 out of 192 subjects) and 6% of PRV-031 (four out of 62 subjects) and placebo
subjects, respectively. This severe adverse event is consistent with the mechanism of action of PRV-031.
Overall,
infections were not increased following PRV-031 treatment. However, in Protégé there were ten cases of herpes zoster
infections (a virus that usually causes chicken pox or shingles) in PRV-031-treated patients that were possibly dose-related,
and none in the placebo group. All of these cases resolved. In the Protégé Encore study, only one patient, who was
randomized to placebo had herpes zoster. A link between PRV-031 and herpes infections remains unclear. Other herpes virus infections
(e.g., cytomegalovirus and Epstein-Barr virus) were not increased with PRV-031 treatment.
Phase
3 Clinical Trial of PRV-031 in Pediatric Patients Newly-Diagnosed T1D (PROTECT Study)
The
PROTECT study (PROvention T1D trial Evaluating C-peptide with Teplizumab) is a randomized, double-blind, placebo-controlled, multicenter
Phase 3 clinical trial in pediatric and adolescent patients (aged 8 to 17 years) with recent-onset T1D. Patients with minimum
beta-cell cell function (C-peptide >0.2 pmol/mL) and within six weeks of T1D diagnosis will receive two courses of teplizumab,
six months apart. Each course will consist of 12 days of teplizumab administered intravenously. The primary endpoint is the change
in C-peptide at 18 months. Secondary endpoints including insulin use, HbA1C levels, hypoglycemic events and safety will also be
evaluated. The study is expected to enroll approximately 300 patients with 2:1 randomization (200 active: 100 placebo) and enrollment
commenced in April 2019. The first patient was dosed in April 2019. We expect to report top line results for the Phase 3 PROTECT
study in 2022.
Phase
2 Clinical Trial of PRV-031 in combination with AG019 in newly diagnosed T1D patients
This
is a Phase 1b/2a clinical trial being conducted in collaboration with ActoBio which will explore the combination of teplizumab
with ActoBio’s AG019 in participants with recent-onset T1D. AG019 is a capsule consisting of engineered Lactococcus lactis
specifically modified to deliver human proinsulin and the tolerance-enhancing cytokine human interleukin-10 to the mucosal lining
of the gastro-intestinal tissues. The primary objective of the study is to assess the safety and tolerability of different doses
of AG019 alone as well as AG019 in association with teplizumab. The secondary objectives of this study are: to obtain PD data
of AG019 alone as well as AG019 in association with teplizumab; and PK data to determine the potential presence of AG019 in systemic
circulation (safety - systemic exposure) and the presence of L. lactis bacteria in fecal excretion (local exposure). The study
will enroll 48 participants and will be conducted in two phases:
|
●
|
Phase
1b: open-label part of the study which will investigate the safety and tolerability of two different doses of AG019 in two
age groups (18 to 40 years of age and 12 to 17 years of age).
|
|
●
|
Phase
2a: randomized, double-blind part of the study which will investigate the safety and tolerability of AG019, in association
with teplizumab, in two age groups (18 to 40 years of age and 12 to 17 years of age).
|
The
Phase 1b part of the study commenced in October 2018.
Pre-Clinical
Evaluation of PRV-031
PRV-031
binds specifically to human T cells with CD3 on the surface. It also binds to CD3+ T cells in chimpanzees, an endangered species
that is inappropriate for extensive experimentation, but does not bind to CD3+ T cells of any other animal species. Due to this
lack of feasible animal models, nonclinical pharmacology, pharmacokinetic, and toxicology studies are limited. Nonetheless, consistent
with its mechanism of action and binding to CD3, PRV-031-treated chimpanzees showed reversible reductions in circulating T cells
and a dose-dependent increase in various immune signaling molecules (TNF-α, IL-6, IL-10 and IFN-γ). At very high PRV-031
doses, approximately 450-fold higher than the highest daily dose administered in humans (826 μg/m
2
), chimpanzees
developed B cell lymphoproliferative disease (similar to lymphoma) and Epstein-Barr virus-like infection. In human tissues, PRV-031
binds to T cells in multiple human tissues without unanticipated binding to other cell types. These results indicate that PRV-031
has a low probability of producing unexpected and unintended toxicities in human clinical trials.
PRV-015
(human anti-interleukin 15 mAb) for NRCD
Overview
Celiac
disease is a systemic autoimmune disease triggered by gluten consumption in genetically susceptible individuals. Approximately
1% of the European and North American population is affected by celiac disease. Gluten is ubiquitous in food and elicits autoimmune
responses in celiac patients, with damage to the mucosal lining of the small intestine. Celiac disease causes debilitating symptoms
and serious medical complications, as the small bowel damage can lead to nutrient malabsorption and results in a range of subsequent
intestinal and extra-intestinal clinical manifestations. The stimulation of intestinal lymphocytes for decades can lead to the
development of lymphoma, with increased mortality.
The
pro-inflammatory cytokine interleukin 15 (IL-15) has been identified as a major mediator in the pathophysiology of celiac disease.
PRV-015, a fully human mAb, binds to and inhibits IL-15 and has emerged as a leading candidate for the treatment of nonresponsive
celiac disease, in which patients continue to have disease activity despite ongoing gluten free diet, or GFD. PRV-015 was initially
developed by Genmab A/S as HuMax-IL15, and by Amgen and Celimmune LLC as AMG 714. PRV-015 has undergone clinical testing in approximately
250 subjects who have received PRV-015 across two Phase 1 (healthy volunteers and psoriasis, rheumatoid arthritis, or RA) and
three Phase 2 clinical trials (celiac disease, refractory celiac disease type II, or RCD-II, RA). No serious adverse events deemed
related to PRV-015 were observed that would preclude further clinical development. Proof of mechanism and/or proof of concept
was demonstrated in RA, celiac disease and refractory celiac disease Type II. The effect of PRV-015 in celiac disease was evidenced
by reduction in inflammation and symptoms after a controlled gluten challenge in a Phase 2a clinical trials with 63 celiac patients.
We plan to initiate a 220-patient Phase 2b study in NRCD, in 2020, after completion of chronic toxicology studies.
Celiac
Disease Background Information
Celiac
disease is a systemic autoimmune disease triggered by gluten consumption in genetically susceptible individuals. Approximately
1% of the western population is affected by celiac disease. This prevalence has been reported to be doubling every 20 years. Gluten,
the antigen responsible for celiac disease, is the main protein present in some of the most common cereals (wheat, barley, rye).
Modern diets are increasingly enriched with gluten and it is also used as an additive in processed foods, cosmetics, and oral
medications. Gluten is also present in trace amounts in foods labeled as “gluten-free”, as a tableting excipient,
and in products such as toothpaste and lipstick. As little as 50mg/day of gluten triggers the disease. A normal diet contains
>10 g/day, 200 times the amount that causes damage and intestinal histological abnormalities. As such, celiac patients face
enormous challenges to follow a strict GFD.
The
pathophysiology of celiac disease is characterized by an abnormal immune response to gluten. Humans lack enzymes to fully digest
gluten, which against the right genetic background triggers inflammation and autoimmunity in the intestine and in other organs.
An adaptive immune response is triggered when gluten peptides are deamidated in the extracellular space, by the enzyme tissue
transglutaminase, normally an intracellular enzyme that is released by damaged cells. This deamidation renders gluten peptides
high-avidity binders to HLA-DQ2 and HLA-DQ8, which present these peptides to intestinal CD4+ T cells, thereby activating these
T cells and initiating the inflammatory cascade. The innate immune system’s intraepithelial lymphocytes, or IELs, primarily
CD8+, are able to directly lyse and destroy intestinal epithelial cells, damaging the mucosal lining of the small intestine, in
response to IL-15 release stimulated by gluten peptides. In healthy individuals, the activated T cells are controlled by Tregs,
but this does not happen in celiac disease as IL-15 confers the effector CD4+ T cells resistance to suppression by Tregs.
Celiac
disease causes debilitating symptoms and serious medical complications. In many patients, gastrointestinal symptoms derived from
intestinal mucosal damage dominate the patient reported symptoms at diagnosis. The normal villi (absorptive finger-like prolongations)
present in the gut of healthy individuals are lost in active celiac disease as a result of mucosal atrophy and crypt enlargement.
Small bowel damage often leads to nutrient malabsorption that can result in a range of further clinical manifestations (anemia,
osteopenia, failure to thrive in children). In addition, extra-intestinal symptoms and systemic manifestations are often present,
such as dermatitis, infertility, or neurological and skeletal disorders. Mortality is increased in subjects with persistent intestinal
mucosal damage.
The
most serious complication of celiac disease is the development of an in situ small bowel T cell lymphoma after many years of exposure,
voluntary or inadvertent, to gluten. This malignant complication of celiac disease, which appears to be independent of gluten
and unresponsive to a strict GFD, is termed RCD-II when the percentage of aberrant IELs is >20% and Type I refractory celiac
disease when the percentage is <20%. In RCD-II, aberrant IELs proliferate in what represents a slow-growing non-Hodgkin lymphoma
localized (in situ) in the small bowel, primarily in the epithelial compartment. RCD-II affects approximately 0.5% of celiac patients
and can lead to overt and systemic enteropathy-associated T cell lymphoma, with very poor prognosis and >80% mortality in five
years.
Current
Treatment Options and Their Limitations
Celiac
disease is the only common autoimmune disorder with no approved medication. The only current available strategy for the management
of celiac disease is a lifelong total avoidance of gluten. While simple in theory, the ubiquity of gluten in foodstuffs, medications,
household substances, cosmetics, and gluten-free items makes total avoidance of gluten difficult, if not impossible.
The
main challenge to the successful maintenance of a GFD is that cereal flours are widely used in the food industry and are present
in numerous food products either naturally or as additives. Although gluten-free products can be purchased, commercially manufactured
gluten-free products may be difficult to find, tend to be less flavorful and are more expensive than regular gluten containing
foods. In addition, labeling of food products is deficient in many countries. Even in countries with superior labeling guidelines
foods labeled “gluten-free” may nevertheless contain gluten. For example, in northern European countries amounts of
up to 100 parts per million are permitted in gluten-free products designated apt for celiac sufferers.
For
these reasons, celiac sufferers are regularly exposed to gluten contamination in the food and beverages they consume. This exposure
to gluten contamination and the associated physiological and psychological consequences results in a self-limitation of social
activities and/or a reduction in the variety of foods consumed. Thus, the only currently available management option of a GFD
presents both a considerable challenge and substantial burden for patients. A study by Shah and collaborators (2014) found the
burden of celiac disease and GFD on patient quality of life to be very high, second only to end-stage renal disease – a
condition that requires multiple, weekly dialysis treatments.
As
a result of the difficulty in maintaining total avoidance of gluten while on a GFD, gluten contamination causes 50% or more of
all diagnosed celiac patients on a GFD to continue to experience disease activity. Patients who continue to have symptoms despite
attempting to maintain a GFD are deemed to have NRCD. NRCD has been defined as “persistent symptoms, signs or laboratory
abnormalities typical of celiac disease despite six to 12 months of dietary gluten avoidance”. As requested by patient support
groups and experts, alternative treatment options that can be administered independently or in combination with a GFD, as well
as treatments for refractory celiac disease, are required in order to improve the quality of life for celiac patients.
Overview
of IL-15 Biology and PRV-015 Mechanism of Action
IL-15
is a pro-inflammatory cytokine that serves as a potent growth, survival, and activation factor for T cells, particularly intestinal
IELs, and for natural killer, or NK, cells. Increased expression of IL-15 has been demonstrated in a variety of inflammatory conditions,
including celiac disease, RA, and psoriasis. IL-15 is considered a central regulator of celiac disease immunopathology and a non-redundant
driver of lymphomagenesis in RCD-II.
Substantial
evidence suggests a pathophysiological role for IL-15 in celiac disease:
Innate
immunity:
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IL-15
is an essential, non-redundant growth and activation factor for the IELs which destroy the intestinal mucosa;
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The
expression of IL-15 in the intestinal epithelium is necessary for villous atrophy; and
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In
some patients, IL-15 drives progression towards lymphomagenesis and potentially fatal RCD-II.
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Adaptive
immunity:
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IL-15
enhances the presentation of deamidated gluten peptides by APCs;
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IL-15
renders the activated CD4+ T cells resistant to inhibition by Tregs; and
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IL-15
has been proven to be a key factor in the loss of tolerance to food antigens.
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By
activating the IELs, IL-15 is believed to be the main mediator in the mucosal damage that ensues in response to gluten exposure
in celiac disease. The expression of IL-15 in the intestinal epithelium is necessary for villous atrophy in animal models of celiac
disease and circumstantial evidence suggests this to be the case in humans, as well. In addition, IL-15 renders effector T cells
resistant to inhibition by Tregs, promoting loss of tolerance to food antigens.
One
of the studied mouse models of celiac disease is an IL-15-transgenic mouse, in which IL-15 overexpression by gut epithelial cells
leads to celiac-like disease, including T and B cell-mediated pathology. IEL apoptosis has been observed in this animal model
after treatment with anti-IL-15 or anti-IL-15-receptor monoclonal antibodies.
