- Findings suggest that both misdiagnosis of C.
difficile recurrent infection in some patients, and dosing that may
have been suboptimal in certain patients, contributed to the
previously reported SER-109 Phase 2 study outcome -
- FDA discussions are ongoing regarding a new,
redesigned clinical study for SER-109 -
- Conference call at 8 a.m. ET today -
Seres Therapeutics Inc., (NASDAQ:MCRB), a leading microbiome
therapeutics platform company, today reported that it has completed
in-depth analyses of the previously reported SER-109 Phase 2,
eight-week clinical study data in patients with multiply recurrent
Clostridium difficile infection. The company also reported the
full, 24-week SER-109 Phase 2 study results and open label
extension study data.
“Since obtaining the unexpected SER-109 clinical study results
last summer, we have undertaken a comprehensive assessment of the
program to understand the reasons for the results,” said Roger J.
Pomerantz, M.D., President, CEO and Chairman of Seres. “We have now
identified specific factors that we believe contributed to the
Phase 2 results, including issues related to both the accurate
diagnosis of C. difficile recurrent infection, and potential
suboptimal dosing of certain subjects in the trial. The SER-109
analyses were recently shared with the FDA, and we are actively
discussing the design of a new clinical trial for SER-109. There
remains a compelling need for an effective, safe, and convenient
FDA approved therapy for patients with recurrent C. difficile
infection, and this investigation provides insights to guide
further clinical development of SER-109.”
Investigation Summary: C. difficile Diagnosis
Analysis was conducted to evaluate both the role of C. difficile
diagnostic testing in defining the correct SER-109 Phase 2 study
entry population, and in the proper diagnosis of C. difficile
recurrences during the study. In the Phase 2 study, 81% of study
subjects (72 of 89 subjects) were enrolled based on polymerase
chain reaction (PCR) based testing for C. difficile, as well as
clinical evaluation. An important and increasingly well-appreciated
limitation of PCR testing is that while a positive result indicates
that C. difficile cytotoxin genes are present, a positive PCR test
does not necessarily indicate that the organism is viable and
producing disease causing cytotoxins, nor that C. difficile is the
source of clinical symptoms.1
Two separate observations were made pertaining to the effects of
discordant results from PCR and cytotoxin assay on the SER-109
trial. The qualifying stool samples evaluated for Phase 2 study
entry were not available for retesting for cytotoxin, however, the
company was able to retest the samples associated with patients
entering the open label extension trial for the presence of the C.
difficile cytotoxin and determined that only 44% of samples (15 of
31 subjects) that tested positive by PCR testing also tested
positive based on C. difficile cytotoxin assay. These results
suggest that a substantial proportion of patients who entered the
SER-109 Phase 2 study may have been C. difficile carriers and,
therefore, C. difficile infection may not have been the source of
the clinical symptoms. In addition, data from this analysis suggest
that the use of PCR to measure C. difficile may have overestimated
study recurrences in both treatment arms of the Phase 2 trial,
further complicating interpretation of study results. This was
shown by reanalysis of samples with cytotoxin assay, from patients
diagnosed as recurrent in the Phase 2 study. In this retesting,
between one quarter and one half of presumed study recurrences may
not have been true C. difficile infections leading to
pathology.
From the analyses described above, the company believes that
misdiagnoses may have occurred both in some patients entering the
SER-109 trial, as well as for recurrences diagnosed during the
trial.
SER-109 Pharmacokinetics, Pharmacodynamics, &
Dosing
The company performed an in-depth analysis to examine SER-109
biological activity in the Phase 2 trial, as measured by microbiome
changes in patients and downstream biological effects in the
gastrointestinal tract. Results demonstrated a statistically
significant increase in the richness of commensal spore-forming
bacterial species in patients treated with SER-109, as compared to
those receiving placebo. These data demonstrate that SER-109
successfully engrafted and was biologically active in the Phase 2
study. In addition, among those patients with an increased
prevalence of specific SER-109 associated bacterial species, a
decreased rate of high confidence recurrences (i.e., recurrences
confirmed by C. difficile cytotoxin assay) was demonstrated.
