Summit Therapeutics Inc. (NASDAQ: SMMT) (“Summit” or the “Company”)
today announced topline results for the Phase III Ri-CoDIFy study
evaluating its investigational drug, ridinilazole, for the
treatment of and Sustained Clinical Response (SCR) for patients
suffering from C. difficile infection (C. diff. infection or CDI).
The study showed that ridinilazole resulted in a higher observed
SCR rate than vancomycin but did not meet the study’s primary
endpoint for superiority. SCR is defined as Clinical Response of
the treated episode of CDI and no recurrence of the infection
through 30 days after the end of treatment.
Patients treated with ridinilazole, a precision
antibiotic, experienced substantially less recurrence of C. diff.
infection as compared to patients administered vancomycin (nominal
p-value = 0.0002). Recurrence, for purposes of the Ri-CoDIFy study,
is defined as a new episode of diarrhea (≥3 unformed bowel
movements) in a 1-day period with a positive C. difficile test that
requires CDI antimicrobial treatment in subjects who achieved
Clinical Response. Particularly promising results were identified
in patients who were considered high-risk, including those
considered immunocompromised or with a history of COVID-19
infection.
“Reduced recurrence rates are very consistent
with our Phase II data and the mechanism of action of this drug,”
said Dr. Fong Clow, Head of Biometrics at Summit. “Although
Ri-CoDIFy did not meet the primary endpoint for the design of this
study, we did see a meaningful reduction in recurrence in the
ridinilazole arm, which we believe is tied to the precision
properties of ridinilazole and its associated relative sparing of
the gut microbiome. We believe this is a viable measurement of the
effect of this drug and has biological significance as to the
potential value of the drug. It is essential that we consider the
value of recurrence, the impact on the microbiome, and the
measurement of this biological outcome when considering the value
of a drug like ridinilazole and its potential benefits to the
patient and human health.”
“We believe this study was indicative of
worthwhile work, as the knowledge that we have acquired as a team
over the past 18 months is priceless,” said Robert W. Duggan,
Chairman and Chief Executive Officer of Summit. “The differences
between episodes of recurrence experienced by patients in the two
arms of this study may be indicative as to the significance of
precision medicinal therapies that spare the microbiome from
damage. A balanced microbiome is critical to human health and
protecting it must be a focus going forward for medicinal therapies
whose desire is to maximize patient safety and optimize human
health: I believe the impact on a balanced microbiome is a critical
component of the evaluation of any drug and will become an
essential part of evaluating drug safety and efficacy as we move
forward in time. Dysbiosis of the microbiome can lead to recurrence
when treating CDI, as we believe the differences in recurrence
rates between the two arms of the study indicate, but also may
increase the risk of other immune-mediated and infectious diseases,
such as COVID-19.1 The opportunity for medicinal therapies to
leverage the microbiome to improve the quality of life from
newborns to the last days of life is an opportunity worth taking
seriously. Team Summit fully anticipates playing a meaningful role
in this opportunity to improve the quality of human life.”
“I am excited to continue to learn more about
ridinilazole’s potential merits for its treatment of CDI patients,”
added Dr. Danelle James, Head of Clinical Development and Medical
Affairs at Summit. “The recurrence rates, a clinically meaningful
outcome, with ridinilazole was substantially lower than vancomycin
– a likely outcome of ridinilazole’s highly-selective nature. We
believe that high-risk patient populations – those considered
immunocompromised and those with a history of COVID-19 – are more
likely to be harmed by an increased level of dysbiosis of the gut
microbiome, and dysbiosis has a greater impact to their overall
health. Innovating the way in which we treat C. difficile infection
via new mechanism, precision antibiotics could add value to not
only patients suffering from CDI by reducing disease recurrence,
but also help in the fight against antimicrobial resistance, a
paradigm that is foundational for antibiotic drug stewardship.”