Figure
1. Multiple actions of IL-15 in the pathophysiology of celiac and refractory celiac disease
PRV-015
(formerly AMG 714 and HuMax-IL15), is a fully human immunoglobulin (IgG1κ) mAb which binds to and inhibits the function
of IL-15 in all its forms (cis, trans, soluble IL-15 bound to IL-15Rα). PRV-015 inhibits IL-15-induced T cell proliferation
and shows a dose-dependent inhibition of IL-15-induced TNF-α production. PRV-015 underwent preclinical testing and was subsequently
evaluated in a Phase 1 and Phase 2 study in subjects with RA, in a Phase 1 study in healthy volunteers and in patients with psoriasis,
and in two Phase 2a studies in celiac disease and refractory celiac disease Type-II.
Phase
2b Clinical Trial of PRV-015 in Celiac Disease (PROACTIVE Study)
We
and our partner Amgen intend to conduct chronic toxicology studies in 2019; a Phase 2b clinical trial (the PROACTIVE study) in
approximately 220 patients with NRCD; and, should regulators require it, a potential small pediatric bridging study. We expect
to commence the Phase 2b PROACTIVE study in the first half of 2020. The pediatric study, if required, would be expected to commence
in 2021.
The
PROACTIVE study (PROvention Amgen Celiac ProtecTIVE Study) will be a randomized, double-blind, placebo-controlled, parallel-group,
multicenter Phase 2 clinical trial in adult patients with NRCD. PRV-015 will be administered every two weeks via subcutaneous
route. The hypothesis of this study is that PRV-015 will be superior to the GFD at intercepting the effects of contaminating gluten
exposure in celiac patients following a GFD, as measured by symptoms and objective signs of intestinal inflammation after 24 weeks
of treatment. Approximately 220 subjects are planned to be enrolled. We expect to report top line results for the Phase 2b PROACTIVE
study in 2022.
Pre-clinical
Evaluation of PRV-015
The
nonclinical development of PRV-015 consisted of a series of
in vitro
studies demonstrating the binding properties of PRV-015
against human IL-15;
in vitro
and
in vivo
studies providing proof-of-concept for the benefit of blocking the IL-15
pathway in celiac disease; and a series of Good Laboratory Practices, or GLP, studies evaluating the nonclinical safety profile
of Hu714MuXHu, the PRV-015 surrogate molecule which is active in macaques.
Pharmacology
PRV-015
was found to be efficacious in a mouse model of celiac disease triggered by the transgenic expression of human IL-15 in the gut
epithelium. In this model, PRV-015 prevented IEL activation and proliferation, as well as histological abnormalities. In addition,
PRV-015 was able to induce apoptosis of human IELs in
ex vivo
culture of small intestinal explants from active celiac disease
and RCD-II patients. In this culture experiment, PRV-015 resulted in a suppression of IL-15-driven anti-apoptotic signaling via
JAK3 and STAT5.
Toxicology
In
vitro studies demonstrated that PRV-015 had high binding affinity for human IL-15, but lower affinity for macaque IL-15. Additionally,
PRV-015 neutralized human IL-15 but did not efficiently neutralize macaque IL-15. To enable preclinical and toxicology studies
in macaques, a surrogate antibody, Hu714MuXHu, was developed by Amgen by fusing the F(ab) portion of a mouse anti-human IL-15
mAb known to neutralize macaque IL-15, M111, with human IgG1 Fc. Hu714MuXHu was shown to neutralize macaque IL-15 with approximately
the same potency as PRV-015 neutralizes human IL-15.
There
was a decrease in NK cell counts and NK cell activity following administration of Hu714MuXHu to monkeys, reflecting a PD response
to IL-15 blockade in this species, given the known role of IL-15 in NK cell biology in animal models (rodents and non-human primates).
Of note, no changes in absolute or relative numbers of NK cells were observed in any of the human studies. This difference between
observations in preclinical studies and clinical trials appears related to a differential sensitivity of human versus cynomolgus
monkey NK cells to IL-15 deprivation. Human NK cells are not dependent on IL-15 for their survival, possibly due to the redundant
role of IL-2 on human NK cells.
Pharmacokinetics
of PRV-015
The
PK of PRV-015 was consistent with a typical human immunoglobulin G1 antibody with no apparent target-mediated disposition within
the investigated dosing range. The mean half-life in human studies has been 20 to 22 days, potentially enabling monthly dosing.
There
was no development of anti-drug antibodies to PRV-015 in healthy volunteers, patients with psoriasis or patients with refractory
celiac disease. Only one RA patient in the phase 2b study was positive for ADA. Approximately 14% of patients with celiac disease
developed ADA in the Phase 2a clinical trial, with an additional 10% presenting pre-existing ADA, a reflection of the abnormal
antibody responses which characterize celiac disease. The ADA were not associated with injection reactions or adverse events,
and they were non-neutralizing, with no impact on PK.
Clinical
Proof of Mechanism for PRV-015
Although
PRV-015 missed the primary endpoint, approximately 60% of patients in both Phase 1 and Phase 2 studies versus a response of approximately
30% of patients in the placebo groups demonstrated a response to treatment. PRV-015 also led to decreases in inflammatory biomarkers
such as C-reactive protein and erythrocyte sedimentation rate. PRV-015 was not effective in psoriasis, suggesting PRV-015’s
action is selective, unlike that of broad systemic immune suppressants.
Upon
gluten challenge in a Phase 2 clinical trial in celiac disease, PRV-015 did not prevent gluten-induced architectural mucosal injury,
and thus missed the primary endpoint, yet the high dose of PRV-015, 300 mg, showed statistically significant attenuation of gluten’s
effects on the change from baseline in intestinal inflammation, in patient-reported symptom questionnaires (the Celiac Disease
Patient Reported Endpoint, CeD PRO, a registrational endpoint in NRCD) and in diarrhea, compared with placebo. The totality of
the results from the patients who had gluten challenge indicate that 300 mg AMG 714 given every two weeks can ameliorate the inflammation
and symptoms caused by substantial gluten exposure, the first demonstration of such dual benefit in intestinal inflammation and
symptoms for any experimental medication for celiac disease. The results suggest that PRV-015 can be a potential adjunctive treatment
for NRCD to the GFD to ameliorate or resolve persistent inflammation seen in the majority of celiac patients already on GFD.
In
the Phase 2a clinical trials in RCD-II, the primary endpoint (reduction in intestinal IELs) was not achieved, yet PRV-015 showed
statistically significant benefit over placebo in reducing T cell receptor clonality (no increase in clonality with PRV-015) and
symptoms (diarrhea). Other endpoints, such as histology, did not reach statistically significant differences between groups, but
the results consistently favored PRV-015 numerically. PRV-015 was well tolerated, with no observed immunogenicity.
Summary
data of the Phase 2a clinical trial as presented at Digestive Disease Week in June 2018 is shown below:
The
CELIM-NRCD-001 study included 62 randomized celiac patients on a gluten-free diet, of which 49 patients underwent a substantial
gluten challenge of 2.5 grams per day for 10 weeks in order to assess the ability of PRV-015 to ameliorate the effects of gluten.
Upon gluten challenge, PRV-015 did not prevent gluten-induced architectural mucosal changes, the primary endpoint in the study.
However, in secondary efficacy assessments, the PRV-015 300 mg dose consistently attenuated the effects of gluten in intestinal
inflammation (intraepithelial lymphocyte density, p=0.03), and in gastrointestinal symptoms as measured by three independent endpoints:
the Celiac Disease Patient Reported Endpoint (CeD-PRO, p=0.02), the Celiac Disease Gastrointestinal Symptom Rating Scale (CeD-GSRS,
p=0.07) and the Bristol Stool Form Scale (BSFS/diarrhea, p=0.0002). The CeD-PRO is a validated endpoint acceptable for registrational
trials. In addition, patients in the PRV-015 300 mg arm had a significantly improved
Physician Global Assessment of disease
(PGA, p=0.03). The totality of the results demonstrated proof-of-concept for PRV-015 300 mg given subcutaneously every two
weeks in the amelioration of inflammation and symptoms caused by the consumption of gluten by celiac patients. Importantly, PRV-015
was well tolerated, and only 14% of patients developed anti-drug antibodies, which were non-neutralizing and not correlated with
impact of efficacy or safety. The PK profile was consistent with a monoclonal antibody, and potentially enables future monthly
dosing.
Summary
of clinical trials
Study
Number (Phase; Sponsor)
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Key
Design Features
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Dose
Route, Duration
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Study
Population
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Hx-IL15-001
(Phase
1;
Genmab)
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Double-blind,
placebo-controlled, single SC infusion, dose escalation, study with open-label, repeat-dose (4 weekly doses) follow-up
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Initial
single dose: 0 or 0.15 to 8 mg/kg SC infusion
Repeated
dose: 0.5 to 4 mg/kg SC infusion once weekly for four weeks. five doses over eight weeks
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30
subjects with RA
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20030210
(Phase
2;
Genmab/
Amgen)
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Double-blind,
placebo-controlled, multiple SC infusion, parallel-group, multicenter study
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0
or 40 to 280 mg SC infusion dose every two weeks for 12 weeks with initial 200% loading dose
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180
subjects with RA
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20050193
(Phase
1;
Amgen)
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Double-blind,
placebo-controlled, single SC or IV doses, dose-escalation study
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SC
doses: 0, 30, 100, 300 or 700 mg (cohorts 1 to 4) IV dose: 0 or 100 mg (cohort 5)
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40
healthy subjects
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20060349
(Phase
1b/2a; Amgen)
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Double-blind,
placebo-controlled, multiple SC doses, dose-escalating study
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0
or 150 mg SC (cohort 1)
0
or 300 mg SC (cohort 2)
Every
two weeks for 12 weeks
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22
subjects with moderate to severe psoriasis
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CELIM-NRCD-001
(Phase 2a; Celimmune)
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Double-blind,
placebo- controlled, SC, parallel group, multicenter study
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0,
150 mg or 300 mg PRV-015 once every two weeks for six consecutive doses over ten weeks
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63
subjects with NRCD
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CELIM-RCD-002
(Phase 2a; Celimmune)
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Double-blind,
placebo controlled IV infusion, parallel group, multicenter study
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0
or 8 mg/kg IV, a total of 7 times over ten weeks
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24
subjects with Type II refractory celiac disease
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Safety
of PRV-015
Approximately
250 subjects have been exposed to PRV-015 to date, including approximately 200 subjects for 12 weeks of biweekly dosing. In all
studies to date, PRV-015 was generally well tolerated by healthy volunteers, patients with active RA, and patients with celiac
disease or RCD-II. While PRV-015 could, theoretically, increase susceptibility to infections as is the case with immune modulators,
PRV-015 has not demonstrated this effect in the six clinical trials completed to date. No deaths or clinically significant changes
in laboratory parameters were observed, including no NK cell depletion.
The
only adverse events clearly increased in PRV-015-treated patients have been injection site reactions, which were more commonly
reported in subjects exposed to PRV-015, in a dose-dependent fashion (up to ~52% on PRV-015 vs ~26% in placebo in the celiac Phase
2a clinical trial), and nasopharyngitis (most cases with suspected allergic origin at a single site in RCD-II). In the population
which will be studied in Phase 2b, celiac disease, there were no SAEs in the Phase 2a clinical trial, while there were six SAEs
(five on PRV-015 and one on placebo) in the RCD-II, a much sicker patient population with immune suppression at baseline. Of the
five SAE on PRV-015 in RCD-II patients, two were infections (both resolved while on PRV-015). There was one episode of mild balance
disorder (considered unlikely to be related to PRV-015 and resolved while on the drug. Another patient had mild cerebellar syndrome
which led to discontinuation from the study.
Celiac
Disease Market
There
is no approved drug for CD. The annual healthcare utilization by NRCD patients in 2013 was $18,206, for $4,796 in matched controls
due to the extra costs of uncontrolled CD investigations and treatment of complications. Given the large prevalence (15 to 20
million patients world-wide, 1% of the population in the Western world and 0.5% in Asia), and the unmet need (50% of patients
on GFD continue to suffer from disease activity due to contaminating gluten in the diet), NRCD is considered a substantial opportunity
for pharmaceutical development of an effective and well-tolerated adjunctive treatment to the GFD.
PRV-6527
(Small Molecule CSF-1R Inhibitor) for CD
Overview
CD,
a type of chronic IBD characterized by inflammation of the gastrointestinal, or GI, tract, can affect any part of the GI tract
from the mouth to the anus but is more commonly found towards the end of the small intestine. It can also affect the eyes, skin,
and joints. Myeloid cells, which originate in the bone marrow, are specialized immune cells, also called APCs believed to play
a central role in CD. CSF-1 binds to its receptor (CSF-1R) on myeloid cells and drives the differentiation and maturation of these
cells into inflammatory dendritic cells and macrophages, which then populate the gut and other tissues. In the gut, these differentiated
myeloid cells present antigens from intestinal bacteria (the microbiome) to white blood cells and trigger inflammatory processes.
