Tag Archives: gastrointestinal microbiota

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

 

 

Crestovo Doses Recurrent C. diff. Infection Patients In PRISM 3 – A Phase 2 Clinical Trial Testing CP-101 Microbiota

Crestovo doses recurrent Clostridium difficile infection (C. difficile) patients in PRISM 3, a phase 2 clinical trial testing CP101 (Microbiota).

The company is developing a Full-Spectrum Microbiota that harnesses the human gut microbiome. CP101, a first-in-class, lead microbiome therapy, is an encapsulated, single dose, orally-administered medicine that contains the full complement of functional microorganisms that may help restore the dysbiotic microbiota to a normal, functioning gut microbial community.

As Published in MD Mag :  http://www.mdmag.com/medical-news/phase-2-clinical-trial-tests-cp101-in-subjects-with-recurrent-c-diff

“CP101 has the potential to be the first therapy seeking FDA-approval utilizing the human gut microbiome,” Joseph Lobacki, chief operating officer, interim chief executive officer, Crestovo, said.

PRISM 3 is a multicenter, randomized, placebo-controlled trial evaluating the efficacy and safety of Microbiota in approximately 240 patients with recurrent C. difficile at clinical sites throughout the US.

Primary outcomes include a proportion of patients with no recurrence of symptomatic, laboratory confirmed C. difficile infection through 8 weeks, following administration of Microbiota, compared to the placebo, as well as a proportion of participants with adverse effects assessed by CTCAE v4.0 through 8 weeks mapped to system organ class.

Secondary outcome measures include a proportion of subjects sustaining clinical cure by a C. difficile subtype; through week 8, time to first recurrent C. difficile during the study at week 8 and 24; and a proportion of patients with no recurrence of symptomatic, laboratory confirmed infection at week 24.

Study arms include high dose full spectrum Microbiota, low dose full spectrum Microbiota and a placebo.

Inclusion criteria includes the ability to provide written informed consent, men or women 18–85 years age, a current diagnosis of a recurrence of non-severe, non-complicated C. difficile, and a clinical response to a standard course of oral vancomycin therapy to treat the current episode of recurrent C. difficile.

Top-line data from PRISM 3 is expected to release in December 2018.

Gut Health and Nutrition

Your digestive, or gastrointestinal (GI), tract is a long, muscular tube that runs from your mouth to your anus. It’s about 30 feet long and works with other parts of your digestive system to break food and drink down into smaller molecules of nutrients. The blood absorbs these and carries them throughout the body for cells to use for energy, growth, and repair.

With such a long GI highway, it’s common to run into bumps in the road. About 60 to 70 million Americans are affected by digestive diseases, like gastroesophageal reflux disease (GERD) or irritable bowel syndrome (IBS). GERD happens when your stomach acid and/or contents come back up into your esophagus (swallowing tube) or throat. This causes uncomfortable symptoms like heartburn and indigestion. IBS is a group of symptoms that includes pain in the abdomen and changes in bowel habits. People with IBS may have constipation, diarrhea, or both. Many more people have other digestive problems, like bloating and stomach pain.

“There are many factors that can impact gut health,” says Dr. Lin Chang, a GI expert at the University of California, Los Angeles. How your body’s built, your family and genetic history, how you manage stress, and what you eat can all affect your gut.

“I see a lot of lifestyle-related GI issues, and there are often no quick fixes for that,” she says. “In general, people do well when they create a more routine schedule, eat a healthy diet and smaller more frequent meals, add in some exercise, and get a good amount of sleep.”

Chang studies the connection between stress and IBS. Her research group has found that people who have early life stress are more likely to develop IBS. “However, this increased risk for IBS went down when people confided in someone they trust about the stress they experienced,” she explains. “Finding healthy ways to manage stress is important for GI health, and your health overall.”

What you eat can help or hurt your digestive system, and influence how you feel. “Increasing fiber is really important for constipation,” says Chang. “Most Americans do not eat a lot of fiber so you have to gradually increase the fiber in your diet. Otherwise you might get gas and more bloating, and won’t stick with [the changes].”

