Category Archives: Clinical Trials

Seres Therapeutics SER-109 Met Phase 3 Primary Endpoint, Positive Results From Pivotal Phase 3 ECOSPOR III Study Evaluating Investigational Oral Microbiome Therapeutic For Recurrent C. difficile Infection

– SER-109 met Phase 3 primary endpoint, showing a highly statistically significant 30.2% absolute reduction in the rate of C. difficile infection recurrence compared to placebo 

– SER-109 was well tolerated, with a safety profile comparable to placebo 

– Efficacy results substantially exceeded FDA regulatory guidance to support BLA filing as a single pivotal trial; Company to meet with the agency to discuss filing for product approval as soon as possible 

 Positive SER-109 Phase 3 data provide validation for Seres’ microbiome therapeutics platform and further development of its pipeline of product candidates 

 Seres Therapeutics, Inc. reported on August 10, 2020, positive topline results from the pivotal Phase 3 ECOSPOR III study evaluating its investigational oral microbiome therapeutic SER-109 for recurrent C. difficile infection (CDI). The study showed that SER-109 administration resulted in a highly statistically significant absolute decrease of 30.2% in the proportion of patients who experienced a recurrence in CDI within eight weeks of administration versus placebo, the study’s primary endpoint. 11.1% of patients administered SER-109 experienced a CDI recurrence, versus 41.3% of placebo patients. The study results were equally compelling when characterized by the alternative metric of sustained clinical response, where 88.9% of patients in the SER-109 arm achieved this objective.

The study’s efficacy results exceeded the statistical threshold previously provided in consultation with the U.S. Food and Drug Administration (FDA) that could allow this single clinical study to fulfill efficacy requirements for a Biologics License Application (BLA). The SER-109 safety results were favorable, with an adverse event profile comparable to placebo.

“We are extremely pleased with these highly clinically meaningful SER-109 Phase 3 study results, greatly exceeding the statistical threshold provided by the FDA. Based on our prior discussions with the FDA, we believe this trial should provide the efficacy basis for submitting an application for product approval. We look forward to meeting with the FDA as soon as possible to discuss the regulatory path forward with the goal of bringing SER-109 to patients as a first-in-class microbiome therapeutic,” said Eric D. Shaff, President and Chief Executive Officer of Seres. “Our results represent the first-ever positive pivotal clinical study results for a targeted microbiome drug candidate. We believe these Phase 3 data provide strong validation for our underlying microbiome therapeutics platform, which has been the scientific basis for the Company, as well as persuasive clinical evidence supporting our other active pipeline programs.”

“We would like to thank all those who participated in this landmark study. Based on these highly positive SER-109 ECOSPOR III results, we believe that this novel microbiome therapeutic candidate could potentially provide a much-needed effective oral treatment option for the approximately 170,000 patients in the U.S. that suffer from recurrent CDI annually,” said Lisa von Moltke, M.D., FCP, Chief Medical Officer of Seres. “Seres applied a data-driven and scientifically rigorous approach to develop SER-109. The proprietary scientific learnings we have obtained continue to drive our overall R&D efforts and the advancement of our other ongoing microbiome therapeutic programs.”

“Recurrent C. difficile infection is a serious disease that devastates patients’ quality of life, and in many severe cases may result in a patient’s death. Today’s treatment options have important shortcomings related to efficacy, safety and route of administration, and novel approaches that target the root causes of the disease are urgently needed. The SER-109 Phase 3 results are highly impressive and represent an exceptional advance in the fight against this disease. I believe that SER-109 has the potential to fundamentally transform the treatment of recurrent C. difficile infection,” said Mark Wilcox, M.D., Professor of Medical Microbiology, University of Leeds.

ECOSPOR III Study Design and Results

The ECOSPOR III study (ClinicalTrials.gov identifier: NCT03183128) is a multicenter, randomized, placebo-controlled study that enrolled 182 patients with multiply recurrent CDI. Patients were randomized 1:1 to receive either SER-109 or placebo, after standard of care antibiotic treatment. SER-109, or placebo, was administered orally for three consecutive days. All patients were required to have a positive C. difficile toxin diagnostic test both at study entry and in the case of suspected recurrence to ensure the selection of individuals with active disease and to confirm the accuracy of the primary endpoint.