We believe that an inhibitor of CSF-1R will “intercept” the differentiation of these inflammatory cells, preventing
their migration from the bone marrow to the intestinal mucosa (i.e., the gut lining) in CD. It is anticipated that significant
clinical benefits, such as preventing the relapse or progression of CD, as well as durable benefit (extended pharmacodynamic effect)
may result from targeting the upstream pathologic mechanism, since APCs are the necessary initiators of the abnormal immune response.
PRV-6527
(previously known as JNJ-40346527) is a highly potent and selective small-molecule oral inhibitor of CSF-1R. It was developed
by Janssen and has undergone clinical testing in 178 subjects to date, across Phase 1 (healthy volunteers; 94 received single
dose up to 600 mg or two doses of 450 mg) and two Phase 2 clinical trials (63 RA patients received 200 mg/day for 12 weeks; and
21 Hodgkin’s lymphoma, or HL, patients received 150 mg/day to 650 mg/day for at least three weeks). No serious adverse events
deemed related to PRV-6527 were observed that would preclude further clinical development and proof of mechanism was demonstrated
based on inhibition of CSF-1R signaling and myeloid cell counts in blood. While clinical data in the RA study was inconclusive
and did not demonstrate efficacy in this disease, unpublished data indicate that PRV-6527 ameliorates Crohn’s-like disease
in mouse models, and that CSF-1R and its pathway are upregulated in CD. In the first quarter of 2018, we initiated a Phase 2a
proof of concept clinical trial, referred to as the PRINCE study, in approximately 80 patients with CD to demonstrate both a clinical
and histologic/tissue (gut mucosa) anti-inflammatory effect after 12 weeks of treatment with PRV-6527. This study will evaluate
doses and dosing duration that were previously tested by Janssen. While biologic proof of mechanism was demonstrated in previous
clinical trials, this does not necessarily predict a similar outcome in the CD study. We completed enrollment of the Phase 2a
PRINCE study in April 2019 and expect to report top line results in the fourth quarter of 2019.
CD
Background Information
CD
is a chronic, immune-mediated IBD characterized as a relapsing, remitting disease that occurs most commonly in the terminal ileum
and the colon, with clinical manifestations such as abdominal cramps and diarrhea, and systemic features such as cachexia, fever,
anemia, and weight loss. Because the disease affects all layers of the GI tract from the mucosal lining to the muscular wall,
complications may include bowel fistulas, abscesses and luminal strictures, which often require multiple surgeries and cumulatively
can lead to short gut syndrome. Studies suggest that 15 years after diagnosis, approximately 70% of patients with CD will have
undergone at least one major intra-abdominal surgery, 35% of patients will have required two such operations, and 20% will have
required at least three operations. Patients with IBD also suffer from reduced quality of life and have an increased risk for
clinical depression.
Current
Treatment Options and Their Limitations
The
current standard of medical care for CD includes treatment with anti-inflammatory agents, corticosteroids, immunomodulators such
as azathioprine or its active metabolite 6-mercaptopurine, methotrexate, biologic agents such as tumor necrosis factor-alpha (TNF-α)
antagonists, anti-integrin therapies, and anti-interleukin (IL) 12/23 therapy. Among these commonly prescribed agents, only the
biologic agents and the corticosteroid budesonide are approved for the treatment of CD. Only about 40-50% of patients respond
to biologic therapy after the acute induction phase and an even smaller proportion, approximately 20%, achieve remission after
52 weeks of treatment. Thus, the majority of patients do not attain long-term clinical benefit. In a systematic review of treatments
for CD, approximately 25% of patients fail to respond initially to biologic therapy, and another 25% stop responding over time,
including those who respond to dose escalation. Furthermore, the majority of biologic therapies are expensive and administered
parenterally.
Thus,
there continues to be a significant unmet need for safe, effective and durable treatments for patients with moderate to severe
CD. This is particularly important since the disease largely affects younger patients during their most formative and productive
years. We believe that oral treatment with a novel mechanism of action such as PRV-6527 may provide additional benefit, as it
may work in patients who did not respond to anti-TNF agents, and since it circumvents the inconvenience of infusions and injections
required to administer biologic therapies.
Overview
of CSF-1R Biology and PRV-6527’s Mechanism of Action
CSF-1R
is a tyrosine kinase receptor present on the surface of myeloid cells. CSF-1R is the receptor for two important molecules in the
biology of myeloid cells: (a) CSF-1, a key growth factor for the development and differentiation of myeloid precursors in the
bone marrow that are believed to give rise to pro-inflammatory macrophages and dendritic cells in gut tissue; and (b) IL-34, a
signaling molecule believed to modulate inflammation in IBD.
Pro-inflammatory
Function of CSF-1
Mac:
macrophage; DC: dendritic cell.
Inflammatory
macrophages and dendritic cells are known to be important disease drivers in CD via production of IL-12 and IL-23, which in turn
stimulate interferon-γ (IFN-γ)-producing white blood cells. Blood CSF-1 and mucosal IL-34 are reported to be elevated
in patients with IBD, and the genes for CSF-1R, CSF-1, and IL-34 are expressed at higher levels in inflamed biopsy tissues compared
with non-lesional biopsies of patients with IBD. The CSF-1R messenger ribonucleic acid, or mRNA, signature (the gene set modulated
by CSF-1R) features prominently CD patients’ gut tissue, especially in patients not responding to anti-TNF medications.
IL-34 has been shown to enhance production of TNF-α and other pro-inflammatory signaling molecules (IL-6) by myeloid cells,
and inhibition of IL-34 in IBD mucosal explants represses the expression of these molecules, all of which support the role of
this pathway in the inflammatory process. In addition, co-morbidities of CD such as osteoporosis and fibrosis are associated with
CSF-1R-dependent macrophage function, which in conjunction with the biologic data, suggests that inhibition of CSF-1R in CD may
reduce inflammation, improve clinical symptoms and prevent progressive tissue damage.
Though
not seen in completed studies, there is a theoretical risk that PRV-6527 may reduce anti-inflammatory macrophages (M2), in addition
to inflammatory macrophages (M1), which could impact its efficacy and safety profile.
Phase
2a Proof-of-Concept Clinical Trial of PRV-6527 in Crohn’s Disease (PRINCE study)
We
initiated the PRINCE study, a proof of concept clinical trial, in the first quarter of 2018 in patients with CD to demonstrate
both a clinical and tissue (gut mucosa) anti-inflammatory effect after 12 weeks of treatment. This is a randomized, double-blind,
placebo-controlled, parallel-group, multicenter Phase 2a clinical trial in adult patients with moderately to severely active CD.
The hypothesis of this study is that PRV-6527 will be superior to placebo in treating these patients, as measured by the change
from baseline in the Crohn’s Disease Activity Index (CDAI) score after 12 weeks of treatment. We completed enrollment (93
patients) of the Phase 2a PRINCE study in April 2019 and expect to report top line results in the fourth quarter of 2019.
To
demonstrate proof of concept, the primary endpoint will be clinical effect, measured by CDAI, at Week 12. Proof of mechanism will
be assessed in secondary endpoints, including mucosal changes on endoscopy and the presence of inflammatory myeloid cells on histological
examination of gut biopsy tissue.
PRV-6527
Study Design
Pre-clinical
Evaluation of PRV-6527
Single-
and repeat-dose toxicology studies have been conducted at doses of up to 250 mg/kg for durations of up to six months in rats,
and at doses of up to 125 mg/kg for durations up to nine months in dogs. PRV-6527 was well-tolerated in these studies. Toxicological
findings included changes in hematologic and chemistry parameters and fibrinoid vasculitis. The data support the doses selected
for the CD study.
Clinical
Proof of Mechanism for PRV-6527
Three
clinical trials in normal healthy volunteers and patients with RA and HL provided evidence of tolerability, favorable pharmacology,
and proof of mechanism for PRV-6527 in terms of effective inhibition of the CSF-1R pathway in human diseases.
The
Phase 1 clinical trial with 120 normal healthy volunteers (94 active; 26 placebo) characterized the safety, tolerability, and
PK of PRV-6527. Single doses of up to 600 mg, and two doses of 450 mg were administered. This study was conducted from January
26, 2010, to January 3, 2011, at the Janssen Clinical Pharmacology Unit in Belgium. Results showed that PRV-6527 was well tolerated
with a long half-life of two to four days. In addition, PD were also studied, and PK/PD relationships were described.
The
Phase 2a clinical trial 40346527ARA2001 in 96 patients with RA (63 active; 33 placebo) characterized the efficacy, safety, PK
and PD of PRV-6527. Patients received 100 mg twice a day (200 mg/day) orally for 12 weeks. This study was conducted from May 30,
2012, to April 30, 2013, in Argentina, Bulgaria, Chile, Czech Republic, Hungary, Poland, Russia, South Korea and Ukraine. Proof
of mechanism was demonstrated by a reduction in peripheral blood myeloid cells. Despite the demonstration of proof of mechanism,
the primary efficacy endpoint, defined as the change from baseline to week 12 in the 28-joint Disease Activity Score with C-reactive
protein (DAS28-CRP), was not met. There was a substantial placebo effect in the study, which made it difficult to discern a potential
effect and thus rendered the efficacy results uninterpretable.
The
Phase 2a clinical trial 40346527HKL1001 in 21 patients with HL (all received active drug) characterized the safety, efficacy,
PK and PD of PRV-6527. Patients received 150 to 650 mg/day for at least three weeks. Three deaths were reported during conduct
of this study. The cause of death in all cases was disease progression. This study was conducted from July 6, 2012, to August
14, 2013, in Germany and France. The results from the study provided additional proof of mechanism for the functional inhibition
of CSF-1R. Limited clinical efficacy activity was observed with PRV-6527 as monotherapy in the treatment of relapsed or refractory
HL. Of the 20 evaluable patients, 11 (55.0%) achieved stable disease (duration of 1.5 to 8 months) and eight (40.0%) had progressive
disease.
In
all studies to date, PRV-6527 was generally well tolerated by healthy volunteers, patients with active RA, and patients with relapsed
or refractory HL. While theoretically increasing susceptibility to infections, as is the case with immune modulators, PRV-6527
has not demonstrated this effect in completed clinical trials. The most frequent treatment-emergent adverse events in PRV-6527-treated
patients affected the following organ systems or resulted in the following symptoms and changes:
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Gastrointestinal:
diarrhea, nausea, vomiting, constipation, abdominal pain, gastroesophageal reflux;
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Hematologic:
anemia, decrease in white blood cells (neutrophils, monocytes, lymphocytes), and reticulocytes;
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Hepatic:
aspartate aminotransferase and alanine aminotransferase, both liver enzymes, increases;
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Pulmonary:
dyspnea (shortness of breath);
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Constitutional
symptoms: pyrexia (fever), headache, back pain; and
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Laboratory
changes: increase in creatine kinase and lactate dehydrogenase.
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CD
Market
CD
is one of the main types of IBD. The market size of IBD is predicted to reach $9.3 billion by 2019, with CD accounting for approximately
65% of the market. Treatment is dominated by biologics, but given the high rate of relapse in responders and remitters along with
an increased risk of infection, there is a clear unmet medical need. Mechanistically, most of the existing treatments exert their
efficacy from inhibiting a variety of downstream inflammatory mediators rather than interfering with the source of inflammation.
However, PRV-6527 targets the source of inflammation. This upstream effect is predicted to block the whole inflammatory cascade,
and in conjunction with the predicted extended PD or biologic effect, could result in an improvement in the efficacy and durability
of response. Furthermore, biologics for CD are delivered via intravenous infusion or injected subcutaneously, whereas novel oral
medications can offer a disruptive opportunity.
PRV-3279
(Humanized CD32B x CD79B Dual Affinity Biologic for SLE and Other Autoimmune Diseases)
Overview
SLE
is a chronic autoimmune disorder that can affect nearly every major organ system, causing inflammation, tissue injury, organ damage,
and in some patients, organ failure. The prognosis of SLE is highly variable in individual patients, often waxing and waning throughout
their lifetime. The natural history of SLE ranges from relatively benign disease to rapidly progressive and even fatal disease.
Comorbidities, such as infections, malignancies, hypertension, lipid disorders and diabetes increase the risk of disability and
death in patients with SLE. Organ systems commonly affected by SLE include the central nervous system, kidneys, gastrointestinal
system, mucous membranes, heart, skin, hematologic system, musculoskeletal system and lungs, with specific organ involvement defining
subsets of the disease (e.g., lupus nephritis). According to the Lupus Foundation of America, at least 1.5 million Americans are
afflicted by SLE and more than 16,000 new cases of lupus are reported annually. It is estimated that five million people throughout
the world suffer from some form of lupus. Lupus affects primarily women of childbearing age (15 to 44 years). However, men, children,
and teenagers can also develop lupus.
The
pathogenesis of SLE is characterized by an abnormal overactivation of B cells and subsequent pathologic production of auto-antibodies
(antibodies that attack one’s own cells and tissues). Uncontrolled activation of B cells is normally terminated when the
activating stimulus is exhausted and when a negative feedback loop is triggered by the engagement of an inhibitory Fc receptor,
or FcR, known as FcgammaRIIb, or CD32B. Mutations in the CD32B gene in humans are associated with an increased likelihood of SLE,
and reduced expression of CD32B is apparent in B cells from SLE patients. It is thought that activation of this inhibitory pathway
could ameliorate the overactive B cell-driven pathology of SLE and other autoimmune diseases. In addition, the excess auto-antibodies
produced bind to target antigens and form immune complexes.
