Certain cancers, including pancreatic, breast, colon and prostate, have been shown to accumulate high levels of hyaluronan (HA). Aberrant accumulation of this component of the tumor’s infrastructure supports a protective network or “halo” that surrounds certain tumors. This pathologic accumulation of HA along with other matrix components also increases tumor interstitial fluid pressure, constricting tumor vasculature and creating a unique microenvironment for the growth of tumor cells compared to normal cells. These mechanisms generate barriers to drug delivery that inhibit the potential effectiveness of many anti-cancer agents. Dismantling the HA component of the tumor architecture disrupts this unique tumor microenvironment and opens the previously constricted vessels which may increase blood flow to the tumor. This may allow cancer therapies to be more efficiently delivered to their target and thus may be more effective.
Halozyme’s FDA-approved, HYLENEX® recombinant human hyaluronidase, rHuPH20, is administered subcutaneously and temporarily and reversibly degrades HA to facilitate the absorption and dispersion of other injected drugs or fluids and for subcutaneous fluid administration. However, rHuPH20 acts only locally at the injection site, is rapidly inactivated in the body, and does not survive in the blood. An investigational PEGylated form of rHuPH20, PEGPH20, in under development by Halozyme to increase the half-life of the compound in the blood and allows investigation for intravenous administration.
A Phase 1 clinical trial was initiated in 2009 to assess PEGPH20 over a range of doses and frequencies to assess the safety and tolerability of the treatment in patients with solid tumor malignancies refractory to prior therapies, which included patients with pancreatic cancer. A Phase 2 trial, with a Phase 1b run-in period, has been initiated for patients with metastatic pancreatic cancer. The patients will receive the standard of care, gemcitabine, with PEGPH20 or with placebo. Additional preclinical investigations are also underway to explore combinations of PEGPH20 with other targeted and cytotoxic agents.
In June 2013, we presented the results from a Phase 1b clinical study of PEGPH20 in combination with gemcitabine for the treatment of patients with stage IV metastatic pancreatic cancer (Phase 1b PEGPH20 Clinical Study) at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting. This study enrolled 28 patients with previously untreated stage IV pancreatic ductal adenocarcinoma. Patients were treated with one of three doses of PEGPH20 (1.0, 1.6 and 3.0 µg/kg twice weekly for four weeks, then weekly thereafter) in combination with gemcitabine 1000 mg/m2 administered intravenously. In this study, the overall response rate (complete response + partial response) by RECIST 1.1 criteria was 42 percent (10 of 24 patients, 95 percent CI 22 - 62 percent) for those treated at therapeutic dose levels of PEGPH20 (1.6 and 3.0 µg/kg) as assessed by an independent radiology review.
In September 2013, at the European Cancer Congress 2013, we presented exploratory post-hoc analysis of progression free survival and overall survival of a small subset of patients treated with PEGPH20 with available biopsy samples and HA scores in the Phase 1b study. Both progression free survival and overall survival were longer in patients with high levels of tumor HA compared to patients with low levels of tumor HA. The observation that patients with tumors characterized by high levels of HA may respond best to PEGPH20 has resulted in our effort to develop a companion diagnostic to enable pre-selection of these patients.
In the second quarter of 2013, we initiated a Phase 2 multicenter, randomized clinical trial evaluating PEGPH20 as a first-line therapy for patients with stage IV metastatic pancreatic cancer. Approximately 124 patients are expected to participate in the study and receive gemcitabine and nab-paclitaxel (ABRAXANE™) either with or without PEGPH20. The primary outcome will be to measure progression-free survival between patients administered with PEGPH20 and those who are not. In addition, in October 2013, SWOG, a cancer research cooperative group of more than 4,000 researchers in over 500 institutions around the world, initiated a 144 patient Phase 1b/2 randomized clinical trial of PEGPH20 in combination with modified FOLFIRINOX chemotherapy (mFOLFIRINOX) compared to mFOLFIRINOX treatment alone in patients with metastatic pancreatic adenocarcinoma.
On October 2, 2014, the FDA granted Orphan Drug designation for PEGylated recombinant human hyaluronidase (PEGPH20) for the treatment of pancreatic cancer. The FDA Office of Orphan Products Development (OOPD) mission is to advance the evaluation and development of products (drugs, biologics, devices, or medical foods) that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions.
In May 2015, we presented interim findings from the ongoing phase 2 clinical study of its investigational new drug PEGPH20 for the potential treatment of patients with metastatic pancreatic cancer at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting. The trial included 135 treated patients in stage 1, of whom a total of 44 patients -- 23 receiving PEGPH20 in combination with ABRAXANE® and gemcitabine (PAG treatment arm) and 21 receiving ABRAXANE and gemcitabine alone (AG treatment arm) -- had available biopsies that were determined in a retrospective analysis to have high levels of hyaluronan (HA). PEGPH20 targets HA to help improve cancer therapy access to tumor cells.
The interim data was presented as part of an oral presentation by Principal Investigator Sunil Hingorani, M.D., Ph.D., Associate Member of the Fred Hutchinson Cancer Research Center and Associate Professor at University of Washington School of Medicine. Click here for a .pdf copy of the ASCO 2015 oral presentation.
Results reported include:
- A more than doubling of median progression-free survival of 9.2 months versus 4.3 months in high HA patients treated with PAG vs. AG (hazard ratio of 0.39; p-value of 0.05);
- A more than doubling of overall response rate of 52 percent versus 24 percent (p-value of 0.038) and a duration of response of 8.1 months compared to 3.7 months in high HA patients treated with PAG versus AG;
- In the 30 high HA patients (15 PAG treatment arm versus 15 AG treatment arm) who were evaluated for response prior to the April 2014 clinical hold and subsequent PEGPH20 treatment discontinuation, the overall response rate was 73 percent versus 27 percent (p-value of 0.01), respectively, consistent with findings presented in January;
- A trend toward improvement in median overall survival of 12 months compared to 9 months in high HA patients treated with PAG versus AG (hazard ratio of 0.62) despite discontinuation of PEGPH20 in more than half of the PAG-treated patients at the time of the clinical hold in April 2014.
Data was also presented on the rate of thromboembolic (TE) events in 55 patients treated in stage 2 of the trial, which is currently randomizing patients at a 2:1 ratio of PAG versus AG. Stage 2 began after a protocol amendment in July 2014, excluding patients at high risk of TE events and adding prophylaxis with low molecular weight heparin (enoxaparin) to all patients in both treatment arms. Reported results included:
- A TE event rate of 13 percent in 38 patients treated with PAG versus 18 percent in 17 patients receiving AG;
- In the 20 PAG patients receiving 1 mg/kg/day of enoxaparin, no TE events have been reported to date.