The primary efficacy endpoint of ECOSPOR III was the proportion of patients with recurrent CDI at up to eight weeks following administration of SER-109 or placebo. As a secondary endpoint, patients are evaluated for CDI recurrence through 24 weeks post-treatment, and the Company plans to present those results at a future date.

SER-109 met the study’s primary endpoint with a significantly lower recurrence rate of 11.1% in SER-109 patients versus 41.3% in placebo patients at eight weeks; p<0.001 tested at the one-sided 0.25 level. Patients administered SER-109 experienced a 30.2% lower rate of recurrence, on an absolute basis, compared to placebo. The SER-109 treatment arm relative risk was 0.27 (95% CI=0.15 to 0.51) versus placebo. The ECOSPOR III recurrence rates translate into a sustained clinical response rate of 88.9% versus 58.7% with SER-109 and placebo, respectively. The SER-109 Number Needed to Treat (NNT) was approximately 3.

In prior discussions, the FDA communicated that demonstration of a statistically very persuasive efficacy finding in the ECOSPOR III primary endpoint, defined as demonstrating a 95% upper confidence level of relative risk lower than 0.833, could support a BLA submission on the basis of this single study. The results of ECOSPOR III demonstrated a SER-109 relative risk of 0.27 (95% CI=0.15 to 0.51) compared to placebo. As a result, Seres believes that this study should support the efficacy basis for BLA submission. SER-109 has obtained FDA Breakthrough Therapy and Orphan Drug designations.

SER-109 was well tolerated, with no treatment-related serious adverse events (SAEs) observed in the active arm, and an adverse event profile similar to placebo. The overall incidence of patients who experienced AEs during the eight-week study period was similar between SER-109 and placebo arms. The most commonly observed treatment-related AEs were flatulence, abdominal distention and abdominal pain, which were generally mild to moderate in nature, and these were observed at a similar rate in both the SER-109 and placebo arms.

A SER-109 open-label study is ongoing ( clinicaltrials.gov identifier: NCT03183141) at selected clinical sites that participated in the ECOSPOR III study, and the Company may initiate the program at additional clinical sites. The FDA has previously indicated that SER-109 administration to at least 300 patients, consistent with standard FDA guidance, would be required to support BLA submission. The ongoing SER-109 open-label study is continuing to contribute to the SER-109 safety database.

The Company plans to immediately request a Breakthrough Therapy designation meeting with the FDA to discuss the requirements to submit a BLA seeking regulatory approval of SER-109. Given the favorable efficacy and safety results seen in ECOSPOR III, the safety results observed in prior SER-109 clinical studies, and the critical unmet need for a therapeutic option for recurrent CDI patients, the Company plans to discuss with the FDA the safety data requirements for a BLA filing.

Seres continues to advance its commercial readiness for the potential launch of SER-109. In June 2020, Seres appointed Terri Young, Ph.D., R.Ph., as Chief Commercial and Strategy Officer. The Company has been conducting activities to support successful future potential commercialization. Seres believes that the commercial opportunity for SER-109 could be substantial, given the dire need for an effective, safe, oral therapeutic, and the strength of the SER-109 Phase 3 study results.

Conference Call Information

Seres’ management will host a conference call today, August 10, 2020, at 8:30 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 3216859. Accompanying slides will be posted on the Seres website ahead of the conference call. To join the live webcast, and to view the accompanying slides, please visit the “Investors and Media” section of the Seres website at www.serestherapeutics.com.

A webcast replay will be available on the Seres website beginning approximately two hours after the event and will be archived for approximately 21 days.

About SER-109

SER-109 is an investigational, oral, biologically-derived microbiome therapeutic that is designed to reduce recurrence of C. difficile infection (CDI), enabling patients to achieve a sustained clinical response by breaking the vicious cycle of CDI recurrence and restoring the diversity of the gastrointestinal microbiome. SER-109 is a consortium of purified bacterial spores of multiple Firmicute species, manufactured by fractionating targeted bacteria from the stool of healthy human donors with further steps to inactivate potential pathogens. The FDA has granted SER-109 Breakthrough Therapy designation and Orphan Drug designation for the treatment of CDI.