When
the B cell receptor, or BCR, (which is the “Y” shaped molecule, resembling an antibody in the figure below) is bound
and activated by an antigen, it initiates a cascade of biochemical changes necessary for the activation of the CD32B inhibitory
pathway, thus triggering the negative feedback loop. CD79B is a subunit of the BCR that plays a key role in this process when
it is close to CD32B. Therefore, if a pharmacologic treatment is to activate the CD32B inhibitory pathway, it also has to simultaneously
bind to CD79B. PRV-3279 (formerly MGD010), is a humanized CD32B x CD79B DART protein developed originally by MacroGenics as a
bi-specific therapy with these properties, and thus a potential treatment for SLE and other similar diseases. It is designed to
simultaneously bind to CD32B and CD79B on B cells.
PRV-3279
and related molecules have shown inhibitory effects on BCR-induced B cell proliferation and antibody secretion (including B cells
obtained from SLE patients) as well as beneficial effects in mouse models of autoimmunity. PRV-3279 is expected to boost the negative
feedback loop on B cells by robustly engaging the available CD32B and CD79B.
PRV-3279
has been studied in humans and was shown to be well tolerated. Proof of mechanism and PRV-3279’s inhibitory effect on antibody
immune responses were demonstrated in a Phase 1a single ascending dose study in healthy volunteers, including a cohort demonstrating
inhibition of the immunogenicity of the hepatitis A vaccine. Immunogenicity of PRV-3279 was also observed, but had no impact on
mechanistic effects, safety or pharmacokinetics, and decreased with increasing doses of PRV-3279, possibly a reflection of its
mechanism of action.
We
plan to continue developing PRV-3279 for the treatment of SLE in the PREVAIL (PRV-3279 EVAluation In Lupus) study. PREVAIL will
be a multiple ascending dose Phase 1b/2a clinical trial in two parts: Part 1 will be a Phase 1b clinical trial in approximately
16 healthy volunteers, and Part 2 will be a Phase 2a clinical trial in SLE patients. Part 2 will have a treatment duration of
at least 12 weeks and will evaluate clinical and biomarker endpoints. We expect to initiate the Phase 1b portion of the clinical
trial in the third quarter of 2019. Our ultimate goal is to determine if PRV-3279 can intercept the pathophysiology of SLE by
preventing the production of auto-antibodies by abnormally active B cells.
Current
Treatment Options for SLE and Their Limitations
The
treatment and management of SLE depends on disease severity and disease manifestations. Hydroxychloroquine plays a central role
in the long-term treatment of SLE and is the cornerstone of SLE therapy. Corticosteroids, nonsteroidal anti-inflammatory drugs
(NSAIDs), and immunosuppressive agents (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate, and mycophenolate mofetil)
have also been used in the treatment and management of SLE. These treatments are only modestly effective and present safety and/or
immune suppression concerns with prolonged use. The B cell-depleting antibody rituximab (Rituxan), while not approved for treatment
of SLE, appears to be beneficial in certain subsets of patients.
In
2011, the FDA approved belimumab (Benlysta), an antibody that targets B lymphocyte stimulator, for the treatment of mild to moderate
SLE in combination with standard therapy, providing additional clinical validation of the therapeutic benefit of B cell-targeted
therapy for autoimmune diseases. However, the modest therapeutic benefit of belimumab and delayed onset of disease intervention
indicate the need for additional therapeutic strategies to inhibit overactive B cells. We believe PRV-3279 can fulfill that requirement
and is uniquely differentiated to allow for rapid inhibition of activated B cells (potentially more effective than belimumab),
while sparing non-activated B cells from depletion or inactivation (potentially safer than rituximab).
Overview
of CD32B Biology
CD32B
is expressed widely on the surface of human B cells. In addition to its expression on B cells, CD32B is also expressed on other
immune cells such as dendritic cells, macrophages, neutrophils, and mast cells. It is a single-chain protein with a portion that
sits outside of the cell membrane, which can be bound by chemical signals.
CD32B
is the only known inhibitory FcR in the immune system. It plays an important role not only for innate and adaptive immune responses,
but also in the maintenance of immune tolerance and controlling autoimmunity. Mice deficient in CD32B have increased antibody
responses due in part to chronic B cell activation, and as a result, develop autoimmune disease similar to human SLE. In contrast,
B cell-specific overexpression of CD32B reduces the incidence and severity of lupus in a mouse lupus model. In humans, mutations
and decreased expression of the CD32B gene are associated with an increased likelihood of SLE. These results underscore the important
role of CD32B in regulating the antibody immune response and suggest that drug-mediated engagement of CD32B could provide therapeutic
benefit in autoimmune diseases by dampening the effects of chronically activated B cells and reducing the production of auto-antibodies.
In particular, preventing the production of auto-antibodies could intercept the disease course in lupus nephritis, a subtype of
lupus driven by accumulation of auto-antibodies and immune complexes (a mass of antibodies and other molecules) in the kidneys.
Mechanism
of Action of PRV-3279
PRV-3279
is in a new class of bispecific scaffold antibody-like molecules called DARTs. It is designed to simultaneously bind to CD32B
and CD79B on B cells. The simultaneous binding of both CD32B and CD79B triggers CD32B-coupled immunoreceptor tyrosine-based inhibitory
motif signaling, which leads to the suppression of B cells activated to produce auto-antibodies, while not causing broad B cell
depletion.
To
prolong its half-life in the body, PRV-3279 contains a human IgG1 Fc region (a specific antibody fragment) that is manipulated
to eliminate its effector function. As a molecule designed to inhibit immune responses, PRV-3279 does not activate any part of
the immune system either in the body or in laboratory tests. PRV-3279 also does not bind to platelets, a unique feature compared
to competing molecules targeting CD32B that are associated with toxicity due to binding to platelets.
Proposed
Multiple Ascending Dose Phase 1b/2a Clinical Trial of PRV-3279 in Healthy Volunteers and Patients with Lupus
We
plan to conduct a two-part study in SLE, the PREVAIL (PRV-3279 EVAluation In Lupus) study. PREVAIL will be a randomized, double-blind,
placebo-controlled Phase 1b/2a clinical trial to evaluate the safety, tolerability, PK, PD, and immunogenicity of multiple ascending
doses of PRV-3279 in a minimum of 16 healthy adult volunteers (Part 1) and the efficacy of PRV-3279 in patients with lupus (Part
2). We expect to initiate the Phase 1b portion of the PREVAIL study in the third quarter of 2019 with top line results expected
to be available in 2020.
Our
ultimate goal is to determine if PRV-3279 can intercept the pathophysiology of SLE by preventing the production of auto-antibodies
by abnormally active B cells. Part 2 will have a treatment duration of at least 12 weeks and endpoints will include lupus clinical
assessments and biomarker measurements. Clinical endpoints will include the Systemic Lupus Erythematosus Disease Activity Index
2000 (SLEDAI-2K), the British Isles Lupus Assessment Group score, urine protein to creatinine ratio, and daily glucocorticoid
use. Additional biomarkers will include urinary/renal markers (e.g., serum creatinine, estimated glomerular filtration rate) and
blood/circulating markers (e.g., auto-antibodies, complement [C3 and C4], B cell function/phenotype, including CD32B expression/response
relationship).
Preclinical
Evaluation of PRV-3279
The
only nonhuman species that PRV-3279 binds to is chimpanzees. An initial non-GLP study with PRV-3279 in chimpanzees demonstrated
it to be well tolerated at all doses, with an assigned no observed-adverse-effect level, or NOAEL, of 10 mg/kg.
Due
to the lack of target binding, chronic four-week and three-month repeat-dose GLP toxicology studies were performed using a surrogate
DART molecule similar to PRV-3279 that was designed to target human CD32B and mouse CD79B in a transgenic mouse line that expresses
human CD32B. A NOAEL at the highest dose of 50 mg/kg was assigned in the three-month study. These studies support the advancement
of PRV-3279 in long-term efficacy studies in humans (up to three months).
Clinical
Evaluation and Proof of Mechanism for PRV-3279
To
date, one clinical trial has been completed with PRV-3279: a first in human, or FIH, double-blind, placebo-controlled Phase 1a
clinical trial to evaluate the safety, tolerability, PK, PD, and immunogenicity of PRV-3279 in healthy adult volunteers. The study
was conducted at a single site in the U.S., from February 2015 to February 2017.
A
total of 49 subjects were randomized; 12 received placebo and 37 received PRV-3279 intravenously at escalating doses from 0.1
mg/kg to 10 mg/kg in six cohorts. PRV-3279 was well tolerated over the range of doses, with only mild adverse events that resolved
quickly, including headache, somnolence (sleepiness), upper respiratory tract infection, folliculitis and night sweats. Target
binding and proof of mechanism were demonstrated by measuring functional B cell inhibition at doses of 1 mg/kg or higher, without
broader B cell activation or depletion observed.
Subsequently,
proof of mechanism was further confirmed in a dose escalation extension of the study in which single doses of PRV-3279 at 3 mg/kg
and 10 mg/kg (16 subjects) were compared with placebo (eight subjects) for the ability to affect B cell responses to a hepatitis
A vaccine, which was administered to participants who had no previous hepatitis A immunity, on day two of the study. At both doses,
PRV-3279 reduced the proportion of volunteers who generated an immune response against the vaccine, as well as the amount of antibody
they produced, in both cases as compared to placebo.
Pharmacokinetics
and Immunogenicity of PRV-3279
PRV-3279
exhibited an approximate half-life of seven days after a single dose. A majority (~86%) of study participants developed antibodies
against PRV-3279 (i.e., immunogenicity) after receiving the 3 mg/kg dose, but no detrimental effect was observed on the pharmacokinetics
of PRV-3279. The proportion of participants developing antibodies against PRV-3279 decreased with increasing dose (29% in the
10 mg/kg dose) and such antibodies did not occur in the multiple dose chimpanzee study, suggesting that PRV-3279 may limit its
own immunogenicity at therapeutic doses, which is consistent with its mechanism of action.
SLE
Market and Other Opportunities for PRV-3279
Sales
of therapies to treat SLE are expected to climb to nearly $2 billion in 2019, approximately 17% annual growth from 2009. This
growth is driven primarily by the entry and uptake of novel treatments that target B cells such as belimumab and off-label use
of rituximab. The uptake of belimumab has been driven largely by safety rather than substantial efficacy, supporting the unmet
need and potential for novel and safe non-depleting B cell therapies with greater efficacy.
In
addition to SLE, PRV-3279 has the potential to treat other B cell- and auto-antibody-driven autoimmune diseases. Such diseases
include multiple sclerosis and RA, where B cell therapies rituximab and recently approved ocrelizumab (Ocrevus) have sales in
excess of $1 billion. Several niche/orphan indications may also be explored, including T1D (potentially in combination with PRV-031),
Sjogren’s syndrome, vasculitis (e.g., polymyalgia rheumatica, giant cell arteritis, Behçets disease), myasthenia
gravis, pemphigus, neuromyelitis optica, anti-NMDA receptor encephalitis, Guillain-Barré syndrome, chronic inflammatory
demyelinating polyneuropathy, Grave’s ophthalmopathy, IgG4-related disease, and idiopathic thrombocytopenic purpura.
Finally,
PRV-3279 also has the potential to prevent or reduce the immunogenicity of biotherapeutics, including but not limited to gene
therapy vectors and transgenes (new proteins expressed as a result of the gene therapy). Provention Bio intends to explore collaborations
with leaders in gene therapy and other biotherapeutic modalities.
PRV-101
(CVB Vaccine) for Acute Infection and T1D
Overview
of CVB Infection of the Pancreas, T1D and PRV-101’s Mechanism of Action
Longitudinal
studies of more than 200,000 children studied for up to two decades in Finland by our technology licensor, Vactech, and its collaborators,
identified CVB infection as a likely environmental trigger in the onset of T1D and T1D-associated CD. CVB infection is very common
and is responsible for various symptoms and complications ranging from mild respiratory disease, gastrointestinal disturbances
and hand-foot-mouth disease to life-threatening cardiomyopathy and meningitis. However, in patients with a certain genetic background,
CVB also may be responsible for the development of autoimmunity. The T1D association with CVB infection was also observed in additional
independent cohorts in 15 countries, including in North America and Australasia. These epidemiological observations have been
substantiated by biological experimentation. Insulin-producing beta cells in the pancreas express specialized receptors associated
with the transport, storage and release of insulin. These receptors appear to be used by CVB to preferentially infect these cells.
Infection by enteroviruses can be detected in the pancreatic beta cells of approximately 60% of type-1 diabetes patients and in
the gut of most patients with T1D-associated CD. Importantly, if mothers have anti-CVB immunity at the time of the pregnancy,
a 50% reduction in the onset of T1D autoimmunity (T1D-associated auto-antibodies) has been observed in their offspring, presumably
due to protection by maternal antibodies passed on to the fetus. This observation strongly suggests the potential efficacy of
CVB vaccination for children and/or mothers, resulting in the development of protective antibodies potentially capable of preventing
or delaying the onset of T1D.
