Green-lighted by the FDA, Halozyme Therapeutics Inc. plans to start by the end of 2016's first quarter the phase III push with PEGPH20, a pegylated form of the firm's recombinant human hyaluronidase, in patients with metastatic pancreatic cancer – and the trial design, which could allow for approval based on either progression-free survival (PFS) or overall survival (OS) endpoints, has analysts enthused.
"We get two shots at it," CEO Helen Torley told BioWorld Today. PFS in pancreatic cancer patients ranges between five and six months, whereas OS usually totals eight to nine months. "That three months' difference, based on the expected enrollment rate, translates into several multiples of that, as to how much sooner you can get to a data readout," which may bring a faster path to market, she said.
"People have tried it before," Torley noted of the two-choice endpoint, but Halozyme's study may have a particular advantage, since it will enroll specifically patients whose tumors accumulate high levels of hyaluronan, a sugar that is sometimes more prevalent in the areas surrounding cancer cells. "These are patients who, based on retrospective case studies, we know have an even worse prognosis" than the median survival for those with pancreatic cancer overall, Torley said. Also, "because we're going after a targeted population, results are enriched by a higher response rate, so it can mean smaller sample sizes than are traditionally required," but the likely enrollment size is not yet decided, she said.
Using PFS as the approval mark will depend on the overall benefit and risk of PEGPH20 when combined with Abraxane (nab-paclitaxel, Celgene Corp.) and standard-of-care gemcitabine, as well as the magnitude of PFS, interim OS data, and the toxicity profile.
Temporarily breaking down hyaluronan – which is present throughout the body – is what San Diego-based Halozyme's marketed, injectable version of hyaluronidase does. Hylenex is approved for better subcutaneous fluid administration to achieve hydration, as well as to increase the dispersion and absorption of other injected drugs. In subcutaneous urography, it's deployed for improving the resorption of radiopaque agents.
But Hylenex acts only locally at the injection site, is quickly inactivated in the body, and does not survive in the blood. That's where the pegylated form for cancer, PEGPH20, comes in, with an increased half-life and intravenous delivery. "There's a certain percentage of patients who have a high level of hyaluronan around their tumors," Torley said, around 50 percent in pancreatic cancer. Attacking hyaluronan at the corridor into the tumor can "reduce the pressure, open up the blood vessels, and deliver more drugs into it."
U.S. regulators' nod for the phase III work apparently signals that their concerns have been satisfied about thromboembolic events that surfaced with the compound. An ongoing phase II trial "started after we put some additional measures in place" with regard to such worries, Torley said. "We have a data safety monitoring committee in place, and we haven't heard anything from them, which we think of as good news." The phase II study began in the second quarter of 2013, and is expected to enroll about 124 patients getting gemcitabine and Abraxane with or without PEGPH20, with PFS the primary measure.
J.P. Morgan analyst Jessica Fye said her firm "had relatively low expectations that filing on PFS would be possible along these lines, and view today's update as a clear positive given that (a) it potentially speeds up time to filing and (b) we have seen strong interim phase II PFS data which we expect should hold up in phase III. Perhaps even more importantly, we view this positive third-party FDA feedback as a key de-risking event for a product that previously has had safety concerns," Fye wrote in a research report. Piper Jaffray analyst Charles Duncan agreed, noting in his report that approval on PFS "may be more capital-efficient than currently projected."
Torley said Halozyme is "still working on the statistics and final design elements" of the global phase III trial. The firm is "developing the approval path for the companion diagnostic in parallel," she said. "Before we start the phase III studies, we'll submit all of the required documents to the FDA," and will seek approval of the test and the drug at the same time.
The company has "no plans at this point" to partner the compound, Torley said. "We have continued over the last year in particular to build a very strong oncology team," and a phase Ib trial with PEGPH20 in non-small-cell lung cancer is ongoing, with data likely in the second half of this year. Breast cancer and some gastric tumors may also prove susceptible to PEGPH20 when given in tandem with other therapies.
Pancreatic cancer is "just the beginning," Torley said. "This whole concept of being able to work with the best therapies to date and increase their access into the tumors and make them even more effective has potential broad applications across several solid tumor settings." In animal models, Halozyme has "been able to demonstrate this repeatedly."
Shares of the company (NASDAQ:HALO) closed Wednesday at $15.28, up 66 cents.