“We would like to extend our true gratitude to
all of those who supported our efforts in the discovery, research,
and clinical development of ridinilazole, helping show the
potential value of ridinilazole to patients, providers, and the
healthcare ecosystem,” added Dr. Maky Zanganeh, Chief Operating
Officer, and a member of Summit’s Board of Directors. “The
patients who participated in our clinical trials, along with their
families and caregivers, are an integral part of the journey
towards achieving our goal of improving overall human health. To
our study investigators, we are truly appreciative of your trust in
Team Summit and ridinilazole, as well as your unparalleled care of
the patients in our trial and your drive to resolve serious unmet
medical needs. Finally, we would like to extend a sincere
appreciation to those organizations, including BARDA, who continue
to provide invaluable support in developing ridinilazole.”
Full results from the Ri-CoDIFy study will be
presented at upcoming medical conferences and published in a
peer-reviewed medical journal. We will continue to evaluate the
underlying data and perform additional analyses, including analyses
specific to the microbiome, in order to discuss our complete
package with the regulatory agencies. The use of ridinilazole is
not approved and its safety and efficacy have not been evaluated by
regulatory authorities, including the FDA.
_____________________________
1 Giovanni, Schneider, Calder, and Fauci.
Refocusing Human Microbiota Research in Infectious and
Immune-Mediated Diseases: Advancing to the Next Stage. The Journal
of Infectious Diseases, Vol. 224, Issue 1: 5-8, Jul 2021.
_____________________________
Update Regarding Corporate Funding Initiatives
The Company is also announcing that it
anticipates commencing a rights offering to be available to all
holders of record of the Company’s common stock in January 2022. It
is anticipated that the record date for the distribution of rights
to all holders of Common Stock will be in mid-January, at a date to
be announced, with share price, gross proceeds, timing, and other
terms also anticipated to be announced in January. Mr. Duggan, who
is the beneficial shareholder of approximately 71% of our
outstanding common stock prior to this rights offering in addition
to his executive leadership responsibilities, has indicated that he
intends to participate in the rights offering and subscribe for the
full amount of his basic subscription rights, but has not made any
formal binding commitment to do so.
The Company intends to register the rights
offering with the Securities and Exchange Commission (the “SEC”) by
filing a prospectus supplement to the Company’s effective shelf
registration statement on Form S-3. When available, a copy of the
prospectus supplement may be obtained at the website maintained by
the SEC at www.sec.gov.
This press release does not constitute an offer
to sell or the solicitation of an offer to buy these securities,
nor will there be any sale of these securities in any state or
other jurisdiction in which such offer, solicitation, or sale would
be unlawful prior to registration or qualification under the
securities laws of any such state or jurisdiction. The rights
offering will be made pursuant to the Company’s shelf registration
statement on Form S-3, which became effective on October 15, 2020,
and a prospectus supplement containing the detailed terms of the
rights offering to be filed with the SEC. Any offer will be made
only by means of a prospectus forming part of the registration
statement.
About the Ri-CoDIFy Study
The Ri-CoDIFy Phase III trial, combining
Ri-CoDIFy 1 (NCT: 03595553) and Ri-CoDIFy 2 (NCT: 03595566), is a
multi-center, international, double-blinded active-controlled
randomized clinical trial comparing ridinilazole, an investigative
drug, against vancomycin that randomized 759 patients with C. diff.
infection. Patients were randomized 1:1 to receive either
ridinilazole or vancomycin. Ridinilazole was administered twice
daily for ten days; vancomycin was administered four times daily
for ten days. Patients receiving ridinilazole were provided with
two placebo pills per day to maintain consistency of administration
between the two arms. For inclusion within the study, each patient
was required to have a positive C. difficile free toxin test and
require antimicrobial treatment for CDI.
The Ri-CoDIFy Phase III study was funded in part
with federal funds from the Biomedical Advanced Research and
Development Authority (BARDA), part of the Office of the Assistant
Secretary for Preparedness and Response at the U.S. Department of
Health and Human Services, under contract number
HHSO100201700014C.
About C. difficile Infection
Clostridioides difficile, or C. difficile,
infection (CDI) is a bacterial infection of the colon that produces
toxins causing inflammation of the colon, severe watery diarrhea,
painful abdominal cramping, nausea, fever, and dehydration.