An
analysis of stool samples collected from these individuals identified enterovirus infections prior to the first detection of T1D
auto-antibodies. Enterovirus RNA was also detected in stool samples. Examination of antibodies present in DIPP children who developed
at least two islet cell auto-antibodies (sign of incipient T1D) and/or progressed to T1D confirmed that among all enteroviruses,
only CVB was significantly associated with initiation of beta cell autoimmunity.
Enterovirus
RNA in Blood is Linked to the Development of T1D
OR:
odd ratio; CI: confidence interval; EV: enterovirus
Proposed
First in Human Phase 1 Clinical Trial of PRV-101
PRV-101
is expected to be a polyvalent (more than one strain) prophylactic CVB vaccine intended for acute CVB infection and the prevention
of CVB-induced T1D. We believe that, if successful, PRV-101 may prevent up to 50% of T1D cases. The vaccine is currently in an
IND-enabling stage, requiring manufacturing and nonclinical studies prior to initiation of FIH studies. Animal safety and efficacy
modeling studies completed to date by Vactech demonstrate that CVB triggers diabetes in two animal models of T1D and that vaccination
against CVB protects mice from acute infection as well as prevents the onset of diabetes triggered by CVB infection.
We
plan to commence a FIH Phase 1 clinical trial in the first half of 2020 in healthy adult volunteers, with top-line data by the
end of 2020. The primary objective of this FIH clinical trial is to evaluate the safety and tolerability of multiple doses of
PRV-101 administered at two different dose levels in adult healthy volunteers. A secondary objective is to evaluate the immunogenicity
(ability to elicit antibodies) of PRV-101 to CVB.
Preclinical
Data for PRV-101
The
mechanism of action and efficacy of PRV-101 is supported by the results of several in vivo studies. Inactivated CVB-based viral
vaccines efficiently protect mice from CVB infections and from viral spread to the pancreas, as seen for CVB1 and CVB3 vaccines.
Similar experiments conducted with a vaccine covering all six CVB serotypes demonstrated that it can induce a strong neutralizing
anti-CVB response in mice and protect the animals against multiple CVB infections from the corresponding live viruses. Independent
experiments confirm that CVB infection can accelerate T1D onset in T1D susceptible NOD (Non-obese diabetic) or SOCS-1-Tg (suppressor
of cytokine signaling 1 transgenic) mice, suggesting that protection from CVB infection would therefore protect against T1D development.
This hypothesis has been recently confirmed in experiments conducted by the Karolinska Institute (Sweden) and the University of
Tampere (Finland), demonstrating that a CVB1 vaccine indeed protected SOCS-1-Tg mice against T1D induced by CVB1. These mice develop
T1D after CVB1 infection as a consequence of a direct infection of insulin-producing beta cells in the pancreas and the subsequent
immune response against the beta cells, mimicking human T1D. A three-injection vaccination course induced robust neutralizing
antibody responses against CVB1 and protected mice from both CVB1 infection and CVB1-driven T1D. CVB1 infection led to a loss
of insulin-producing cells in unvaccinated mice, which also was prevented by the vaccine. These data strongly support the development
of PRV-101 for the prevention of T1D.
Formalin-Inactivated
CVB1 Vaccine is effective against CVB1-Induced T1D in a Mouse Model
As
seen in the left panel below, CVB1 infection led to loss of insulin-producing cells, and this pathology was completely prevented
by the CVB1 vaccine (right panel). In this experiment, while 50% of unvaccinated mice develop T1D as a consequence of CVB1 infection,
all vaccinated mice were protected (not shown).
Important
from a safety point of view, the formalin-inactivated CVB1 vaccines did not cause any undesirable effects in the pancreas. There
was no vaccine-induced pancreatic pathological change, islet autoimmunity or diabetes in the vaccinated mice.
Finally,
maternal CVB infection during gestation in mice protects the offspring from CVB infection and subsequent T1D development, presumably
through transfer of specific antibodies from the mother to the fetus, corroborating previous findings in humans in the DIPP study
and further supporting the use of a prophylactic vaccine to protect against CVB-associated-T1D.
IND-Enabling
Program to Support FIH Study
The
planned CVB vaccine toxicology program will consist of non-GLP and GLP safety and immunogenicity studies conducted in mice. These
studies are designed to identify and characterize potential toxicities associated with PRV-101 treatment, including those arising
from the immune responses induced by the product. They will mirror the administration regimen that will be used in the proposed
FIH study by same route of administration.
Pharmacology
studies will be conducted to determine the exact composition of the vaccine. It is currently considered that such CVB vaccine
should ideally be a polyvalent vaccine (encompassing several CVB serotypes). After completion of these studies, we plan to undertake
GMP manufacturing of the final vaccine for clinical trials.
CVB
Infection Market
Enteroviruses
are responsible for an estimated ten to 15 million symptomatic infections in the U.S. annually. CVB contributes to a major part
of the healthcare costs of enteroviruses as they cause the most serious complications and are among the most frequently reported
enteroviral infections according to the CDC. Acute CVB infection is usually asymptomatic or causes common cold-type symptoms.
It often leads also to a febrile illness associated by rash, hand-foot-mouth disease and/or mild GI distress. However, CVB infections
cause also more severe manifestations including pericarditis, myocarditis, meningitis and pancreatitis.
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Myocarditis:
CVB is the most common etiologic agents for myocarditis in the Western world, responsible for up to 33% of cases of myocarditis.
Myocarditis is an important cause of sudden unexpected death: the prevalence of myocarditis in children and adolescents leading
to sudden unexpected death has been reported to be as high as 8% to 42%. In certain individuals, acute myocarditis progresses
to chronic myocarditis and dilated cardiomyopathy, which is a severe life-threatening condition.
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Otitis
media:
otitis media (middle ear inflammation) may develop in patients with upper respiratory disease caused by enterovirus.
Otitis media constitutes 18% of physician visits in the U.S. (largest single reason in children). The costs of otitis media
treatment in the U.S. were estimated to be approximately $3 billion in 2014.
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Meningitis:
CVB is a common cause of enteroviral meningitis. Meningitis beyond the neonatal period is characterized by the sudden
onset of fever of 38-40°C. Headache and photophobia are almost universally reported in these patients. Reports on the
incidence of viral meningitis vary from approximately 50,000 hospitalized cases to over 2 million cases of aseptic meningitis
per year. Based on 300,000 annual cases of aseptic meningitis in the United States (of which enteroviruses, and coxsackie
viruses in particular, are the most common cause), the economic impact is estimated to be $1.5 billion in direct costs alone.
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PRV-300
(Anti-TLR3 Human mAb)
TLRs
are sensor molecules of the innate immune system, which detect certain microbial pathogens and initiate protective immune responses.
TLR3 is the main sensor for double-stranded RNA, or dsRNA, which is found in various phases of replication and propagation of
multiple common viruses. There is increasing evidence that TLR3 plays an important role in the pathologic response to emerging
viral infections and the excessive immune response they trigger. TLR3 has also been implicated in chronic pathologic inflammation
triggered by non-viral RNA (
i.e.
, dsRNA and mRNA originating from damaged human cells in the absence of an infection).
This appears to be the case in inflammatory disorders.
Monoclonal
antibodies, or mAbs, are manmade immune proteins used to treat various diseases. PRV-300 (previously known as CNTO 3157 and JNJ-42915925)
is a first-in-class, fully human, IgG4κ mAb that binds the extracellular domain of TLR3 with high specificity and affinity.
Binding of PRV-300 to TLR3 blocks the binding of RNA molecules to the cell surface and the endosomal TLR3 receptor, thereby inhibiting
TLR3-specific intracellular signaling that leads to production of inflammatory mediators (e.g., cytokines and chemokines) that
are known to contribute to ulcerative colitis, or UC, activity. In addition, TLR3 protein levels and the TLR3 pathway mRNA signature
are significantly increased in intestinal biopsies from active UC compared with those from controls and inactive UC, Also, the
blockade of TLR3 significantly reduced pathology in mouse models of colitis. Therefore, the blockade of TLR3 with PRV-300 may
provide an effective therapy to intercept the upstream stages in the pathophysiology of UC and potentially prevent relapse or
exacerbation.
PRV-300
was developed by Janssen, which undertook clinical testing in 155 subjects across three Phase 1 clinical trials: a) 47 healthy
volunteers received single intravenous doses of 0.003 mg/kg to 10 mg/kg and 13 patients with asthma received 3 mg/kg or 10 mg/kg
intravenously weekly for 4 weeks; b) 47 healthy volunteers received a single dose of 100 mg, 300 mg or 600 mg subcutaneously and
eight patients received a 300 mg single dose intravenously; and c) nine healthy subjects received a single dose of 10 mg/kg intravenously,
and 31 patients with asthma received 10 mg/kg followed by 3 mg/kg weekly for three weeks, intravenously. No serious adverse events
deemed related to PRV-300 were observed that would preclude further clinical development and proof of mechanism was demonstrated
based on inhibition of TLR3-dependent cytokine release in the peripheral blood of dosed subjects. While clinical efficacy was
not demonstrated in allergic asthma in a rhinovirus (common cold) challenge model, several lines of evidence suggested a plausible
beneficial role for the blockade of this pathway in the interception of disease exacerbation and chronicity. These data include
in vivo, ex vivo, histologic and gene expression analyses.
In
the first quarter of 2018, we initiated a Phase 1b clinical trial in patients with UC to evaluate the effect of PRV-300 on endoscopic
and histologic endpoints, and a biopsy-based mucosal mRNA signature. The latter provided a benchmark against which to assess the
efficacy of PRV-300. This study tested dose levels that were previously tested by Janssen, but with more doses and longer dosing
duration. Enrollment of 37 patients was completed in the third quarter of 2018.
In
May 2019, we announced that our clinical trial of PRV-300 met the primary safety and tolerability endpoint over the twelve-week
study period and also demonstrated TLR3 target engagement and proof-of-mechanism. However, improvements in secondary and exploratory
clinical, endoscopic, histologic and other UC-related efficacy endpoints were not observed over background medication, suggesting
that elevated TLR3 gene signatures previously observed in UC patients, as well as in PULSE, are downstream or circumstantial effects
that do not contribute significantly to causal pathology.
We
plan to return the rights to PRV-300 to Janssen and exercise our termination rights under the TLR3 License Agreement in the second
half of 2019.
Significant
Contracts and Agreements Related to Research and Development Activities
License
and Acquisition Agreements
MacroGenics
Asset Purchase Agreement
In
May 2018, we entered into an Asset Purchase Agreement with MacroGenics pursuant to which we acquired MacroGenics’ interest
in teplizumab (renamed PRV-031), a humanized mAb for the treatment of T1D. As partial consideration for the MacroGenics Asset
Purchase Agreement, we granted MacroGenics a warrant to purchase 2,162,389 shares of our common stock at an exercise price of
$2.50 per share. In July 2019, these warrants were exercised by MacroGenics on a cashless basis. We are obligated to pay MacroGenics
contingent milestone payments totaling $170.0 million upon the achievement of certain regulatory approval milestones. In addition,
we are obligated to make contingent milestone payments to MacroGenics totaling $225.0 million upon the achievement of certain
sales milestones. We have also agreed to pay MacroGenics a single-digit royalty on net sales of the product. We have also agreed
to pay third-party obligations, including low single-digit royalties, a portion of which is creditable against royalties payable
to MacroGenics, aggregate milestone payments of up to approximately $1.3 million and other consideration, for certain third-party
intellectual property under agreements we are assuming pursuant to the Asset Purchase Agreement. Further, we are required to pay
MacroGenics a low double-digit percentage of certain consideration to the extent it is received in connection with a future grant
of rights to PRV-031 by us to a third party. We are obligated to use reasonable commercial efforts to develop and seek regulatory
approval for PRV-031.
Amgen
License and Collaboration Agreement
In
November 2018, we entered into the Amgen Agreement with Amgen for PRV-015. Under the terms of the Amgen Agreement, we will conduct
and fund the Phase 2b PROACTIVE trial in NRCD and lead the development and regulatory activities for the program. Amgen has agreed
to make an equity investment of up to $20.0 million in the Company, subject to certain terms and conditions set forth in the Amgen
Agreement. The equity investment will coincide with our future financing events or receipt of non-dilutive milestone payment from
a third party including but not limited to Janssen related to our CSF-1R program. Amgen is also responsible for the manufacturing
of PRV-015. At any point until 120 days after the delivery by us of the final data package from the Phase 2b trial to Amgen, Amgen
reserves the right to assume control over all activities with respect to PRV-015, including pricing and marketing decisions, after
the payment of a $150.0 million milestone. If Amgen elects not to pay the $150.0 million milestone, we may elect to negotiate
a license agreement for PRV-015 (formerly AMG 714) rights, which each of Amgen and us are required to negotiate in good faith
and execute. Under the license agreement, we will be obligated to make certain contingent milestone payments to Amgen and other
third parties totaling up to $70.0 million upon the achievement of certain clinical and regulatory milestones and a low double-digit
royalty on net sales of any approved product based on the IL-15 technology. The Amgen Agreement may be terminated by us without
cause (in which case the exclusive global rights to the technology will transfer back to Amgen) and by either party upon a material
breach. The agreement expires upon the expiration of Amgen’s last obligation to make royalty payments to us (or, our last
obligation to make royalty payments to Amgen, if the program rights are transferred to us).