Chang says you should eat at least 20–30 grams of fiber a day for constipation. You can spread out your fiber in small amounts throughout the day. Start with small servings and gradually increase them to avoid gas, bloating, and discomfort.

Try to eat fruits and vegetables at every meal * cooked well for post-C.diff. infection patients until tolerated.

A variety of fruits, vegetables, whole grains can provide a healthy mix of different fibers and nutrients to your diet. An added benefit is that the more fiber and whole foods you eat, the less room you’ll have for less healthy options.

But some fiber-rich foods, called high FODMAP foods, can be hard to digest. Examples include certain fruits and vegetables, dairy products, and wheat and rye products.

If you have IBS, your doctor may recommend a diet low in FODMAPS.

Researchers are coming to understand the complex community of bacteria and other microbes that live in the human GI tract. Called gut flora or microbiota, these microbes help with our digestion.

But evidence has been growing that gut microbes may influence our health in other ways too. Studies suggest that they may play roles in obesity, type 2 diabetes, IBS, and colon cancer. They might also affect how the immune system functions. T

his can affect how your body fights illness and disease.

Recent studies have found that microbes’ effects on the immune system may impact the development of conditions such as allergy, asthma, and rheumatoid arthritis.

You might have heard that probiotics—live microbes that are similar to those found in the human gut—can improve your gut health. These are also called “friendly bacteria” or “good bacteria.” Probiotics are available in dietary supplements and in certain foods, such as yogurt.

There is some evidence that probiotics may be helpful in preventing diarrhea associated with antibiotics and improving symptoms of IBS, but more needs to be learned.

Researchers still don’t know which probiotics are helpful and which aren’t. They also don’t know how much of the probiotics people would have to take or who would most likely benefit from them.

Certain food additives called emulsifiers are something else that may affect your gut health. Emulsifiers are added to many processed foods to improve texture and extend shelf life. But studies show they can affect our gut flora.

“Our work and other research indicate that emulsifiers and other food additives can negatively impact the microbiota and promote inflammatory diseases,” says Georgia State University’s Dr. Andrew Gewirtz. His group has been studying the relationships between food additives, gut bacteria, and disease in mice. The team also plans to examine how different food additives may affect people.

Based on what his team and others have found, Gewirtz advises, “The take home message: Eat a balanced diet and less processed foods.”

“The GI system is complicated and such an important part of our health,” Chang says. “It takes a real partnership between patient and doctor to get to the root of issues. Everyone has to find a healthy routine that works for them.”

She encourages you to take an active role in finding a doctor who makes you feel comfortable. The right doctor will listen carefully to your health history and symptoms. You can help keep your gut in check by talking with your doctor and—together—making the right choices for you.

To Learn More About FODMAP, Probiotics, Prebiotics, C. difficile and post-C.difficile nutrition

join Karen Factor, RD every 3rd Thursday each month for free sessions.  Sign up today through

the website:  https://cdifffoundation.org/cdiffsupport/

To read this article in its entirety click on the following link:

https://newsinhealth.nih.gov/issue/May2017/Feature1

References
Adverse childhood experiences are associated with irritable bowel syndrome and gastrointestinal symptom severity. Park SH, Videlock EJ, Shih W, Presson AP, Mayer EA, Chang L. Neurogastroenterology & Motility. 2016 Aug;28(8):1252-60. doi: 10.1111/nmo.12826. Epub 2016 Apr 8. PMID: 27061107.

Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Chassaing B, Koren O, Goodrich JK, Poole AC, Srinivasan S, Ley RE, Gewirtz AT. Nature. 2015 Mar 5;519(7541):92-6. doi: 10.1038/nature14232. Epub 2015 Feb 25. PMID: 25731162.

Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms. Alcock J, Maley CC, Aktipis CA. Bioessays. 2014 Oct;36(10):940-9. doi: 10.1002/bies.201400071. Epub 2014 Aug 8. PMID: 25103109.