CDI can also result in more serious disease complications,
including bowel perforation, sepsis, and death. CDI is a
contagious infectious disease that represents a serious healthcare
issue in hospitals, long-term care facilities, and the wider
community. Summit estimates that there are approximately
500,000 cases of CDI each year across the United States with acute
care costs exceeding $5.4 billion in the US based on a
meta-analysis published in the Journal of Global Health, June 2019.
CDI is considered an urgent threat by the United States Centers for
Disease Control and Prevention (CDC).
About Summit Therapeutics
The overriding objective of Summit Therapeutics
is to create value for patients, hospital caregivers, and
community-based healthcare providers, as well as healthcare payers
around the world. We seek to create value by developing drugs with
high therapeutic efficacy - curing the cause or effect of the
patient's condition with minimal or zero disease recurrence or
antimicrobial resistance, for the longest extent possible - and
minimizing the trauma caused to the patient and healthcare
ecosystem by minimizing serious side effects, disease recurrence,
and inaccessibility to our treatments as a result of financial or
other barriers. Summit Therapeutics, empowered by its Discuva
Platform, the Company’s innovative antibiotic discovery engine, and
supported by BARDA and CARB-X funding, intends to be the leader in
patient-friendly and paradigm-shifting treatments for infectious
diseases and other significant unmet medical needs while being an
ally to physicians. Our new mechanism pipeline product
candidates are designed with the goal to become the
patient-friendly, new-era standard of care, by working in harmony
with the human microbiome to treat prospective patients suffering
from infectious diseases, initially focusing on Clostridioides
difficile infection (CDI). Currently, Summit’s lead product
candidate, ridinilazole, is a novel, first-in-class drug engaged in
a global Phase III trial program versus vancomycin, for use as
first-line therapy for the treatment of initial and recurrent
Clostridioides difficile infection, and to show superiority in
sustained clinical response. Commercialization of
ridinilazole is subject to regulatory approvals. SMT-738, the
second candidate within Summit’s portfolio, is currently in the
IND-enabling phase for the treatment of multidrug resistant
infections, specifically those caused by carbapenem-resistant
Enterobacteriaceae (CRE).
For more information, please visit
https://www.summittxinc.com and follow us on Twitter
@summitplc. For more information on the Company’s Discuva
Platform, please visit
https://www.summittxinc.com/our-science/discuva-platform.
Contact Summit Investor Relations:
Dave GancarzHead of Stakeholder Relations &
Corporate Strategydavid.gancarz@summitplc.com
General Inquiries:
investors@summitplc.com
Summit Forward-looking Statements
Any statements in this press release about the
Company’s future expectations, plans and prospects, including but
not limited to, statements about the clinical and preclinical
development of the Company’s product candidates, the therapeutic
potential of the Company’s product candidates, the potential
commercialization of the Company’s product candidates, the timing
of initiation, completion and availability of data from clinical
trials, the potential submission of applications for marketing
approvals, the impact of the COVID-19 pandemic on the Company’s
operations and clinical trials and other statements containing the
words "anticipate," "believe," "continue," "could," "estimate,"
"expect," "intend," "may," "plan," "potential," "predict,"
"project," "should," "target," "would," and similar expressions,
constitute forward-looking statements within the meaning of The
Private Securities Litigation Reform Act of 1995. Actual
results may differ materially from those indicated by such
forward-looking statements as a result of various important
factors, including: the uncertainties inherent in the
initiation of future clinical trials, availability and timing of
data from ongoing and future clinical trials and the results of
such trials, global public health crises, including the coronavirus
COVID-19 outbreak, that may affect timing and status of our
clinical trials and operations, whether preliminary results from a
clinical trial will be predictive of the final results of that
trial or whether results of early clinical trials or preclinical
studies will be indicative of the results of later clinical trials,
expectations for regulatory approvals, laws and regulations
affecting government contracts and funding awards, availability of
funding sufficient for the Company’s foreseeable and unforeseeable
operating expenses and capital expenditure requirements and other
factors discussed in the "Risk Factors" section of filings that the
Company makes with the Securities and Exchange Commission.
