Q&A: Phase 2b trial shows belapectin may reduce incidence of new esophageal varices

Galectin Therapeutics has begun a phase 2b/3 clinical trial of belapectin to treat cirrhosis in patients with nonalcoholic steatohepatitis.

Healio Gastroenterology spoke with Pol Boudes, MD, chief medical officer of Galectin Therapeutics and Harold Shlevin, PhD, former chief executive officer and a current member of the board of directors, to discuss the design of the trial and their goals for making the drug available to patients with NASH.

Healio: Why did you decide to do a trial on belapectin targeting cirrhotic NASH patients?

Boudes: Belapectin, a potent galectin-3 inhibitor, is in development for NASH and we started the standard development program, phase 1 and phase 2. The phase 2 data in cirrhotic NASH patients was really interesting because we discovered that the drug was actually preventing the development of esophageal varices. So far there is no drug that can do this kind of prevention. We had to find a population that would be suitable for this activity, and we discovered that in patients with NASH cirrhosis but have not yet developed varices, we could prevent them from developing. We compared belapectin with placebo and, in these patients, there was a striking effect. Due to the interesting results and because it’s groundbreaking, we wanted to go to the next step beyond phase 2 and confirm this by studying a larger number of patients. This is why we designed the NASH-RX trial, which is a seamless, adaptive, phase 2b/3 trial. We potentially have a trial that can lead to registration of the drug and its availability to patients as it explores an outcome that represents evidence of a direct clinical benefit. There is a real medical need for a treatment for NASH, especially for the cirrhotic population. There is no drug registered at the moment for NASH. And if you look at all the people trying to find a treatment for NASH, they are trying to address NASH before it has progressed to the cirrhotic stage. They don't address the issue of established cirrhosis in NASH patients; Galectin’s approach is unique in this regard.

Shlevin: The preclinical data are very robust, not just ours, but the literature data about the important involvement of galectin-3 in the fibrotic process and the importance of a galectin-3 inhibitor to stop this process, and that goes back to data generated in early 2000’s and published by the National Academy of Science. Those genetic knock-out experiments pretty much nailed the involvements of the galectin-3 mechanism as important in the course of a disease like liver cirrhosis. We looked at the clinical impact, what does this mean for the life of patients. Most companies focus on the earlier stages of NASH. Early on things like simple changes in diet to lose weight and exercise, if you can get a patient to do that it would largely reduce NASH, but not later on when the patient has become cirrhotic. That is when the medical need begins to skyrocket and it's progressing. Ultimately in the worst cases, these patients require a liver transplant. That is their only alternative at the moment.

Healio: Can you describe the design of the NASH trial?

Boudes: We designed a seamless trial that goes from phase 2b to phase 3 without interruption. This saves time, as we do not have to pause between phase 2b and 3 and do not have to go through the long and cumbersome process of initiating a new phase 3 trial. The trial will start the phase 2b with 315 patients, three groups of 105 patients. All the patients are going to have an endoscopy at baseline. The patient population includes patients with cirrhosis of the liver due to NASH, but we say they are not decompensated because they do not have yet experienced severe complication of their cirrhosis, such as variceal bleeding or ascites.

The trial will last 18 months, and we will repeat the endoscopy at 18 months to see who developed varices. We will compare the two groups receiving belapectin with a placebo group. When we have the last data on 18-month endoscopy, we will open the database, and we will have a blinded interim analysis run by an independent group.

At this point, we may stop the trial and not proceed to phase 3. This could be the case if we don’t see any activities, or if we reproduce the results we have seen in the previous trial. In this later scenario, the positive risk/benefit of belapectin may be overwhelming and we may have to offer treatment to all our patients, including the one that has been enrolled in the placebo group. If the results trend in the right direction we will go into phase 3, and only select the best dosage of belapectin. We will require additional patients for the study. These new patients will follow the same process as the phase 2 patients, with an endoscopy at baseline and at 18 months. At this point in time, we will combine the two phases of the study and run the final analysis with a large set of 18-month data. Also, phase 2b patients will continue their treatment for an additional 18 months, until the final analysis. This will provide important additional, long-term safety data. This type of design is called adaptive, because the trial potential changes are planned in advance and can be implemented without amending the protocol, which in itself, is always a long process, particularly for international studies. Overall, we will have a little more than 500 patients; based on the different adaptations, we could go up to approximately 1,000 patients. By focusing on esophageal varices, if we have positive results, it will be, contrary to other trials using liver biopsies as the endpoint. In our instance, we will immediately have something that is clinically relevant. The significance of the results will not be difficult to interpret.

Shlevin: For a trial of this size, we have a lot of outside advisors who help us with the design and work with us in consultation with the FDA and other regulators. The trial’s design went through a number of iterations, all of which were really designed to focus more on clinical outcomes, to focus on testing that reflected what really occurred in the clinic in day-to-day practice with cirrhotic patients. That is why we don't have certain measurements in this advanced trial, unlike what we did in the earlier phase 2 trial.

Although we perform endoscopy once every 18 months, some of us want to do it more frequently. But we needed to come back to what's clinical practice, what do we know about the disease and its progression. Performing an endoscopy every 18 month for instance is part of the accepted medical practice for a patient with compensated cirrhosis. A lot of those features that reflect clinical practice around the world are underlying and underscoring how this trial was designed.

When you think about it, asking the patient to take a drug over a long period is a challenge. It requires patient dedication. These patients with cirrhosis who know they are not healthy are more likely to be retained in the trial. Cirrhotic patients in general, as exhibited by our earlier phase 2 study, recognize the importance of having a specific treatment for this disease, as currently there are no such treatments available. These patients tend to be more compliant and follow protocol procedures, and patients’ retention is less of an issue.

Healio: What were you hoping to accomplish with this trial once it's over what, what's the next step?

Shlevin: Ideally, the next step is to commercialize the product and sell it. We care less about having a partner or not to sell it, we care more about making the drug available for patients.

Boudes: We also want to ensure we do it in the safest way and that the drug is very well tolerated, which is a really important factor. Belapectin, a pectin derivative, is not a complex chemical structure for the human body compared to other chemical entities, and that's very important because cirrhotic patients can be a bit fragile and do not always tolerate drugs well as the liver is the main site of their metabolism. This is one reason why people always need to do large clinical trials to explore drug safety as thoroughly as possible. If belapectin is determined to be effective and safe, it will be a real medical breakthrough for patients with NASH cirrhosis. At this juncture though, it will also be interesting to see if belapectin would work in other types of cirrhosis.