HONG KONG, Feb 11, 2020 - (ACN Newswire) - Aptorum Group
Limited (NASDAQ: APM) ("Aptorum Group"), a biopharmaceutical
company focused on the development of novel therapeutics to address
global unmet medical needs, announces further positive data from
its current investigational new drug (IND)-enabling studies for
ALS-4, a small drug molecule candidate indicated for the treatment
of infections caused by Staphylococcus aureus (or "S. aureus"),
including methicillin-resistant Staphylococcus aureus (MRSA, one of
the "super-bugs"), based on a novel anti-virulence non-bactericidal
approach. Subject to completion of the current studies, Aptorum
Group targets to submit IND for ALS-4 in second half of 2020 and
commence a phase 1 trial in North America.
ALS-4 is a small molecule which inhibits dehydrosqualene desaturase
of S. aureus (incl. MRSA), an enzyme that is critically involved in
the biosynthesis of staphyloxanthin, a commonly visible "golden
pigment" covering the bacteria. Staphyloxanthin is believed to be
primarily responsible for the bacteria's defense mechanism against
the attack from reactive oxygen species (ROS) deployed by
phagocytic cells and neutrophils.1
Through inhibiting the production of staphyloxanthin, we believe
that ALS-4 renders S. aureus highly susceptible to the host's
immune defense (see below for in vivo data and experimental
outline). This novel mechanism is significantly different from the
bactericidal approach found in currently marketed antibiotics used
to treat S. aureus, which are experiencing increasing drug
resistance issues2. Specifically, MRSA infections in humans
typically exhibit high rates of morbidity and mortality and can
cause metastatic or complicated infections such as infective
endocarditis or sepsis, with relapse and hospital readmission after
S. aureus bacteremia common and costly3.
Based on our testing in a rat bacteremia survival model, a lethal
(109 CFU) dose of MRSA (USA300-LAC) was introduced through the tail
vein. ALS-4 was administered orally at 10mg/kg per animal 30
minutes after the infection for twice a day thereafter (N=9). A
control untreated group was given a sterile vehicle solution (N=9).
Survival was monitored for 7 days. 0 out of 9 animals (0%) in the
control untreated group survived past day 4, in contrast, 5 out of
9 animals (56%) treated with ALS-4 survived past day 7, which is
determined to be statistically significant compared with the
control group (p=0.013).
In addition we conducted a study in a non-lethal rat bacteremia
infection model. The animals were challenged with a non-lethal (107
CFU) dose of MRSA (USA300-LAC) through the tail vein. In order to
simulate a more realistic clinical scenario, treatment was
introduced 14-days after the model induction, where ALS-4 was
administered orally twice a day at 10mg/kg per animal (N=8). A
control untreated group was given a sterile vehicle solution (N=8).
After 7 days of ALS-4 treatment, the kidneys were collected and the
bacterial titers were measured. Remarkably, ALS-4 reduced the organ
bacterial load by 99.5%, from 63,096 plus-minus 18 CFU/g in the
control group to 316 plus-minus 49 CFU/g in the ALS-4 treated
group, which is determined to be statistically significant
(p=0.01).
Last but not least, ALS-4 has successfully inhibited
staphyloxanthin production in 11 strains of S. aureus. These
include 5 strains of Methicillin-sensitive S. aureus (MSSA):
SH1000, HG003, USA300-JE2, Newman, and ATCC29213 with an IC50 of
70.5 plus-minus 6nM, 54.4 plus-minus 4nM, 37.7 plus-minus 4nM, 23.7
plus-minus 1nM, and 30.02 plus-minus 5nM respectively; 5 strains of
Methicillin-resistant S. aureus (MRSA): USA300, USA300-3,
USA300-LAC, ST239III, and COL, with an IC50 of 30.8 plus-minus 5nM,
42.8 plus-minus 6nM, 43.6 plus-minus 5nM, 16.3 plus-minus 8nM, and
0.9 plus-minus 1nM respectively; and 1 strain of
vancomycin-intermediate S. aureus (VISA), Mu3 with an IC50 of 2.6
plus-minus 1nM.
Based on our testing, we believe ALS-4 increases the susceptibility
of S. aureus including MRSA to oxidative damage by inhibiting
production of staphyloxanthin,. In a hydrogen peroxide killing
assay, after the addition of 1.5% H2O2, ALS-4 demonstrated an
additional reduction of bacterial CFU by 93.5%, from 61,600
plus-minus 6437 CFU/ml in the untreated group to 4,000 plus-minus
230 CFU/ml in the ALS-4 treated group, which is determined to be
statistically significant (p=0.003).
With respect to the study carried out to investigate the capability
of ALS-4 to induce antibiotic resistance in S. aureus after
prolonged exposure, USA300-LAC was cultured in 3 different
conditions for 10 days. For the treatment group 1 micromolar of
ALS-4 was added; for the positive control group 0.12 microgram/mL
of clindamycin and 16 microgram/mL of erythromycin was added from
day 1 to day 4, after which clindamycin was withdrawn. For the
negative control group, dimethyl sulfoxide (DMSO) was added. On day
11, the bacteria were harvested and then cultured for 16 hr for the
determination of the MIC of clindamycin. The prolonged exposure to
ALS-4 or DMSO does not affect the MIC value of clindamycin (0.12
microgram/mL); while the prolonged exposure to clindamycin +
erythromycin triggers antibiotics resistance rapidly with the MIC
increased from 0.12 microgram/mL to greater than 5
microgram/mL.