The company also assessed whether the SER-109 dose impacted the
degree of microbiome changes observed. All Phase 2 patients
received 1 X 108 bacterial spores, whereas patients in the prior
SER-109 Phase 1b open label study received doses ranging
approximately 700-fold, from 3 X 107 to 2 X 1010 spores. The
company also performed high-resolution whole metagenomics
sequencing of stool samples collected from patients in both the
SER-109 Phase 1b, as well as the Phase 2 trial as part of this
analysis. The analysis indicated that subjects in the open-label
Phase 1b study who received a higher dose achieved a significantly
greater increase in diversity of commensal spore-former bacteria by
1 week post-treatment, as compared to both Phase 1b and Phase 2
subjects treated with lower doses. These results suggest that the
dose used in the SER-109 Phase 2 study may have been suboptimal in
certain patients, and may have resulted in a less robust drug
effect, contributing to decreased efficacy in Phase 2, as compared
to the Phase 1b study.
Much of the SER-109 Phase 2 microbiome-related learnings are
based on advancements in the computational analytics and higher
resolution whole metagenomics sequencing techniques that Seres is
pioneering, and several of these methods were developed after the
SER-109 Phase 2 study was designed. Insights obtained from this
work may also benefit Seres’ broad preclinical and clinical
microbiome development pipeline.
Analysis of SER-109 Phase 2 Study Clinical Drug
Product
The company also conducted a thorough and detailed investigation
of the potential impacts of manufacturing and formulation changes
implemented in the Phase 2 study. No issues regarding product
quality or formulation were identified which would have impacted
the Phase 2 study results.
Summary of SER-109 24-Week and Open Label Extension Study
Results
The full, 24-week Phase 2 study results continue to demonstrate
that SER-109 was generally well tolerated. The most common adverse
events associated with SER-109 included diarrhea, abdominal pain
and flatulence. The Phase 2 study population represented older
individuals, many in poor health, and a high rate of serious
adverse events (SAEs) was reported in both study arms. A
numerically higher rate of SAEs was observed in the SER-109 arm
(15.0% versus 10.3% for placebo), however there was no detectable
pattern in the SAEs observed, and none of these were considered to
be SER-109 drug-related by the study investigators.
As expected with recurrent C. difficile infection, relatively
few additional recurrences occurred beyond 8 weeks, and the 24-week
data provides relatively little new information regarding efficacy.
Based on 24-week data, five further patients recurred in the
SER-109 arm, but three of the five recurrences (60%) were in
patients who terminated the trial early, resulting in an imputed
recurrence. In the placebo arm, one patient also terminated the
trial early, resulting in an imputed recurrence. Early
terminations, and loss of patients to follow-up, are common in the
long safety follow-up portions of clinical trials.
Phase 2 study subjects who experienced a C. difficile recurrence
had the option to enroll in an open label extension study, where
they were treated with SER-109 and were followed for an additional
24 weeks. In total, 34 patients entered the open label extension
study and 11 patients recurred during the initial 8-week study
period, a 32% recurrence rate.
Conference Call Information
Seres’ management will host a conference call today, January 31,
2017, at 8:00 a.m. ET. To access the conference call, please dial
844-277-9450 (domestic) or 336-525-7139 (international) and
reference the conference ID number 62194071. To join the live
webcast and access slides to accompany the conference call, please
visit the “Investors and Media” section of the Seres website
at www.serestherapeutics.com. A webcast replay and the
accompanying slides will be available on the Seres website
beginning approximately two hours after the event and will be
archived for 30 days.
About Seres Therapeutics
Seres Therapeutics, Inc. is a leading microbiome therapeutics
platform company developing a novel class of biological drugs that
are designed to treat disease by restoring the function of a
dysbiotic microbiome, where the natural state of bacterial
diversity and function is imbalanced. The Phase 2 study of Seres’
program SER-109 has been completed in multiply recurrent C.
difficile infection. Seres’ second clinical candidate, SER-287, is
being evaluated in a Phase 1b study in patients with
mild-to-moderate ulcerative colitis (UC). Seres is also developing
SER-262, the first ever synthetic microbiome therapeutic candidate,
in a Phase 1b study in patients with primary C. difficile
infection. For more information, please visit
www.serestherapeutics.com. Follow us on Twitter @SeresTx.