SER-109 is fundamentally distinct from fecal microbiota transplantation (FMT). SER-109 is comprised of a highly-purified consortia of spore-based commensal bacteria and designed to be manufactured in accordance with Good Manufacturing Practice conditions using stringent standards to ensure product quality and consistency. To support product safety, Seres utilizes a unique manufacturing process that inactivates numerous potential pathogens, including species of non-spore bacteria, such as Escherichia coli, and viruses such as SARS-CoV-2.

About C. difficile Infection (CDI) and Current Treatments

C. difficile infection (CDI) is one of the top three most urgent antibiotic-resistant bacterial threats in the U.S., according to the Centers for Disease Control, and is a leading cause of hospital-acquired infection in the U.S. It is responsible for the deaths of approximately 20,000 Americans each year. CDI is associated with debilitating diarrhea, which significantly impacts quality of life in every functional domain. Since the discovery of C. difficile more than four decades ago, vancomycin has been the most commonly used drug for patient management. Current approaches provide only modest improvements in sustained clinical response rates, leaving behind a significant pool of patients with recurrent disease. Unapproved FMT, used in cases that are not responsive to approved drugs, remains poorly characterized clinically and has been associated with serious safety concerns, including the transmission of bacterial pathogens and the potential transmission of viruses such as SARS-CoV-2, the virus that causes COVID-19. The recent quarantine and shipping hold of FMT from a major stool bank highlights the urgent need for an approved effective and safe treatment for recurrent CDI.

About Seres Therapeutics

Seres Therapeutics, Inc., (Nasdaq: MCRB) is a leading microbiome therapeutics platform company developing a novel class of multifunctional bacterial consortia that are designed to functionally interact with host cells and tissues to treat disease. Seres’ SER-109 program achieved the first-ever positive pivotal clinical results for a targeted microbiome drug candidate and has obtained Breakthrough Therapy and Orphan Drug designations from the FDA. The SER-109 program is being advanced for the treatment of recurrent C. difficile infection and has the potential to become a first-in-class FDA-approved microbiome therapeutic. Seres’ SER-287 program has obtained Fast Track and Orphan Drug designations from the FDA and is being evaluated in a Phase 2b study in patients with active mild-to-moderate ulcerative colitis. Seres is developing SER-401 in a Phase 1b study in patients with metastatic melanoma, SER-301 for ulcerative colitis and SER-155 to prevent mortality due to gastrointestinal infections, bacteremia, and graft versus host disease. For more information, please visit www.serestherapeutics.com

SOURCE: Seres Therapeutics

Summit Therapeutics plc Phase 2 Clinical Trial Ridinilazole In Development For the Treatment of C. difficile Infection

Summit Announces Publication of Phase 2 Clinical Analyses of Gut Microbiome Health

July 13, 2020 – Summit Therapeutics plc announced the publication of data from the Phase 2 clinical trial of the company’s precision antibiotic, ridinilazole, in development for the treatment of C. difficile infection (‘CDI’) in the American Journal of Physiology – Gastrointestinal and Liver Physiology. The data published in collaboration with researchers at Tufts University and Tufts Medical Center demonstrated that ridinilazole’s microbiome preservation resulted in a gut environment expected to inhibit the growth of C. difficile. In contrast, vancomycin treatment resulted in a gut environment that may more highly favor the growth of C. difficile. The difference in gut environment could explain the approximately 60% relative reduction in recurrence observed in patients treated with ridinilazole over vancomycin in the Phase 2 trial.

“This is the first scientific article ever to show the effect of antibiotics treating CDI on the bile acid composition in the human gut. In addition, CoDIFy is the first clinical study to highlight the differential effects of antibiotics on bile acids, which are known to create environments that can either promote or protect against CDI,” said Dr. Ventzislav Stefanov, Executive Vice President and President of Discuva. “The protective gut environment observed after ridinilazole treatment, compared to vancomycin, provides a strong rationale for the higher sustained clinical response observed in patients taking ridinilazole in the CoDIFy clinical trial.”