Any change to our ongoing trials could cause delays, affect our
future expenses, and add uncertainty to our commercialization
efforts, as well as to affect the likelihood of the successful
completion of clinical development of ridinilazole.
Accordingly, readers should not place undue reliance on
forward-looking statements or information. In addition, any
forward-looking statements included in this press release represent
the Company’s views only as of the date of this release and should
not be relied upon as representing the Company’s views as of any
subsequent date. The Company specifically disclaims any
obligation to update any forward-looking statements included in
this press release.
Appendix: Glossary of Critical Terms
Contained Herein & Other Summit Press Releases
Antibiotic resistance genes – Genes known
to be involved in bacterial resistance; such genes may include for
example beta-lactamases which can inactivate various beta-lactam
antibiotics.
Bile acids – a collection of
steroid-based gut metabolites, the balance of the amount of and
types of bile acids in the gut microbiome are believed to play an
important role in the development of or prevention of an initial
and potential recurrent instance of C. difficile infection.i
Bloodstream infections – an infectious
disease defined by the presence of viable bacterial or fungal
microorganisms in the bloodstream that elicit or have elicited an
inflammatory response.ii
Carbapenem-Resistant Enterobacteriaceae
(CRE) – Enterobacteriaceae that are resistant to carbapenems, a
type of antibiotic used to treat some of the most resistant forms
of gram-negative bacteria. This resistance means that there
are fewer options available to treat infections caused by these
bacteria, as CRE do not respond to commonly used antibiotics.
In many cases, including infections such as urinary tract
infections caused by CRE germs, more complex treatments are
required. Instead of taking oral antibiotics at home, patients with
these infections might require hospitalization and intravenous (IV)
antibiotics. Occasionally CRE are resistant to all available
antibiotics. CRE are a threat to public health.iii
Clostridia – a class of bacteria that
exist within a healthy gut microbiome that likely plays a largely
crucial role in microbiome homeostasis by interacting with the
other resident microbe populations and providing specific and
essential functions to the overall microbiome. While most groups of
Clostridia have a commensal, or co-existing, relationship with the
rest of the gut microbiome, some Clostridia can be pathogenic, when
larger concentrations of the bacteria exist, such as Clostridioides
difficile bacteria.iv
Clostridioides difficile (C. difficile
or C. diff.) – a germ (bacterium) that can cause severe
diarrhea and colitis (an inflammation of the colon). C.
difficile can live naturally in the intestines (gut) of humans and
not cause any problem. Sometimes changes in the gut microbiome lead
the bacteria to grow and produce toxins from which illness can
develop.v
C. diff. Infection (CDI) – a
bacterial infection of the colon that produces toxins causing
inflammation of the colon and severe watery diarrhea, very painful
and persistent abdominal cramping, nausea, fever, and dehydration.
CDI can also result in more serious disease complications,
including bowel perforation (a tear in the gastrointestinal tract),
sepsis, and death. Most cases of C. diff. infection occur
while a person is taking antibiotics or not long after a person has
finished taking antibiotics. CDI is an insidious and
debilitating disease that necessitates patient isolation because of
its contagious nature, making it able to be passed from one person
to another either in a hospital or long-term care facility setting
or in the community.vi
DDS-04 – a series of new mechanism
antibiotics targeting Enterobacteriaceae. DDS-04 acts via
LolCDE, an essential bacterial complex responsible for the
transport of lipoproteins from the inner to outer membrane in
gram-negative bacteria. Because this complex has not been a
previous target of existing antimicrobials, bacterial resistance
does not yet exist to this targeted approach, potentially allowing
for the treatment of highly-resistant Enterobacteriaceae-caused
infections. Some of these infections, particularly in a
subset of CRE-caused infections, do not have effective treatments
through currently available antibiotics.vii
Discuva Platform – Summit Therapeutics’ proprietary
platform that enables the identification of novel antimicrobials to
expand Summit’s pipeline of investigational drugs. The
Discuva Platform focuses on identifying new antibiotics against
bacteria where increasing resistance has limited treatment via
existing antibiotics currently on the market.viii
Enterobacteriaceae – a large family of
different types of bacteria (germs) that commonly cause infections
both in healthcare settings, such as hospitals and long-term care
facilities, and in communities. Examples of germs in the
Enterobacteriaceae family include Escherichia coli (commonly known
as E. coli) and Klebsiella pneumoniae. Enterobacteriaceae are
frequent carriers of resistance genes to many of the currently
available antibiotics used to treat bacterial infections.
