Category Archives: C. difficile Treatment Clinical Studies

Acurx Pharmaceuticals Phase 2 Clinical Trial of ibezapolstat Is In Progress

Acurx Pharmaceuticals, LLC (“Acurx” or the “Company”), a privately held, clinical stage biopharmaceutical company developing new antibiotics for difficult-to-treat bacterial infections, announced on July 27th, 2020 that a Phase 2 clinical trial of the Company’s lead antibiotic product candidate is in progress. In this trial, orally-administered ibezapolstat given 450 mg twice daily for 10 days will be evaluated for the treatment of patients with CDI. FDA has granted Qualified Infectious Disease Product (QIDP) designation and Fast-Track status to ibezapolstat for patients with CDI.

Up to 6 study centers in the U.S. will participate in the first segment (Segment 2A) of the trial. Additional information about the trial, including eligibility criteria, can be found at www.clinicaltrials.gov (Study identifier: NCT04247542). This Phase 2, multicenter, open-label single-arm segment (Segment 2A) will be followed by a double-blind, randomized, active-controlled segment (Segment 2B), and is designed to evaluate both clinical cure and sustained clinical cure, safety, and pharmacokinetics. All patients in both segments will have stool samples tested for ibezapolstat concentrations and microbiome effects. Pharmacokinetic testing for systemic exposure will be performed on blood samples in Segment 2A. All of the first 6 patients enrolled in the trial have met the study’s primary endpoint, Clinical Cure at end of treatment. All patients who have reached the 30-day follow-up milestone, no recurrence of CDI, have achieved Sustained Clinical Cure, the study’s secondary endpoint. Ibezapolstat has been well-tolerated in all patients to date. After the first 10 patients have completed treatment, the study’s Trial Oversight Committee will assess the ibezapolstat safety profile in relationship to treatment outcomes and will advise the company on any recommended trial modifications which could include early termination of Phase 2A and acceleration of the double-blind Segment 2B.

Robert J. DeLuccia, Co-Founder & Managing Partner of Acurx, stated “With today’s heightened awareness of antimicrobial resistance, even more so in the current Covid-19 environment, and the need for new classes of antibiotics to fight this global crisis, we are very excited to advance ibezapolstat to this stage of clinical development.” He further stated, “This is a significant value-creating development milestone for our Company. We believe this now clinically validated target of inhibition of bacterial DNA pol IIIC will pave the way forward for our pipeline of new oral/I.V. antibiotics in pre-clinical development to treat other Gram-positive life-threatening infections in skin/skin structure, community acquired pneumonia, bone & joint and bacteremia. This will include pathogens resistant to currently available antibiotics, and classified as priority pathogens by the WHO, CDC and FDA, all of whom emphasize the need for new classes of antibiotics to prepare for the next global infectious disease threat.”

Additionally, the U.S. Center for Diseases Control recently issued its 2019 update on antimicrobial resistance https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf and reaffirmed that CDI remains an URGENT threat causing at least 12,800 deaths in 2017, highlighting the need for new antibiotics, particularly those with a novel mechanism of action. It further reported that more than 2.8 million antibiotic-resistant infections occur in the U.S. each year and more than 35,000 people die as a result, nearly twice as many annual deaths than previously reported by CDC in 2013. These deaths are attributed to antimicrobial-resistant pathogens including Enterococcus (including vancomycin-resistant strains or VRE), Staphylococcus (including methicillin-resistant strains or MRSA), and Streptococcus (including antibiotic-resistant strains), which are the targets of Company’s second antibiotic candidate currently in preclinical development.