The Phase 2 clinical trial enrolled 100 patients, half of whom received ridinilazole and the other half vancomycin. The publication, “Ridinilazole, a narrow spectrum antibiotic for treatment of Clostridioides difficile infection, enhances preservation of microbiota-dependent bile acids,” was authored by X. Qian, K. Yanagi, A. Kane, N. Alden, M. Lei, D. Snydman, R. Vickers, K. Lee and C. Thorpe. In the published data, there was a higher ratio of pro-C. difficile to anti C.-difficile bile acids at the start of treatment for both ridinilazole- and vancomycin-treated patients. This was expected, as patients who get CDI have perturbed microbiomes. However, during treatment, patients treated with vancomycin showed a further decrease in anti-C. difficile bile acids and had stools dominated by pro-C. difficile bile acids. In contrast, this did not occur in ridinilazole-treated patients. By the end of the study period, ridinilazole-treated patients’ bile acid ratios trended towards a healthy, non-CDI state. These results support the data from the Phase 2 clinical trial, in which patients receiving ridinilazole showed a statistically significant improvement in sustained clinical responses.

SOURCE: https://seekingalpha.com/pr/17929120-summit-announces-publication-of-phase-2-clinical-analyses-of-gut-microbiome-health

Major Article: SER-109, an Investigational Microbiome Drug to Reduce Recurrence After Clostridioides difficile Infection: Lessons Learned From a Phase 2 Trial

SER-109, an Investigational Microbiome Drug to Reduce
Recurrence After Clostridioides difficile Infection: Lessons
Learned From a Phase 2 Trial.

Barbara H. McGovern,1,a,  Christopher B. Ford,1,a , Matthew R. Henn,1,a , Darrell S. Pardi 2
Sahil Khanna,2  Elizabeth L. Hohmann,3  Edward J. O’Brien,1
Christopher A. Desjardins,1, Patricia Bernardo,1, Jennifer R. Wortman,1, Mary-Jane Lombardo,1
Kevin D. Litcofsky,1, Jonathan A. Winkler,1, Christopher W. J. McChalicher,1, Sunny S. Li,1,
Amelia D. Tomlinson,1,Madhumitha Nandakumar,1 David N. Cook1,
Roger J. Pomerantz,1, John G. Auninš,1, and Michele Trucksis1,

1 Seres Therapeutics, Cambridge, Massachusetts, USA, 2 Mayo Clinic, Gastroenterology Division, Rochester, Minnesota, USA, and 3 Massachusetts General Hospital, Infectious Diseases Division, Boston, Massachusetts, USA

Background. Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs.

Methods. In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing.

Safety, C. difficile–positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed.

Results. 89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo
(44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years
(45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11–2.81), while the <65 group showed no benefit. Early engraftment of SER-109
was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed
an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal.

Adverse events were generally mild to moderate in severity.

Conclusions. Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial. Clinical Trials Registration. NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw=2&rank=4.

To view publication in its entirety please click on the following link to be redirected:

https://academic.oup.com/cid/search-results?page=1&q=SER-109%2C%20an%20Investigational%20Microbiome%20Drug%20to%20Reduce%20Recurrence%20After%20Clostridioides%20difficile%20Infection%3A%20Lessons%20Learned%20From%20a%20Phase%202%20Trial&fl_SiteID=5269&SearchSourceType=1&allJournals=1

Seres Therapeutics SER-109, Investigational Microbiome Drug to Reduce rCDI, What Was Learned From a Phase 2 Clinical Trial

Abstract

Background

Recurrent C. difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, open-label Phase (Ph)1 study in subjects with multiply rCDI.

To read publication in its entirety please click on the following link to be redirected. Thank you.

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa387/5817059?rss=1

Methods

In a Ph2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile-positive diarrhea through week 8, SER-109 engraftment and bile acid changes were assessed.

Results

89 subjects were enrolled; 67% were female; 80.9% diagnosed by PCR. rCDI rates were lower in the SER-109 arm than placebo (44.1% versus 53.3%, respectively) but did not meet statistical significance. In a pre-planned analysis, rates were reduced among subjects ≥65 years (45.2% versus 80%, respectively; RR:1.77, 95% CI:1.11-2.81) while the <65 group showed no benefit. Early engraftment of SER-109 was associated with non-recurrence (p <0.05) and increased secondary bile acid concentrations (p<0.0001). Whole metagenomic sequencing from this study and our prior Ph1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that Ph2 dosing was suboptimal. Adverse events were generally mild-to-moderate in severity.