Janssen
License CSF-1R
In
April 2017, we entered into a License, Development and Commercialization Agreement, pursuant to which Janssen Pharmaceutica NV
granted us exclusive global rights for the purpose of developing and commercializing JNJ-40346527 (renamed PRV-6527), a colony
stimulating factor 1 receptor (CSF-1R) inhibitor for IBDs including CD. We are obligated to conduct a single Phase 2a proof-of-mechanism
and proof-of-concept clinical trial for the CD indication. Janssen will supply product for the clinical trial. For 90 days following
the conclusion of the Phase 2a clinical trial, Janssen will have an option to buy back the rights for future development for a
one-time payment of $50.0 million and future single-digit royalties on future net sales for a period of ten years from first sale
or expiration of the intellectual property, whichever is shorter. If Janssen does not exercise its option to buy-back the rights,
all rights will remain with us and we will be obligated to make contingent milestone payments to Janssen totaling $35.0 million
upon the achievement of certain clinical and regulatory milestones for the first indication and an additional $20.0 million upon
the achievement of certain clinical and regulatory milestones for a second indication. In addition, we have agreed to pay Janssen
tiered single-digit royalties on net sales of any approved product based on the CSF-1R technology and three additional payments
totaling $100.0 million upon the achievement of certain annual net sales levels. The CSF-1R License Agreement may be terminated
by us without cause (in which case the exclusive global rights to the technology will transfer back to Janssen) and by either
party upon a material breach and expires upon the expiration of our last obligation to make royalty payments to Janssen. Janssen
will supply drug product for our Phase 2a study. Janssen will also allow us to access their proprietary benchmark data, which
includes imaging, tissue and biomarker data.
MacroGenics
License Agreement
In
May 2018, we entered into a License Agreement with MacroGenics, pursuant to which MacroGenics granted us exclusive global rights
for the purpose of developing and commercializing MGD010 (renamed PRV-3279), a humanized protein and a potential treatment for
SLE and other similar diseases. As partial consideration for the MacroGenics License Agreement, we granted MacroGenics a warrant
to purchase 270,299 shares of our common stock at an exercise price of $2.50 per share. In July 2019, these warrants were exercised
by MacroGenics on a cashless basis. We are obligated to make contingent milestone payments to MacroGenics totaling $42.5 million
upon the achievement of certain developmental and approval milestones for the first indication, and an additional $22.5 million
upon the achievement of certain regulatory approvals for a second indication. In addition, we are obligated to make contingent
milestone payments to MacroGenics totaling $225.0 million upon the achievement of certain sales milestones. We have also agreed
to pay MacroGenics a single-digit royalty on net sales of the product. Further, we are required to pay MacroGenics a low double-digit
percentage of certain consideration to the extent received in connection with a future grant of rights to PRV-3279 by us to a
third party. We are obligated to use commercially reasonable efforts to develop and seek regulatory approval for PRV-3279. The
license agreement may be terminated by either party upon a material breach or bankruptcy of the other party, by us without cause
upon prior notice to MacroGenics, and by MacroGenics in the event that we challenge the validity of any licensed patent under
the agreement, but only with respect to the challenged patent.
Vactech
License
In
April 2017, we entered into a License Agreement with Vactech, pursuant to which Vactech granted us exclusive global rights for
the purpose of developing and commercializing the CVB vaccine platform technology. In consideration of the licenses and other
rights granted by Vactech, we issued two million shares of our common stock to Vactech. We recorded the issuance of the shares
at their estimated fair value of approximately $1.70 per share for a total of $3.4 million as a license fee expense included as
part of research and development expenses for the year ended December 30, 2017. We paid Vactech a total of approximately $0.5
million for transition and advisory services during the first 18 months of the term of the agreement. Vactech is obligated to
transition its intellectual property, provide reference samples, assist with the technology transfer to a third-party contract
manufacturer, and participate on our scientific advisory board. In addition, we may be obligated to make a series of contingent
milestone payments to Vactech totaling up to an additional $24.5 million upon the achievement of certain clinical development
and regulatory filing milestones. In addition, we have agreed to pay Vactech tiered single-digit royalties on net sales of any
approved product based on the CVB platform technology and three additional payments totaling $19.0 million upon the achievement
of certain annual net sales levels. The Vactech Agreement may be terminated by us on a country by country basis without cause
(in which case the exclusive global rights to the technology will transfer back to Vactech) and by either party upon a material
breach or insolvency of the other party. If we terminate the agreement with respect to two or more specified European countries,
the agreement will be deemed terminated with respect to all of the EU, and if we terminate the agreement with respect to the United
States, the agreement will be deemed terminated with respect to all of North America and expires upon the expiration of our last
obligation to make royalty payments to Vactech.
Janssen
License TLR3
In
April 2017, we entered into a License, Development and Commercialization Agreement with Janssen, pursuant to which Janssen Sciences
Ireland UC granted us exclusive global rights for the purpose of developing and commercializing JNJ-42915925 (renamed PRV-300),
an anti-TLR3 antibody. Under the TLR3 License Agreement, we will be obligated to make contingent milestone payments to Janssen
totaling $31.0 million upon the achievement of certain clinical and regulatory milestones for the first indication and an additional
$17.0 million upon the achievement of certain clinical and regulatory milestones for a second indication. In addition, we have
agreed to pay Janssen a single-digit royalty on net sales of any approved product based on the TLR3 technology and three additional
payments totaling $60.0 million upon the achievement of certain annual net sales levels. The TLR3 License Agreement may be terminated
by us without cause (in which case the exclusive global rights to the technology will transfer back to Janssen) and by either
party upon a material breach or insolvency of the other party and expires upon the expiration of our last obligation to make royalty
payments to Janssen. Janssen supplied drug product for the completed Phase 1b PULSE study.
We
intend to return the rights to PRV-300 to Janssen and exercise our termination rights under the TLR3 License Agreement in the
second half of 2019.
Intravacc
Development Services Agreement
In
March 2018, we entered into a Development Services Agreement with The Institute of Translational Vaccinology, or Intravacc, pursuant
to which Intravacc will provide services related to process development, non-GMP and GMP manufacturing of our polyvalent CVB vaccine,
including providing proprietary technology for manufacturing purposes. We will pay Intravacc approximately €10 million for
their services over the development and manufacturing period which we expect will last for approximately 18 to 24 months. Each
party retains its existing intellectual property and will share newly developed intellectual property via a fully-paid non-exclusive
license between the parties for all development work through phase 1 clinical trials. Any future use, including commercial use,
of Intravacc’s technology will be subject to a separate nonexclusive license agreement. The Intravacc Development Services
Agreement may be terminated by us with ninety days’ notice without cause and by either party upon a material breach or insolvency
of the other party.
AGC
Biologics Agreement
In
February 2019, we entered into services agreement with AGC Biologics, or AGC to manufacture and supply teplizumab, PRV-031, for
our anticipated clinical supply needs. We may terminate the agreement or any statement of work thereunder with approximately 12
months’ prior written notice to AGC. If we provide less than 12 months’ notice of termination, we may incur a cancellation
fee depending on the timing of such notice. AGC may terminate the agreement if we do not, over a specified period, purchase and
take delivery from AGC of a specified minimum quantity of API for teplizumab. Each party also has the right to terminate the agreement
for other customary reasons such as material breach and bankruptcy. The agreement contains provisions relating to compliance by
AGC with current Good Manufacturing Practices, cooperation by AGC in connection with potential marketing applications for PRV-031,
indemnification, confidentiality, dispute resolution and other customary matters for an agreement of this kind.
Parexel
Services Agreement
In
February 2019, we entered into a services agreement with Parexel, or the Parexel Services Agreement, pursuant to which we retained
Parexel to perform implementation and management services in connection with the PROTECT study of PRV-031. We may terminate the
services agreement or any work order for any reason and without cause with 90 days’ written notice. Either party may terminate
the agreement in the event of a material breach or, bankruptcy petition by the other party or, if any approval from a regulatory
authority is revoked, suspended or expires without renewal. We currently anticipate that aggregate costs relating to all work
orders under the Parexel Services Agreement for the PROTECT study will be approximately $43.0 million over the period of the study.
Intellectual
Property
We
believe that our current patent applications and any future patents and other proprietary rights that we own, or control through
licensing, are and will be essential to our business. We believe that these intellectual property rights will affect our ability
to compete effectively with others. We also rely and will rely on trade secrets, know-how, continuing technological innovations
and licensing opportunities to develop, maintain and strengthen our competitive position. We seek to protect these, in part, through
confidentiality agreements with certain employees, consultants, advisors and other parties. Our success will depend in part on
our ability, and the ability of our licensor, to obtain, maintain (including making periodic filings and payments) and enforce
patent protection for our/their intellectual property, including those patent applications to which we have secured exclusive
rights.
We
plan to spend considerable resources and focus in the future on obtaining U.S. and foreign patents. We have and will continue
to actively protect our intellectual property. No assurances can be given that any of our patent applications will result in the
issuance of a patent or that the examination process will not require us to narrow our claims. In addition, any issued patents
may be contested, circumvented, found unenforceable or invalid, and we may not be able to successfully enforce our patent rights
against third parties. No assurance can be given that others will not independently develop a similar or competing technology
or design around any patents that may be issued to us. We intend to expand our international operations in the future and our
patent portfolio, copyright, trademark and trade secret protections may not be available or may be limited in foreign countries.
PRV-031
(teplizumab anti-CD3 antibody)
Through
our agreement with MacroGenics, we have acquired a patent portfolio that includes eight issued patents, including three U.S. patents
and five ex-U.S. patents in Australia, Israel, Mexico and Singapore. The issued patents are set to expire no earlier than dates
ranging from 2019 and 2028, subject to any disclaimers, patent term adjustments or extensions available under the law.
These
issued patents disclose humanized antibodies that bind to CD3, and use of these antibodies in treating autoimmune disorders, including
T1D and RA.
PRV-015
(IL-15)
Through
our agreement with Amgen we have licensed a patent portfolio that includes: i) 78 issued patents, including seven U.S. patents,
42 patents in European countries, and 29 patents in other ex-U.S. jurisdictions; and ii) 19 pending patent applications, including
two pending U.S. patent applications, one pending European patent application, and 16 pending patent applications in other ex-U.S.
jurisdictions.
The
patents and patent applications disclose anti-IL-15 antibodies, methods of using the same, manufacturing conditions and dosages
of the same.
The
issued patents are set to expire no earlier than dates ranging from 2022 and 2027, subject to any disclaimers or extensions under
the law. In the event that the pending patent applications issue as patents, although there can be no assurance that the patent
applications will issue, the patents would be set to expire no earlier than dates ranging from 2026 and 2037, subject to any disclaimers,
patent term adjustments or extensions available under the law.
PRV-6527
(CSF-1R)
Through
our agreement with Janssen Pharmaceutica NV, we have licensed a patent portfolio that includes: i) 73 issued patents, including
one U.S. patent, one patent in European countries, and 71 patents in other ex-U.S. jurisdictions; and ii) three pending patent
applications, one pending U.S. patent application, one pending European patent application, and one pending patent applications
in other ex-U.S. jurisdictions. The issued patents are set to expire no earlier than dates ranging from 2027 and 2030 subject
to any disclaimers, patent term adjustments or extensions under the law. In the event that the pending patent applications issue
as patents, although there can be no assurance that the patent applications will issue, the patents would be set to expire no
earlier than dates ranging from 2027 and 2030, subject to any disclaimers, patent term adjustments or extensions available under
the law.
PRV-3279
(CD32B/CD79B diabody)
Through
our agreement with MacroGenics, we have a licensed patent portfolio that includes: i) 213 issued patents, including ten U.S. patents,
142 patents in European countries, and 61 patents in other ex-U.S. jurisdictions; and ii) 52 pending patent applications, including
nine pending U.S. patent applications, four pending European patent applications, and 39 pending patent applications in other
ex-U.S. jurisdictions.
The
patents and patent applications disclose a platform technology for making diabodies, specific anti-CD32B antibodies, specific
anti-CD79B antibodies, specific diabodies that co-ligate both CD32B and CD79B, as well as use of these antibodies and diabodies
in treating various disorders, including cancer, autoimmune disorder, inflammatory disorder, and IgE-mediated allergic disorder.
The
issued patents in the U.S. and various ex-U.S. countries generally have terms of 20 years from their respective priority filing
dates, subject to available extensions, and are thus set to expire no earlier than dates ranging from 2023 and 2034 subject to
any disclaimers, patent term adjustments or extensions available under the law. In the event that the pending patent applications
issue as patents, although there can be no assurance that the patent applications will issue, the patents would be set to expire
no earlier than dates ranging from 2023 and 2037, subject to any disclaimers, patent term adjustments or extensions available
under the law.