Because they are bacteria, Enterobacteriaceae can be passed from
person to person.ix
Escherichia coli (E. coli) – a type of
Enterobacteriaceae found in the environment, foods, and intestines
of people and animals. E. coli are a large and diverse group of
bacteria. Although most strains of E. coli are harmless, others can
make a person sick. Some kinds of E. coli can cause diarrhea, while
others cause urinary tract infections, bloodstream infections,
respiratory illness and pneumonia, and other illnesses.x
Gastrointestinal tract – a series of
hollow organs joined in a long, twisting tube from the mouth to the
anus. These organs also include the esophagus, stomach, small
intestine, and large intestine.xi
Gut microbiome – within the human
gastrointestinal tract, the gut microbiome is a collection of
microbiota, consisting of trillions of microorganisms that inhabit
the gut. The gut microbiota is considered an important
partner to human cell systems, interacting extensively with other
organs in the body to influence a wide range of functions from
digestion to immunity. The balance of the different types of
cells and microorganisms within the microbiome is considered to be
important in the microbiome's ability to properly play its role
within the human body. Disruption in the balance of
microorganisms within the gut microbiome (known as dysbiosis) is
believed to impact the gut microbiome's role in keeping a person
healthy and free of certain conditions or diseases.xii xiii
Gut microbiota – the trillions of
microorganisms, including symbiotic and pathogenic microorganisms,
that inhabit the gut. Examples of these microorganisms
include bacteria, fungi, viruses, protists, and archaea.
Gut resistome – within the human
gastrointestinal tract, the diversity and dynamics of the
antibiotic resistance genes that are harbored by the gut
microbiota. Examples of the gut resistome include genes
associated with resistance to carbapenem antibiotics.xiv
Hospital-acquired pneumonia (HAP)
– pneumonia that occurs 48 hours or more after a patient has been
admitted to a hospital and was not present and incubating at the
time of admission. Ventilator-associated pneumonia (VAP) is a
significant sub-set of HAP, often occurring in intensive care units
(ICUs) with a patient on a ventilator. Common pathogens of
HAP and VAP include Enterobacteriaceae and Pseudomonas
species. Due to the presence of the bacteria in a hospital,
these bacteria may be resistant to different antibiotics,
potentially causing the resulting infection to be more difficult to
treat.xv
Klebsiella pneumoniae – a type of
Enterobacteriaceae that can cause different types of
healthcare-associated infections, including pneumonia, bloodstream
infections, wound or surgical site infections, and meningitis.
Increasingly, Klebsiella bacteria have developed resistance to
antibiotics, most recently to the class of antibiotics known as
carbapenems. Klebsiella bacteria are normally found in the human
intestines (where they do not cause disease). In healthcare
settings, Klebsiella infections commonly occur among sick patients
who are receiving treatment for other conditions. Patients
whose care requires devices like ventilators (breathing machines)
or intravenous (vein) catheters, and patients who are receiving
long courses of certain antibiotics are most at risk for Klebsiella
infections. Healthy people typically do not develop Klebsiella
infections.xvi
Sepsis – the body’s extreme response to
an infection and a life-threatening medical emergency. Sepsis
occurs when an existing infection triggers a chain reaction
throughout a person’s body via the bloodstream. Without
timely treatment, sepsis can rapidly lead to tissue damage,
multi-organ failure, and death. Almost any type of infection
can lead to sepsis. Infections that lead to sepsis most often start
in the lung, urinary tract, skin, or gastrointestinal tract.