About the Phase 2 Clinical Trial.  In Segment 2A of this trial, up to 20 subjects with diarrhea caused by C. difficile will be treated with ibezapolstat 450 mg orally for 10 days and evaluated for clinical cure. All cured subjects will be followed for sustained clinical cure at 28 ± 2 days. In Segment 2B, approximately 64 additional subjects with CDI will be enrolled and randomized in a 1:1 ratio to either ibezapolstat 450 mg every 12 hours or vancomycin 125 mg orally every 6 hours for 10 days and followed for 28 ± 2 days for recurrence. The two treatments will be identical in appearance, dosing times, and number of capsules administered to maintain the blind. Subjects in both segments will be evaluated for clinical and sustained clinical cure, safety, and tolerability. All subjects in both segments will have stool samples tested for microbiome profiles.
Additional information about the trial, including eligibility criteria can be found at: www.clinicaltrials.gov (Study identifier: NCT04247542).

About ibezapolstat, FDA QIDP and Fast Track Designation.  In June 2018, FDA granted Qualified Infectious Disease Product (QIDP) designation to ibezapolstat as an oral treatment for patients with CDI. In addition, in January 2019, FDA granted Fast Track designation to ibezapolstat for the oral treatment for patients with CDI. 

FDA Fast Track Designation is a process designed to facilitate the development and expedite the regulatory pathway of new drugs to treat serious or life-threatening conditions and that fill a high unmet medical need. Ibezapolstat is a novel, first-in-class, orally administered antibacterial. It is the first of a novel class of DNA polymerase IIIC inhibitors under development by Acurx to treat bacterial infections. Acurx acquired ibezapolstat from GLSynthesis, Inc. in February 2018.

FDA’s QIDP Designation provides that ibezapolstat will be eligible to benefit from certain incentives for the development of new antibiotics provided under the Generating Antibiotic Incentives Now Act (the GAIN Act). These incentives include Priority Review and eligibility for Fast Track status, the latter of which Acurx has already applied for and been granted by FDA. Further, if ultimately approved by the FDA, ibezapolstat is eligible for an additional five-year extension of Hatch-Waxman marketing exclusivity. Ibezapolstat is being developed as a targeted, narrow spectrum oral antibiotic for the treatment of patients with CDI. Acurx is planning to advance ibezapolstat into a Phase 2 clinical trial in first quarter 2020. The CDC (Centers for Disease Control & Prevention) has designated Clostridium difficile bacteria as an urgent threat highlighting the need for new antibiotics to treat CDI.

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.

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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. 

Rebiotix, a Ferring Company, Completes Enrollment for First-Ever, Pivotal Phase 3 Clinical Trial RBX2660

Rebiotix, a Ferring Company, completes enrollment for first-ever, pivotal Phase 3 Clinical Trial of Microbiota -based RBX2660

Enrollment completion for the first Phase 3 clinical trial in microbiome industry

 The largest randomized, double-blinded study, with over 300 patients enrolled aimed to demonstrate the potential benefit of RBX2660 in reducing rates of recurrent Clostridioides difficile (C. diff) infection

 Rebiotix intends to use the results from the Phase 3 trial to serve as the basis for licensure application to the US Food and Drug Admin (FDA)

 Saint-Prex, Switzerland – On February 4, 2020

Rebiotix, a Ferring company, announced today that it has completed enrollment of the pivotal Phase 3 clinical trial for RBX2660, an investigational therapy aimed at breaking the cycle of recurrent Clostridioides difficile (C. diff) infection, which is responsible for the deaths of thousands of people in the US alone. The Centers for Disease Control and Prevention (CDC) has classified C. diff as an urgent public health threat, with limited options for treatment.

 

RBX2660 was developed under Rebiotix’s investigational microbiota-based MRT™ drug platform with the goal of delivering standardized, stabilized formulations to meet unmet medical needs. Conducted in the US and Canada, this is the first Phase 3 trial of its kind to be completed using a broad consortia microbiota-based formulation.

 

“Rebiotix was founded to harness the power of the human microbiome to treat debilitating diseases,” said Lee Jones, Rebiotix Founder, and CEO. “Microbiota-based therapies have shown tremendous potential as an innovative, non-antibiotic therapy, starting with C. diff. The completion of enrollment of this trial is a critical next step in making microbiota-based products accessible to patients – we are excited about this important milestone and look forward to sharing results later this year.”