Forward-looking Statements
This press release contains forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of
1995. All statements contained in this press release that do not
relate to matters of historical fact should be considered
forward-looking statements, including without limitation statements
regarding our SER-109 development plans, the timing, design, and
potential results of a new clinical study for SER-109, the
potential for a redesigned trial to provide different results, and
the impact any analysis may have on clinical outcomes.
These forward-looking statements are based on management’s
current expectations. These statements are neither promises nor
guarantees, but involve known and unknown risks, uncertainties and
other important factors that may cause our actual results,
performance or achievements to be materially different from any
future results, performance or achievements expressed or implied by
the forward-looking statements, including, but not limited to, the
following: we have incurred significant losses, are not currently
profitable and may never become profitable; our need for additional
funding, which may not be available; our limited operating history;
the unpredictable nature of our early stage development efforts for
marketable drugs; the unproven approach to therapeutic intervention
of our microbiome therapeutics; the lengthy and expensive process
of clinical drug development, which has an uncertain outcome;
potential delays in enrollment of patients which could affect the
receipt of necessary regulatory approvals; potential delays in
regulatory approval, which would impact the ability to
commercialize our product candidates and affect our ability to
generate revenue; any fast track or Breakthrough Therapy
designation may not lead to faster development, regulatory approval
or marketing approval; our possible inability to receive orphan
drug designation should we choose to seek it; our reliance on third
parties to conduct our clinical trials and the potential for those
third parties to not perform satisfactorily; our reliance on third
parties to manufacture our product candidates, which may delay,
prevent or impair our development and commercialization efforts;
our lack of experience in manufacturing our product candidates; the
potential failure of our product candidates to be accepted on the
market by the medical community; our lack of experience selling,
marketing and distributing products and our lack of internal
capability to do so; failure to compete successfully against other
drug companies; potential competition from biosimilars; failure to
obtain marketing approval internationally; post-marketing
restrictions or withdrawal from the market; anti-kickback, fraud,
abuse, and other healthcare laws and regulations exposing us to
potential criminal sanctions; recently enacted or future
legislation; compliance with environmental, health, and safety laws
and regulations; protection of our proprietary technology;
protection of the confidentiality of our trade secrets; changes in
United States patent law; potential lawsuits for infringement of
third-party intellectual property; our patents being found invalid
or unenforceable; compliance with patent regulations; claims
challenging the inventorship or ownership of our patents and other
intellectual property; claims asserting that we or our employees
misappropriated a third-party’s intellectual property or otherwise
claiming ownership of what we regard as our intellectual property;
adequate protection of our trademarks; ability to attract and
retain key executives; managing our growth could result in
difficulties; risks associated with international operations;
potential system failures; the price of our common stock may
fluctuate substantially; our executive officers, directors, and
principal stockholders have the ability to control all matters
submitted to the stockholders; a significant portion of our total
outstanding shares are eligible to be sold into the market;
unfavorable or lacking analyst research or reports; and we are
currently subject to securities class action litigation. These and
other important factors discussed under the caption “Risk Factors”
in our Quarterly Report on Form 10-Q filed with the Securities and
Exchange Commission, or SEC, on November 10, 2016 and our other
reports filed with the SEC, could cause actual results to differ
materially from those indicated by the forward-looking statements
made in this press release. Any such forward-looking statements
represent management’s estimates as of the date of this press
release. While we may elect to update such forward-looking
statements at some point in the future, we disclaim any obligation
to do so, even if subsequent events cause our views to change.
These forward-looking statements should not be relied upon as
representing our views as of any date subsequent to the date of
this press release.
Reference:
1. Polage, C. R., et al. (2015). Overdiagnosis of Clostridium
difficile Infection in the Molecular Test Era. JAMA Internal
Medicine, 175(11), 1792–1801.
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version on businesswire.com: http://www.businesswire.com/news/home/20170131005440/en/
IR or PR Contact:Seres
TherapeuticsCarlo Tanzi, Ph.D., 617-203-3467Head of Investor
Relations and Corporate
CommunicationsCtanzi@serestherapeutics.com
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