Conclusions

Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current Ph3 trial.

DEINOVE Announced Enrollment of First Patient in Phase II Trial Testing DNV3837 in Clostridioides difficile infections

On January 27, 2020, DEINOVE announced the inclusion of the first patient in the Phase II trial testing DNV3837.

 

  • The Phase II clinical trial aims to evaluate the efficacy, safety, and pharmacokinetics of DNV3837 in patients with Clostridioides difficile gastrointestinal infection (CDI).
  • The trial will be conducted mainly in 15 centers in the United States, in two successive stages:
    • a cohort of 10 patients with moderate to severe CDI treated with DNV3837,
    • a randomized cohort study testing DNV3837 against the standard of care in 30 patients with severe CDI.
  • The final results of this trial are expected by the end of 2020.
  • DEINOVE is the only French player to conduct a clinical trial with an antibiotic.
  • On 17 January, the WHO warned about the extreme lack of new antibiotics and the threat posed by antibiotic resistance.

DEINOVE (Euronext Growth Paris: ALDEI), a French biotech company that uses a disruptive approach to develop innovative antibiotics and bio-based active ingredients for cosmetics, announced the inclusion of the first patient in the Phase II trial testing DNV3837.

DNV3837 targets the treatment of Clostridioides difficile infections (CDI), a disease classified as a priority by the WHO and one of the global leading causes of healthcare-related infections*.

DNV3837 is an intravenous antibiotic that, when converted to its active form DNV3681, crosses the gastrointestinal barrier and accumulates in the intestinal lumen, allowing it to precisely target the infection site. DNV3837 has demonstrated a promising efficacy profile and acceptable tolerance in Phase I trials (on healthy volunteers). It has also demonstrated its ability to eliminate Clostridioides bacteria without affecting the gut microbiota. It has been granted Fast Track status and QIDP designation**.

The Phase II trial aims to evaluate the efficacy of DNV3837 in pathological conditions (through monitoring of symptoms, stool analysis, etc.), as well as to consolidate the safety and pharmacokinetic data of the antibiotic candidate.

This trial is concentrated in the United States. It will take place in two stages:

  • In the first phase, involving 5 centers, a cohort of 10 patients with moderate to severe CDI will be treated with DNV3837. At the end of this phase, the DSMB*** will review the interim results.
  • The second phase will involve 30 patients with severe CDI and will be carried out in 15 investigation centers. This will be an open-label randomized trial testing DNV3837 (in 2/3 of patients) against an approved standard of care**** (1/3 of patients) for comparison purposes.

The results of this clinical trial should be available by the end of 2020.

 “The start of this Phase II clinical trial is a significant step forward for DEINOVE and a great hope for patients. We are very proud to provide a potential solution to this unmet medical need and, to this end, work with the best American specialists in this area. The investigation centers are very committed to conducting this trial which, in the event of positive results, will be an important milestone towards the registration of DNV3837,” said Dr. Georges Gaudriault, Scientific Director of DEINOVE.

This announcement echoes warnings issued by the WHO about the lack of antibiotics renewal.

Dr. Tedros Adhanom Ghebreyesus, Director-General of WHO, declared last January 17 « Never has the threat of antimicrobial resistance been more immediate and the need for solutions more urgent ».

https://www.who.int/news-room/detail/17-01-2020-lack-of-new-antibiotics-threatens-global-efforts-to-contain-drug-resistant-infections

 

* Source: CDC (US Centers for Disease Control and Prevention)

** ‘Fast Track’ status facilitates the development of the molecule through a faster and more flexible regulatory review of the application. The QIDP designation gives the drug exclusive access to the market for an additional five-year period. These designations are granted by the FDA to drugs under development that meet critical and unmet therapeutic needs.

*** DSMB – Data Safety Monitoring Board: a group of independent experts tasked to review the data generated during the trial and make recommendations on patient safety as well as trial relevance and validity.

**** Standard treatments approved in the United States for the treatment of CDIs include vancomycin, fidaxomicin and metronidazole (all three antibiotics). The choice will be at the discretion of the clinicians.