PRV-101
(CVB/T1D)
Through
our agreement with Vactech, we have a licensed patent portfolio that includes one issued U.S. patent, two pending U.S. patent
applications, and 38 patents in various European countries (i.e., one granted European patent validated in 38 European Patent
Convention member states). The pending U.S. patent applications and the European country patents disclose use of a CVB vaccine
composition in the prevention or treatment of T1D.
The
patents issued in the U.S. and various European countries generally have terms of 20 years from their respective priority filing
dates, subject to available extensions, and are thus set to expire no earlier than 2032, subject to any disclaimers, patent term
adjustments or extensions available under the law.
PRV-300
(TLR3 Antagonist)
Through
our agreement with Janssen Sciences Ireland UC we have a licensed patent portfolio that includes: i) 137 issued patents, including
eight U.S. patents, 77 patents in European, or EP, countries (i.e., two granted European patents validated in a combined total
of 77 European Patent Convention, or EPC, member states), and 51 patents in other ex-U.S. jurisdictions (including: i) two Eurasian
Patent Office, or EAPO, patents validated in a total of 20 Eurasian Patent Convention member states; and ii) 31 issued patents
in ex-U.S. countries other than EP and EAPO); and ii) 34 pending patent applications, including one pending U.S. patent application,
two pending European patent applications, two pending EAPO patent applications and 29 pending patent applications in other ex-U.S.
jurisdictions.
These
issued patents and patent applications disclose antibodies that bind TLR3 and that function as TLR3 antagonists, and use of these
antibodies in treating various disorders, including respiratory disorders, inflammatory conditions, and metabolic disorders, as
well as in reduction of cholesterol.
The
issued patents generally have terms of 20 years from their respective priority filing dates, subject to available extensions,
and thus the issued patents are set to expire no earlier than dates ranging from 2029 and 2031. In the event that patents issue
based on the pending patent applications, although there can be no assurance that any of the patent application will be granted,
such patents would be expected to expire between 2029 and 2031, subject to any disclaimers, patent term adjustments or extensions
available under the law.
We
plan to return the rights to PRV-300 to Janssen and exercise our termination rights under the TLR3 License Agreement in the second
half of 2019.
Sales
and Marketing
We
are a clinical stage company without a history of revenue or manufacturing, late stage clinical development or marketing experience.
Because late stage clinical development, as well as establishing a full manufacturing and distribution structure, is expensive
and time consuming, we intend to explore alternative commercialization strategies, including:
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developing
drug candidates through the earlier stages of clinical development with the objectives of rapid, cost effective risk reduction
and value creation and then establishing strategic partnership for late stage clinical development and subsequent commercialization;
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developing
a robust pipeline of promising drug candidates at various stages of the development process to establish optionality and regular
value inflection opportunities and revenue(s);
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strategically
entering into co-development partnership(s) to retain potential for commercialization rights on selected drug candidate(s)
and market opportunities; and
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partnering
with industry participants to incorporate our technology into new and existing drugs.
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We
expect that partnering with pharmaceutical or biotherapeutic companies may accelerate product acceptance into our target market
areas and gain the sales and marketing advantages of the partner’s distribution infrastructure. We intend to continue to
strengthen our market position and solidify our leadership position in immunotherapy by continuing to improve our technology,
broadening our clinical and therapeutic applications, identifying new clinical and therapeutic applications and forming strategic
relationships with our licensors.
Manufacturing
We
do not currently own or operate manufacturing facilities for the production of clinical or commercial quantities of any of our
product candidates. Although we rely and intend to continue to rely upon third–party contract manufacturers to produce our
products and product candidates, we have recruited personnel and consultants with experience to manage these third–party
contract manufacturers. In certain cases, our collaboration partners for each respective program are responsible for providing
clinical drug supply or drug product for those program’s clinical trials. In other cases, we have engaged third-party manufacturers
to provide services related to process development, non-GMP and GMP manufacturing and other related services.
The
table below lists the third-party responsible for manufacturing drug supply for each of our programs:
Product
Candidate
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Supplier
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Party
Responsible for Costs
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PRV-031
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Existing
drug supply – MacroGenics
Future
drug supply – AGC Biologics
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MacroGenics
Provention
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PRV-015
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Amgen
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Amgen
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PRV-6527
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Existing
drug supply – Janssen
Future
drug supply - Janssen
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Janssen
Provention/Janssen
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PRV-3279
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Existing
drug supply – MacroGenics
Future
drug supply – vendors being evaluated
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MacroGenics
Provention
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PRV-101
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Intravacc
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Provention
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We
have historically relied upon an existing supply of PRV-031 produced by MacroGenics for use in our clinical trials of PRV-031.
This existing supply is insufficient to fully supply the ongoing PROTECT study to completion. In February 2019, we entered into
an agreement with AGC Biologics to manufacture PRV-031 for our anticipated clinical trial needs. In order to obtain regulatory
approval, the PROTECT study will need to include data from a sufficient number of subjects dosed with the supply of PRV-031 produced
by AGC Biologics to demonstrate safety and efficacy. In addition, we will require AGC Biologics to satisfy process validation
requirements with regard to PRV-031 and we will be required to demonstrate to the FDA and other regulatory authorities the comparability
of AGC Biologics product to MacroGenics product, in order for PRV-031 to obtain regulatory approval.
Competition
We
face substantial competition from well-established large pharmaceutical companies, as well as innovative new entrants. Nevertheless,
we believe our strategic intent is sufficiently differentiated in that we are focusing on intercepting or potentially preventing
the onset and progression of immune-mediated and inflammatory diseases by selecting and developing product candidates that are
aimed at relevant and predominantly upstream pathophysiological targets.
The
symptomatic treatment of T1D is a highly competitive market with large incumbents such as Sanofi, Novo Nordisk and Eli Lilly providing
insulin and blood glucose monitoring products and working on new ways to manage the disease. Our goal is to delay or prevent the
onset of T1D and spare patients the need to live with blood glucose monitoring and daily insulin injections and this therapy’s
many complications and clinically relevant shortfalls. We believe our enteroviral vaccine approach is unique in that it aims to
prevent the onset of T1D prior to the rise of auto-antibodies programmed to attack insulin producing beta cells. We are aware
of competitive vaccine technologies in development that are attempting to alter the autoimmune cycle once these auto-antibodies
have been detected. However, we believe our vaccine approach may intercept the process prior to this cycle being initiated. Other
immunomodulation therapies have shown preservation of beta cell function in early phase studies of new-onset T1D including anti-thymocyte
globulin (ATG), CTLA4-Ig (costimulatory blocker), anti-CD20 (Rituxan) and LFA3-Ig (alefacept). All of these Phase 2 studies were
conducted by the academic community or by T1D networks and do not appear to be in active development by industry sponsors. The
most recent data were reported with Thymoglobulin® which is an approved anti-thymocyte globulin obtained by immunization of
rabbits with human thymocytes, and is indicated for the treatment of renal transplant acute rejection in conjunction with concomitant
immunosuppression and for induction in adult renal transplant recipients. Low dose ATG was administered intravenously for 2 days
in early onset T1D (within 100 days of diagnosis). While C-peptide preservation was observed, due to the risk of serum sickness,
ATG was administered during a 2-3 day hospitalization and required pre-medication, including intravenous corticosteroids.
PRV-015
has the potential to be the first drug ever approved for CD since it is the only medication which has shown simultaneous improvement
in symptoms and inflammation to date, and since most clinical-stage products are early in development and have not established
proof-of-concept. Competition includes experimental medications in development by Innovate (INN-202/larazotide acetate, Phase
2b study completed in 2014; Phase 3 announced), ImmunogenX (IMGX-003/latiglutenase, Phase 2b study completed in 2016 missed primary
endpoint, phase 2a announced), ImmusanT (NexVax 2, phase 2a on-going), Zedira/Dr. Falk (ZED1227, phase 2a on-going), Cour (NP-GLI,
Phase 1/2 on-going) and PvP Biologics (KumaMax, Phase 1 on-going).
The
market for IBD, including CD, is currently led by large pharmaceutical companies serving the autoimmune market with anti-TNF biologics.
Among these companies are AbbVie, Eli Lilly, Johnson & Johnson and Pfizer. New drugs are continually being developed in this
highly-competitive space by large pharma and early to mid-stage biotech companies. However, many of these drugs used for CD focus
on attempting to bring about remission or treating the symptoms of advanced stages of IBD, by neutralizing the inflammatory signals
that are released once the immune system has been pathologically activated. We are using a novel approach intended to intercept
the autoimmune cycle before these inflammatory signals are received and have an opportunity to trigger significant tissue damage.
Our drugs target “upstream” mechanisms of action that may provide benefit for a wider patient population, including
patients that have already been treated with anti-TNF drugs that failed to adequately or sustainably control their disease. One
of our assets is a small molecule intended for oral administration, which is potentially a significant further differentiating
factor in CD, a crowded market currently dominated by injectable biologics.
The
market for lupus is currently led by large pharmaceutical companies commercializing older, off-patent products such as steroids,
immunosuppressive agents including azathioprine, cyclosphosphamide, cyclosporine and mycophenolate. In addition, Glaxo SmithKline
and Roche offer recently approved B cell-targeted agents. GSK received approval for belimumab (Benlysta) in 2011, the first drug
approval in lupus in 50 years. Despite modest efficacy and slow onset of effect, belimumab’s annual sales are currently
approximately $600 million. Roche’s rituximab (Rituxan), a blockbuster drug, is used off-label in lupus despite not having
been approved in SLE. The lupus field is competitive and new experimental drugs are being tested in late stage trials by large
pharmaceutical companies and early to mid-stage biotech companies and include: the anti-interferon alpha receptor anifrolumab
(MedImmune/Astra Zeneca), anti-CD19/CD32B XmAb5871 (Xencor) and calcineurin inhibitor voclosporin (Aurinia Pharmaceuticals). We
expect that PRV-3279 will be differentiated from the competition because of greater and faster-onset efficacy, better safety (PRV-3279
does not deplete B cells and is not expected to be immune-suppressive), and less gastrointestinal side effects (since PRV-3279
is a highly specific mAb with likely minimal off-target side effects).
Government
Regulation
Our
business activities, including the manufacturing, research, development and marketing of our product candidates, are subject to
extensive regulation by numerous governmental authorities in the United States and other countries. Before marketing in the United
States, any new drug developed by us or our collaborators must undergo rigorous preclinical testing, clinical trials and an extensive
regulatory clearance process implemented by the FDA under the Federal Food, Drug, and Cosmetic Act, as amended. The FDA regulates,
among other things, the development, testing, manufacture, safety, efficacy, record keeping, labeling, storage, approval, advertising,
promotion, import, export, sale and distribution of biopharmaceutical products. The regulatory review and approval process, which
includes preclinical testing and clinical trials of each product candidate, is lengthy, expensive and uncertain. Moreover, government
coverage and reimbursement policies will both directly and indirectly impact our ability to successfully commercialize any future
approved products, and such coverage and reimbursement policies will be impacted by enacted and any applicable future healthcare
reform and drug pricing measures. In addition, we are subject to state and federal laws, including, among others, anti-kickback
laws, false claims laws, data privacy and security laws, and transparency laws that restrict certain business practices in the
pharmaceutical industry.
In
the United States, drug product candidates intended for human use undergo laboratory and animal testing until adequate proof of
safety is established. Clinical trials for new product candidates are then typically conducted in humans in three sequential phases
that may overlap. Phase 1 trials involve the initial introduction of the product candidate into healthy human volunteers. The
emphasis of Phase 1 trials is on testing for safety or adverse events, dosage, tolerance, metabolism, distribution, excretion
and clinical pharmacology. Phase 2 involves studies in a limited patient population to determine the initial efficacy of the compound
for specific targeted indications, to determine dosage tolerance and optimal dosage, and to identify possible adverse side effects
and safety risks. Once a compound shows evidence of effectiveness and is found to have an acceptable safety profile in Phase 2
evaluations, Phase 3 trials are undertaken to more fully evaluate clinical outcomes. Before commencing clinical investigations
in humans, we or our collaborators must submit an IND to the FDA.
Regulatory
authorities, Institutional Review Boards and Data Monitoring Committees may require additional data before allowing clinical trials
to commence, continue or proceed from one phase to another, and could demand that studies be discontinued or suspended at any
time if there are significant safety issues. We have in the past and may in the future rely on assistance from our third-party
collaborators and contract service providers to file our INDs and generally support our development and regulatory activities
approval process for our potential products. Clinical testing must also meet requirements for clinical trial registration, institutional
review board oversight, informed consent, health information privacy, and GCPs. Additionally, the manufacture of our drug product,
must be done in accordance with current GMPs.
To
establish a new product candidate’s safety and efficacy, the FDA requires companies seeking approval to market a drug product
to submit extensive preclinical and clinical data, along with other information, for each indication for which the product will
be labeled. The data and information are submitted to the FDA in the form of a New Drug Application, or NDA, or Biologics License
Application, or BLA which must be accompanied by payment of a significant user fee unless a waiver or exemption applies. Generating
the required data and information for regulatory approval takes many years and requires the expenditure of substantial resources.