 

The Phase 3 trial builds on the company’s extensive history with the formulation, including several hundred participants previously enrolled in multiple Phase 2 clinical trials. The robust data collected over the course of the company’s multi-year clinical development program will be eventually presented to the US FDA as part of a Biological License Application (BLA).

 

Ferring Pharmaceuticals, also with a rich and vast history of microbiome research of its own, led the industry by becoming the first major pharmaceutical company to acquire a microbiome therapeutics company in April 2018. Headquartered in Saint-Prex, Switzerland, Ferring is expected to have the first regulatory approved microbiota-based therapeutic in the world through the potential approval of the RBX2660 in the US.

 

About Clostridioides difficile Infection

Clostridioides difficile (also known as C. diff) is a bacterium that causes diarrhea and colitis (inflammation of the colon). C. diff, impacts nearly a half a million people each year in the United States; of those impacted, up to one in five patients will experience a recurrent episode.1 In 2019, the U.S. Centers for Disease Control listed C. diff as an urgent threat to public health.2

 

About RBX2660

RBX2660 is currently in Phase 3 clinical development for the reduction of recurrent Clostridioides difficile (C. diff) infection. RBX2660 has been granted Fast Track, Orphan, and Breakthrough Therapy Status designations from the US FDA. For more information about the RBX2660 Phase 3 study, visit http://www.clinicaltrials.gov (NCT03244644).

 

About Rebiotix

Rebiotix Inc., part of the Ferring Pharmaceuticals Group, is a late-stage clinical microbiome company focused on harnessing the power of the human microbiome to revolutionize the treatment of challenging diseases. Rebiotix has a diverse pipeline of investigational drug products built on its pioneering microbiota-based MRT™ drug platform. The platform consists of investigational drug technologies designed to potentially rehabilitate the human microbiome by delivering a broad consortium of live microbes into a patient’s intestinal tract. For more information on Rebiotix and its pipeline of human microbiome-directed therapies for diverse disease states, visit http://www.rebiotix.com.

 

About Ferring Pharmaceuticals

Ferring Pharmaceuticals is a research-driven, specialty biopharmaceutical group committed to helping people around the world build families and live better lives. Headquartered in Saint-Prex, Switzerland, Ferring is a leader in reproductive medicine and maternal health, and in specialty areas within gastroenterology and urology. Founded in 1950, privately-owned Ferring now employs approximately 6,500 people worldwide, has its own operating subsidiaries in nearly 60 countries and markets its products in 110 countries.

 

References:

1Centers for Disease Control and Prevention. What Is C. Diff?,17 Dec. 2018. Available at: https://www.cdc.gov/cdiff/what-is.html.

2Centers for Disease Control and Prevention. Biggest Threats and Data, 14 Nov. 2019. Available at: https://www.cdc.gov/drugresistance/biggest-threats.html.

 

Source:  Rebiotix, Press Release

http://www.rebiotix.com

Acurx Pharmaceuticals LLC Lead Product ACX-362E Has Successfully Completed First-In-Man Phase I Clinical Trial To Treat C.difficile Infection

 Acurx Pharmaceuticals, LLC is, a privately-held, clinical stage, biopharmaceutical company developing new antibiotics for difficult-to-treat bacterial infections, announced that its lead product candidate, ACX-362E, has successfully completed the 32-subject, double-blinded, placebo-controlled, single-ascending dose portion of this first-in-man Phase 1 clinical trial. ACX-362E is a novel, oral antibacterial agent for the treatment of Clostridioides difficile infection (CDI), an acute, serious, potentially life-threatening, intestinal infection.

