San Diego based oncology outfit, Halozyme Therapeutics, Inc. (NASDAQ:HALO), just announced the first dosing in a clinical trial of its lead candidate, PEGPH20. The trial is a phase III with a target indication of pancreatic cancer, and could be a real upside driver for the company if it produces favorable results. With this in mind, let’s have a look at the theory behind the drug, and what to look for as far as data is concerned going forward.
So, as mentioned, the drug is a pancreatic cancer indication called PEGPH20. The first thing to note is that the drug is not designed to actually treat cancer itself – it is designed to improve and enhance the efficacy of a host of already approved (and many SOC) chemotherapy agents. All humans have what is called hyaluronan (readers might know this by another term – hyaluronic acid) inside their bodies. Its primary function is rooted in cell proliferation and migration – essentially, it helps cells get to where they need to be and, on arrival, replicate as per their individual function. It’s also associated with a number of tumors, however. Oncologists will often measure the level of hyaluronan in the tissue surrounding a tumor, and use this level to offer up a prognosis for the patient. Generally, the higher the level, the poorer the prognosis. Why? Because it seems to block the MOA of traditional chemotherapy agents, in two distinct ways. First, it creates an environment that is well suited to proliferation, which would be fine, if it wasn’t promoting the proliferation of cancerous cells, but it is. Second, it forms a sort of barrier around the tumor, meaning the drug being used to attack the tumor cannot reach it – or at least, not to its full potential.
This is where PEGPH20 comes in. It’s a formulation of an enzyme called rHuPH20, which has the ability to break down hyaluronan. The breaking down is only temporary, but if administered in combination with a chemotherapy drug, the temporary nature of the degradation doesn’t really matter; it breaks down the hyaluronan barrier for long enough that the drug can act unencumbered on the tumor, theoretically increasing the drug’s efficacy.
So that’s the theory – what data back it up to-date?
The company completed a phase I/II early last year, and reported topline from the trial a couple of months later. The phase I element of the study dosed all patients (n = 146) with a combination of PEGPH20 and gemcitabine, an SOC chemotherapy drug currently marketed as Gemzar by Eli Lilly and Co (NYSE:LLY). After optimum dose was attained through the phase I, the company double blinded the trial into a phase II, and treated half (approx.) of the patients with PEGPH20 and gemcitabine, and half with gemcitabine and placebo. Topline from the trial showed a doubling in PFS between patients treated with the combination therapy and patients treated with gemcitabine alone, adding an average of 4.9 months to the PFS baseline. There were some bumps along the way, however. Safety became a real concern at the end of phase I stage, and the FDA put a temporary hold on the trial while it evaluated the drug. Things went ahead as planned after a short hold, but safety and tolerability will definitely play a big part in the agency’s decision making when, and if, Halozyme puts forward an NDA based on the just-initiated phase III.
Which brings us nicely to what we’re looking for from phase III topline. Efficacy seems like it shouldn’t be too much of a problem, with preclinical and early stage data across quite a wide array of patients suggesting superiority for the combination treatment. It’s the already mentioned tolerability issues that might trip the drug up. High instances of pretty serious AEs like peripheral edema and neutropenia littered the phase II, and if they occur at similar rates in the phase III, it’s touch and go as to whether the efficacy data will justify an approval. In Halozyme’s favor, is the indication. It’s late stage pancreatic, so patient’s will likely be willing to put up with some serious side effects to allay the seriousness of the disease. Expect topline late 2017, and keep an eye out for interim before the close of this year. One to watch.