Based on our study we believe ALS-4 is unlikely to be prone to drug
resistance since it is non-bactericidal. Growth inhibition studies
were performed on different strains of S. aureus and other
bacteria, including 3 strains of MSSA (ATCC29212, SH1000 and
HG003), 1 strain of MRSA (USA300), 1 strain of VISA (ATCC700698
Mu3), as well as 6 different bacteria (E. coli, A. baumannii, S.
cerevisiae, B. subtilis, E. faecalis, and K. pneumoniae). In all of
the tested strains of bacteria, no growth inhibition effect was
observed at the highest tested concentration of ALS-4 (250uM).
Therefore ALS-4 does not appear to have any direct bacteriostatic
or bactericidal activity against many species of bacteria, thus
greatly reducing the selection pressure for drug resistance to
emerge.
We also assessed the potential impact on the efficacy of
vancomycin, the mainstay of treatment for infections caused by
MRSA, when used in conjunction with ALS-4. 8 different strains of
S. aureus (USA300 FPR3757, USA300-3, USA300-LAC, USA300-JE2, Mu3,
HG003, ATCC29213 and clinical isolate ST239III) were used in this
study. Our data showed that no effect on the MIC of vancomycin was
observed when the concentration of ALS-4 was below 25 microgram/mL.
Therefore, we believe that ALS-4 does not interfere with the action
of vancomycin.
In addition, compared with the current mainstay of treatment for S.
aureus infections such as vancomycin or daptomycin which is
typically administered in an IV injectable form (with the exception
of an oral form vancomycin specifically for treatment of
Clostridium difficile diarrhea and staphylococcal enterocolitis
only), an oral active agent enables wider market penetration
targeting both outpatient as well as potential prophylactic
markets.
GLP Toxicity Data
ALS-4 is currently undergoing IND-enabling studies and has so far
shown positive safety profiles. As elucidated in our previous press
release dated September 9, 2019, ALS-4 did not show any
mutagenicity in the in vitro Ames tests. Our currently generated in
vitro micronucleus test results also showed that ALS-4 is not
genotoxic, indicating the non-mutagenic nature of the drug.
Furthermore, the results of the in vitro hERG assay study predicts
a low risk of ALS-4 causing cardiac QT prolongation.
For further general presentation, please visit:
http://ir.aptorumgroup.com/static-files/bcf77574-7bd6-4b9d-8110-d53837238f16
For further technical presentation, please visit:
http://ir.aptorumgroup.com/static-files/66346f79-7a03-474a-89be-0eaafaa00d9d
About Aptorum Group Limited
Aptorum Group Limited (Nasdaq: APM) is a pharmaceutical company
dedicated to developing and commercializing novel therapeutics to
tackle unmet medical needs. Aptorum Group is pursuing therapeutic
projects in orphan diseases, infectious diseases, metabolic
diseases and other disease areas.
For more information about Aptorum Group, please visit
www.aptorumgroup.com.
Disclaimer and Forward-Looking Statements
This press release includes statements concerning Aptorum Group
Limited and its future expectations, plans and prospects that
constitute "forward-looking statements" within the meaning of the
Private Securities Litigation Reform Act of 1995. For this purpose,
any statements contained herein that are not statements of
historical fact may be deemed to be forward-looking statements. In
some cases, you can identify forward-looking statements by terms
such as "may," "should," "expects," "plans," "anticipates,"
"could," "intends," "target," "projects," "contemplates,"
"believes," "estimates," "predicts," "potential," or "continue," or
the negative of these terms or other similar expressions. Aptorum
Group has based these forward-looking statements, which include
statements regarding projected timelines for application
submissions and trials, largely on its current expectations and
projections about future events and trends that it believes may
affect its business, financial condition and results of operations.
These forward-looking statements speak only as of the date of this
press release and are subject to a number of risks, uncertainties
and assumptions including, without limitation, risks related to its
announced management and organizational changes, the continued
service and availability of key personnel, its ability to expand
its product assortments by offering additional products for
additional consumer segments, development results, the company's
anticipated growth strategies, anticipated trends and challenges in
its business, and its expectations regarding, and the stability of,
its supply chain, and the risks more fully described in Aptorum
Group's Form 20-F and other filings that Aptorum Group may make
with the SEC in the future. As a result, the projections included
in such forward-looking statements are subject to change. Aptorum
Group assumes no obligation to update any forward-looking
statements contained in this press release as a result of new
information, future events or otherwise.
1 mBio 2017 8(5): e01224-17
2 Microbiol Spectr. 2019 Mar;7(2)
3 Clin Infect Dis. 2019 Nov 27;69(12):2112-2118
Contacts
Investors:
Tel: +852 2117 6611
Email: investor.relations@aptorumgroup.com
Media:
Tel: + 852 2117 6611
Email: info@aptorumgroup.com
Source: Aptorum Group Limited
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