Market Overview

Three Pivotal Phase III Trials To Watch In Biotech


Here is a look at three critical clinical development programs that are at or near the final Phase 3 stage and could present a biotech investor a nice opportunity to pick up an exposure to the programs in question ahead of late stage data readouts.

The three companies in focus are GlaxoSmithKline plc (ADR) (NYSE: GSK), Seres Therapeutics Inc (NASDAQ: MCRB) and Oramed Pharmaceuticals, Inc. (NASDAQ: ORMP).


Back at the end of March, GSK initiated a phase 3 study investigating the safety and efficacy of mepolizumab. It is actually an already approved asset, currently indicated for the treatment of severe eosinophilic asthma. Eosinophils are a type of white blood cell that plays an important role in combating infection and parasitic presence. When combined with two other types of white blood cell, mast cells, and basophils, they control mechanisms associated with allergy and asthma.

With the current phase 3 study, the company is trying to expand on the current approval base and widen the drug's target population to include severe hypereosinophilic syndrome (HES). In patients with this condition, overproduction of eosinophils results in excessive inflammation and organ damage. This, in turn, leads to a loss of function and a degradation of quality-of-life over time. If left untreated, it can be deadly.

Mepolizumab works by inhibiting interleukin-5, a cytokine immune signaler that regulates the growth, activation, and survival of eosinophils. A reduction in the amount of active IL-5 should lead to a parallel reduction in the number of eosinophils in the patient being treated.

The current standard of care treatment is mostly ineffective and there currently exists a patient base of around 20,000 that stand to benefit from a global regulatory green light for mepolizumab in this indication.

It's a rare disease, but these sorts of rare disease drugs generally command premium pricing and will often qualify for the FDA's Orphan program in the US, which is true of mepolizumab here.

The phase 3 is global, double-blind placebo-controlled and will enroll approximately 120 patients. For a rare disease of only 20,000 addressable patients, this is quite the substantial headcount. The placebo comparison sets up the potential for an interim readout at some point late next year and top line data should hit press in February 2019.

Here's the protocol.


Last month, Seres initiated a Phase III study billed ECOSPOR IV. The study is designed to assess the efficacy of a drug called SER-109, which the company is trying to get approved as a potential therapy for patients with multiple recurrent Clostridium difficile (C. difficile) infection. C. difficile infection can come about on the back of repeated and chronic antibiotic usage and it's basically the imbalance of the flora in the gut arising from the spore-forming bacterium that gives it its name. Primary symptoms include diarrhea and abdominal discomfort. It's not generally considered a high-risk infection but in certain patients, it can continuously recur and symptoms can be incredibly difficult to live with. It's also one of the top three most urgent antibiotic-resistant bacterial threats in the United States, according to the Centers for Disease Control, and it is the leading cause of hospital-acquired infection in the United States, being responsible for the deaths of approximately 29,000 Americans each year. So while it is not often deadly, it is very costly in terms of hospitalizations.

It's this population that Seres is going after with SER-109.  The drug is an oral microbiome therapeutic designed to repair the dysbiosis in the microbiome of the patient. This is just another way of saying fixing the imbalance of the microbiome in the gut.

Just as with mepolizumab, it's got both Breakthrough and Orphan designation in the US but, unlike mepolizumab, the Phase 3 trial isn't set up to compare the drug with placebo. Instead, it's an open label study designed to assess efficacy across the entire recruited population.

The primary endpoint of the study is a recurrence of CDI up to 8 weeks after treatment and both time to recurrence of CDI and recurrence of CDI up to 4, 12 and 24 weeks after treatment serve as secondary endpoints. Enrolment should come in at around 100 patients total, with primary completion and subsequent top line readout slated for April 2019.

Here's the protocol.


The Phase 3 that earns Oramed a place on this list has not yet been initiated, but the company is set to meet with the FDA as part of an end of phase 2b meeting in just two days time on August 31, a possible catalyst for the stock if the company gets the green light to move forward with its planned pivotal trial. After this, we will almost certainly get some detailed information as to both the protocol for the Phase 3 and the timeframe to initiation.

The drug in focus here is called ORMD-0801 and it is targeting type II diabetes. This is an area dominated by some of the biggest names in healthcare including GSK listed above, so Oramed will have to bring a highly differentiated asset to market if it is to capture any real portion of the billions of dollars that are spent in the diabetes space annually. The upcoming Phase 3 is the final hurdle it needs to clear before it can try and stake a claim to these revenues.

ORMD-0801 is an orally administered insulin pill. Oral insulin has long been out of reach in this space, primarily because insulin is fragile and gets broken down in the gastrointestinal tract if taken orally. With ORMD-0801, Oramed has developed a protective mechanism and combined it with an absorption enhancer to try and get as much active insulin through the small intestine and to the liver as possible.

It's still not going to be possible to match the level of insulin that can be delivered through subcutaneous injection, the current insulin standard of care, but if it works even to a minor degree (what the threshold is, is the question), there is the potential for offering these sorts of oral insulin tablets to pre-diabetic patients. For example, those who don't necessarily need subcutaneous injections yet, but could benefit from a post-meal insulin boost. Further, there is evidence to suggest that this sort of early intervention can extend the time the patient can wait before transferring to subcutaneous injection.

In other words, it's not a cure-all, but in a market this big, there's considerable potential for real-world benefit and sales for Oramed. Data from the Phase 2B study suggested efficacy in this population, and in this setting, and it is a reasonable assumption that the Phase 3 will aim to replicate this data (i.e. not compare ORMD-0801 to insulin injections, but compare it to placebo in pre-insulin diabetic patients) in a larger patient population in the upcoming pivotal trial.

The company expects this trial to initiate before the end of this year, which sets up the potential for topline readout in and around those detailed above – somewhere early to mid-2019, assuming things run smoothly.

Once submitted, protocol will be available here.


Discclosure: the author holds no positions in any of the stocks mentioned in this piece. 

Posted-In: Biotech General


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