Information generated in this process is susceptible to varying interpretations that could delay, limit or prevent regulatory
approval at any stage of the process. The failure to demonstrate adequately the quality, safety and efficacy of a product candidate
under development would delay or prevent regulatory approval of the product candidate. Under applicable laws and FDA regulations,
each NDA or BLA submitted for FDA approval is given an internal administrative review within 60 days following submission of the
NDA or BLA. If deemed sufficiently complete to permit a substantive review, the FDA will “file” the NDA or BLA. The
FDA can refuse to file any NDA and BLA that it deems incomplete or not properly reviewable. The FDA has established internal goals
of eight months from submission for priority review of NDAs or BLAs that cover product candidates that offer major advances in
treatment or provide a treatment where no adequate therapy exists, and 12 months from submission for the standard review of NDAs
and BLAs. However, the FDA is not legally required to complete its review within these periods, these performance goals may change
over time and the review is often extended by FDA requests for additional information or clarification. Moreover, the outcome
of the review, even if generally favorable, may not be an actual approval but a “complete response letter” that describes
additional work that must be done before the NDA or BLA can be approved. Before approving an NDA or BLA, the FDA can choose to
inspect the facilities at which the product is manufactured and will not approve the product unless the manufacturing facility
complies with GMPs. The FDA may also audit sites at which clinical trials have been conducted to determine compliance with GCPs
and data integrity. The FDA’s review of an NDA or BLA may also involve review and recommendations by an independent FDA
advisory committee, particularly for novel indications. The FDA is not bound by the recommendation of an advisory committee.
In
addition, delays or rejections may be encountered based upon changes in regulatory policy, regulations or statutes governing product
approval during the period of product development and regulatory agency review.
Before
receiving FDA approval to market a potential product, we or our collaborators must demonstrate through adequate and well-controlled
clinical trials that the potential product is safe and effective in the patient population that will be treated. In addition,
under the Pediatric Research Equity Act, or PREA, an NDA or BLA or supplement thereto must contain data to assess the safety and
effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration
for each pediatric subpopulation for which the product is safe and effective, unless a waiver applies. If regulatory approval
of a potential product is granted, this approval will be limited to those disease states and conditions for which the product
is approved. Marketing or promoting a drug for an unapproved indication is generally prohibited. Furthermore, FDA approval may
entail ongoing requirements for risk management, including post-marketing, or Phase 4, studies. Even if approval is obtained,
a marketed product, its manufacturer and its manufacturing facilities are subject to payment of significant annual fees and continuing
review and periodic inspections by the FDA. Discovery of previously unknown problems with a product, manufacturer or facility
may result in restrictions on the product or manufacturer, including labeling changes, warning letters, costly recalls or withdrawal
of the product from the market.
Any
drug is likely to produce some toxicities or undesirable side effects in animals and in humans when administered at sufficiently
high doses and/or for sufficiently long periods of time. Unacceptable toxicities or side effects may occur at any dose level at
any time in the course of studies in animals designed to identify unacceptable effects of a product candidate, known as toxicological
studies, or during clinical trials of our potential products. The appearance of any unacceptable toxicity or side effect could
cause us or regulatory authorities to interrupt, limit, delay or abort the development of any of our product candidates. Further,
such unacceptable toxicity or side effects could ultimately prevent a potential product’s approval by the FDA or foreign
regulatory authorities for any or all targeted indications or limit any labeling claims and market acceptance, even if the product
is approved.
In
addition, as a condition of approval, the FDA may require an applicant to develop a Risk Evaluation and Mitigation Strategy, or
REMS. A REMS uses risk minimization strategies beyond the professional labeling to ensure that the benefits of the product outweigh
the potential risks. To determine whether a REMS is needed, the FDA will consider the size of the population likely to use the
product, seriousness of the disease, expected benefit of the product, expected duration of treatment, seriousness of known or
potential adverse events, and whether the product is a new molecular entity. REMS can include medication guides, physician communication
plans for healthcare professionals, and elements to assure safe use, or ETASU. ETASU may include, but are not limited to, special
training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and
the use of patient registries. The FDA may require a REMS before approval or post-approval if it becomes aware of a serious risk
associated with use of the product. The requirement for a REMS can materially affect the potential market and profitability of
a product.
Any
trade name that we intend to use for a potential product must be approved by the FDA irrespective of whether we have secured a
formal trademark registration from the U.S. Patent and Trademark Office. The FDA conducts a rigorous review of proposed product
names and may reject a product name if it believes that the name inappropriately implies medical claims or if it poses the potential
for confusion with other product names. The FDA will not approve a trade name until the NDA or BLA for a product is approved.
If the FDA determines that the trade names of other products that are approved prior to the approval of our potential products
may present a risk of confusion with our proposed trade name, the FDA may elect to not approve our proposed trade name. If our
trade name is rejected, we will lose the benefit of any brand equity that may already have been developed for this trade name,
as well as the benefit of our existing trademark applications for this trade name.
We
and our collaborators and contract manufacturers also are required to comply with the applicable FDA GMP regulations. GMP regulations
include requirements relating to quality control and quality assurance as well as the corresponding maintenance of records and
documentation. Manufacturing facilities are subject to inspection by the FDA. These facilities must be approved before we can
use them in commercial manufacturing of our potential products and must maintain ongoing compliance for commercial product manufacture.
The FDA may conclude that we or our collaborators or contract manufacturers are not in compliance with applicable GMP requirements
and other FDA regulatory requirements, which may result in delay or failure to approve applications, warning letters, product
recalls and/or imposition of fines or penalties.
If
a product is approved, we must also comply with post-marketing requirements, including, but not limited to, compliance with advertising
and promotion laws enforced by various government agencies, including the FDA’s Office of Prescription Drug Promotion, through
such laws as the Prescription Drug Marketing Act, federal and state anti-fraud and abuse laws, including anti-kickback and false
claims laws, healthcare information privacy and security laws, post-marketing safety surveillance, and disclosure of payments
or other transfers of value to healthcare professionals and entities. In addition, we are subject to other federal and state regulation
including, for example, the implementation of corporate compliance programs.
If
we elect to distribute our products commercially, we must comply with state laws that require the registration of manufacturers
and wholesale distributors of pharmaceutical products in a state, including, in certain states, manufacturers and distributors
who ship products into the state even if such manufacturers or distributors have no place of business within the state. Some states
also impose requirements on manufacturers and distributors to establish the pedigree of product in the chain of distribution,
including some states that require manufacturers and others to adopt new technology capable of tracking and tracing product as
it moves through the distribution chain.
Outside
of the United States, our ability to market a product is contingent upon receiving a marketing authorization from the appropriate
regulatory authorities, including the EMA. The requirements governing the conduct of clinical trials, marketing authorization,
pricing and reimbursement vary widely from country to country. At present, foreign marketing authorizations are applied for at
a national level, although within the European Community, centralized registration procedures are available to companies wishing
to market a product in more than one European Community member state. If the regulatory authority is satisfied that adequate evidence
of safety, quality and efficacy has been presented, marketing authorization will be granted. This foreign regulatory development
and approval process involves all of the risks associated with achieving FDA marketing approval in the U.S. as discussed above.
In addition, foreign regulations may include applicable post-marketing requirements, including safety surveillance, anti-fraud
and abuse laws, and implementation of corporate compliance programs and reporting of payments or other transfers of value to healthcare
professionals and entities.
Reimbursement
Potential
sales of any of our product candidates, if approved, will depend, at least in part, on the extent to which such products will
be covered by third-party payors, such as government health care programs, commercial insurance and managed healthcare organizations.
These third-party payors are increasingly limiting coverage and/or reducing reimbursements for medical products and services.
A third-party payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate
will be approved. Further, one payor’s determination to provide coverage for a drug product does not assure that other payors
will also provide coverage for the drug product. In addition, the U.S. government, state legislatures and foreign governments
have continued implementing cost-containment programs, including price controls, restrictions on reimbursement and requirements
for substitution of generic products. Adoption of price controls and cost-containment measures, and adoption of more restrictive
policies in jurisdictions with existing controls and measures, could further limit our future revenues and results of operations.
Decreases in third-party reimbursement or a decision by a third-party payor to not cover a product candidate, if approved, or
any future approved products could reduce physician usage of our products, and have a material adverse effect on our sales, results
of operations and financial condition.
In
the United States, the Medicare Part D program provides a voluntary outpatient drug benefit to Medicare beneficiaries for certain
products. We do not know whether our product candidates, if approved, will be eligible for coverage under Medicare Part D, but
individual Medicare Part D plans offer coverage subject to various factors such as those described above. Furthermore, private
payors often follow Medicare coverage policies and payment limitations in setting their own coverage policies.
Healthcare
Laws and Regulations
Sales
of our product candidates, if approved, or any other future product candidate will be subject to healthcare regulation and enforcement
by the federal government and the states and foreign governments in which we might conduct our business. The healthcare laws and
regulations that may affect our ability to operate include the following:
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The
federal Anti-Kickback Statute makes it illegal for any person or entity to knowingly and willfully, directly or indirectly,
solicit, receive, offer, or pay any remuneration that is in exchange for or to induce the referral of business, including
the purchase, order, lease of any good, facility, item or service for which payment may be made under a federal healthcare
program, such as Medicare or Medicaid. The term “remuneration” has been broadly interpreted to include anything
of value.
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Federal
false claims and false statement laws, including the federal civil False Claims Act, prohibits, among other things, any person
or entity from knowingly presenting, or causing to be presented, for payment to, or approval by, federal programs, including
Medicare and Medicaid, claims for items or services, including drugs, that are false or fraudulent.
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The
U.S. federal Health Insurance Portability and Accountability Act of 1996 (HIPAA) created additional federal criminal statutes
that prohibit among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare
benefit program, including private third-party payors or making any false, fictitious or fraudulent statement in connection
with the delivery of or payment for healthcare benefits, items or services.
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HIPAA,
as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (HITECH) and their implementing
regulations, impose obligations on certain types of individuals and entities regarding the electronic exchange of information
in common healthcare transactions, as well as standards relating to the privacy and security of individually identifiable
health information.
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The
federal Physician Payments Sunshine Act requires certain manufacturers of drugs, devices, biologics and medical supplies for
which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions,
to report annually to the Center for Medicare & Medicaid Services information related to payments or other transfers of
value made to physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their
immediate family members.
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Also,
many states have similar laws and regulations, such as anti-kickback and false claims laws that may be broader in scope and may
apply regardless of payor, in addition to items and services reimbursed under Medicaid and other state programs. Additionally,
we may be subject to state laws that require pharmaceutical companies to comply with the federal government’s and/or pharmaceutical
industry’s voluntary compliance guidelines, state laws that require drug manufacturers to report information related to
payments and other transfers of value to physicians and other healthcare providers or marketing expenditures, as well as state
and foreign laws governing the privacy and security of health information, many of which differ from each other in significant
ways and often are not preempted by HIPAA.
Additionally,
to the extent that our product is sold in a foreign country, we may be subject to similar foreign laws.
Agreement
with SVB Leerink LLC and Cantor Fitzgerald & Co.
On
August 2, 2019, we entered into the Sales Agreement with Leerink and Cantor as sales agents, pursuant to which we may offer and sell, from
time to time, through the Agents shares of our common stock.
We
are not obligated to sell any shares under the Sales Agreement. Subject to the terms and conditions of the Sales Agreement, the
Agents will use commercially reasonable efforts consistent with their respective normal trading and sales practices, applicable
state and federal law, rules and regulations and the rules of The Nasdaq Capital Market (“Nasdaq”) to sell shares
from time to time based upon our instructions, including any price, time or size limits specified by us. Upon delivery of a placement
notice, and subject to our instructions in that notice, and the terms and conditions of the Sales Agreement generally, the Agents
may sell our common stock by any method permitted by law deemed to be an “at the market offering” as defined by Rule
415(a)(4) promulgated under the Securities Act of 1933, as amended. The Agents’ obligations to sell shares under the Sales
Agreement are subject to satisfaction of certain conditions, including the effectiveness of the registration statement on Form
S-3 (the “Registration Statement”) filed by us with the SEC on August 2, 2019 and other customary closing conditions.
We will pay the Agents a commission of 3.0% of the aggregate gross proceeds from each sale of shares and have agreed to provide
the Agents with customary indemnification and contribution rights. We have also agreed to reimburse the Agents for certain specified
expenses.
Shares
of common stock may be offered and sold pursuant to the Registration Statement and the sales agreement prospectus that forms a
part of such Registration Statement, following such time as the Registration Statement is declared effective by the SEC, for an
aggregate offering price of up to $50.0 million.
The
foregoing summary of the Sales Agreement does not purport to be complete and is qualified in its entirety by reference to the
full text of the Sales Agreement, which is attached as an exhibit to the Registration Statement and incorporated by reference
into this Item 5 of Part II of this Quarterly Report on Form 10-Q.