ACX-362E is Acurx’s lead compound in a pipeline of molecules that target a previously unexploited mechanism of action, namely, inhibition of the bacterial enzyme DNA polymerase IIIC (pol IIIC).  Pol IIIC is required for DNA replication of many Gram-positive pathogens, including not only Clostridioides but also Enterococcus, Staphylococcus, and Streptococcus.  Although the trial data remain blinded, ongoing monitoring of the data show dose levels up to 600mg have been generally well tolerated. Blood levels of ACX-362E show low systemic exposure, as predicted by prior animal studies and desirable in treating CDI.  Additionally, fecal concentrations of ACX-362E at higher dose levels have exceeded the concentrations known to inhibit C. difficile by several hundred-fold.

“We are very encouraged by these initial data which corroborate our nonclinical findings, showing that at well-tolerated doses ACX-362E reaches concentrations in the colon that are projected to be therapeutically relevant for patients with CDI” said Robert J. DeLuccia, Co-Founder and Managing Partner of Acurx.  “This gives us confidence that the ongoing multiple-dose segment of the trial will provide data to guide selection of our Phase 2 dose and improve the probability of success and timeline efficiency of our Phase 2 clinical trial planned to start later this year.”

Dr. Kevin Garey, Professor, University of Houston College of Pharmacy and the Principal Investigator for microbiomic aspects of the Phase 1 clinical trial said: “The emerging fecal concentration data are comparable to those observed with precedent products that have advanced to demonstrate clinical success. I look forward to the multiple-dose safety data and to the results of the microbiomic analyses that our laboratory is performing which will form a template for a new paradigm in microbiome studies associated with drug discovery and development of CDI-directed antibiotics.”

About the Phase 1 Clinical Trial
This Phase 1 trial, conducted in the U.S., is a double-blinded, placebo-controlled study to determine safety, tolerability, pharmacokinetics and fecal concentrations of ACX-362E in healthy volunteers.  It is being conducted in two parts; first, single ascending doses are administered to four cohorts of 8 subjects each, and second, multiple ascending doses are given that simulate the anticipated clinical treatment regimen. Safety information is analyzed through assessment of adverse events and other standard safety measures, while concentrations of ACX-362E are determined in both the blood and the feces, the latter being the critical site of drug delivery for treating CDI.  In addition, Acurx has partnered with the laboratory of Dr. Kevin Garey at the University of Houston to perform state-of-the-art microbiomic testing of gastrointestinal flora in trial subjects.

About ACX-362E, FDA QIDP and Fast Track Designation
FDA Fast Track Designation is a process designed to facilitate the development and expedite the regulatory pathway of new drugs to treat serious or life-threatening conditions and that fill a high unmet medical need. ACX-362E is a novel, first-in-class, orally-administered antibacterial.  It is the first of a novel class of DNA polymerase IIIC inhibitors under development by Acurx to treat bacterial infections. Acurx acquired ACX-362E from GLSynthesis, Inc. in February 2018.

ACX-362E is a Qualified Infectious Disease Product (QIDP) for the treatment of patients with Clostridium difficile infection (CDI).  Under QIDP designation, ACX-362E will now be eligible to benefit from certain incentives for the development of new antibiotics provided under the Generating Antibiotic Incentives Now Act (the GAIN Act). These incentives include Priority Review and eligibility for Fast Track status. Further, if ultimately approved by the FDA, ACX-362E is eligible for an additional five-year extension of Hatch-Waxman marketing exclusivity. ACX-362E is being developed as a targeted, narrow spectrum oral antibiotic for the treatment of patients with CDI.  Acurx anticipates completing the Phase 1 clinical trial in the second quarter of 2019 and is planning to advance ACX-362E into a Phase 2 clinical trial in the fourth quarter of 2019. The CDC (Centers for Disease Control & Prevention) has designated Clostridium difficile bacteria as an urgent threat highlighting the need for new antibiotics to treat CDI.

RESOURCE:  https://www.acurxpharma.com/news-media/press-releases/detail/8/acurx-announces-first-in-man-clinical-trial-data-of