Sepsis is a condition and is not contagious; however, the
underlying cause of the infection (e.g., bacteria) can be spread
from person to person. Bacterial infections cause most cases
of sepsis.xvii
Shotgun metagenomic analysis – shotgun metagenomic
sequencing sequences all genomic DNA present in a sample. This
allows a more accurate taxonomic annotation of the microbiota
compared to other techniques such as 16S rRNA amplicon sequencing
as well as antibiotic resistance gene profiling and metabolic
function profiling.
Urinary tract infections (UTI) – common
infections that happen when bacteria, often from the skin or
rectum, enter the urethra, and infect the urinary tract. The
infections can affect several parts of the urinary tract, but the
most common type is a bladder infection. Kidney infections
are another type of UTI and can be more serious than bladder
infections. UTIs are usually caused by bacteria and are
treated with antibiotics. People who have had multiple UTIs
requiring multiple courses of antibiotics are at increased risk of
developing antibiotic-resistant infections that can become
increasing complex to treat.xviii
Vancomycin – an antibiotic that is used
to treat CDI
_____________________________
i Qian, X, et. al. Ridinilazole, a narrow spectrum antibiotic
for treatment of Clostridioides difficile infection, enhances
preservation of microbiota-dependent bile acids. Am J Physiol
Gasterintest Liver Physiol 319: G227-G237, 2020.
ii Viscoli C. Bloodstream Infections: The peak of the iceberg.
Virulence. 7(3):248-251, 2016.
iii United States Centers for Disease Control and
Prevention.
https://www.cdc.gov/hai/organisms/cre/index.html. Accessed
February 2021.
iv Lopetuso, L.R., et al. Commensal Clostridia: leading players
in the maintenance of gut homeostasis. Gut Pathog 5, 23, 2013.
v Virginia Department of Health.
https://www.vdh.virginia.gov/epidemiology/epidemiology-fact-sheets/clostridiodes-difficile/.
Accessed February 2021.
vi United States Centers for Disease Control and
Prevention. https://www.cdc.gov/cdiff/what-is.html.
Accessed February 2021.
vii Summit Therapeutics, Inc.
https://www.summittxinc.com/our-programmes/enterobacteriaceae/.
Accessed February 2021.
viii Summit Therapeutics, Inc.
https://www.summittxinc.com/our-science/discuva-platform/.
Accessed February 2021.
ix United States Centers for Disease Control and
Prevention.
https://www.cdc.gov/hai/organisms/ESBL.html. Accessed
February 2021.
x United States Centers for Disease Control and
Prevention. https://www.cdc.gov/ecoli/index.html.
Accessed February 2021.
xi US National Institute of Health, National Institute of
Diabetes and Digestive and Kidney Diseases.
https://www.niddk.nih.gov/health-information/digestive-diseases/digestive-system-how-it-works.
Accessed February 2021.
xii Cani PD. Human gut microbiome: hopes, threats and
promises. British Medical Journal (BMJ) Gut
67:1716-1725, 2018.
xiii Qian, X, et. al. Ridinilazole, a narrow spectrum antibiotic
for treatment of Clostridioides difficile infection, enhances
preservation of microbiota-dependent bile acids. Am J Physiol
Gasterintest Liver Physiol 319: G227-G237, 2020.
xiv van Schaik, W. The human gut resistome. Philos Trans R Soc
Lond B Biol Sci. 370(1670):20140087, 2015.
xv Shebl E, Gulick PG. Nosocomial Pneumonia. StatPearls.
Updated 2020 Jul 21.
xvi United States Centers for Disease Control and
Prevention.
https://www.cdc.gov/hai/organisms/klebsiella/klebsiella.html.
Accessed February 2021.
xvii United States Centers for Disease Control and
Prevention. https://www.cdc.gov/sepsis/index.html.
Accessed February 2021.
xviii United States Centers for Disease Control and
Prevention.
https://www.cdc.gov/antibiotic-use/community/for-patients/common-illnesses/uti.html.
Accessed February 2021.
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