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, has been developed by Halozyme which dramatically increases the half-life of the compound in the blood and allows for intravenous administration.
In pre-clinical models, treatment of mice bearing tumors with PEGPH20 alone was found to significantly reduce the growth of tumors that accumulate HA. Experiments with other tumor types suggest that PEGPH20 is selectively active against tumors that contain high levels of HA. Multiple preclinical studies have demonstrated that PEGPH20 degrades tumor-associated HA and reduces interstitial fluid pressure in tumors with elevated HA. An estimated 20% to 30% of solid tumors are thought to contain high levels of HA.
Additional animal studies demonstrate that administration of PEGPH20 in combination with other chemotherapeutic agents, such as docetaxel, liposomal doxorubicin or gemcitabine, decrease tumor burden and can increase survival when compared to either agent used alone. These studies supported progression to clinical trials to study the effectiveness of PEGPH20 as an enhancer of chemotherapeutic agents in tumors rich in HA.
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.
We are currently conducting clinical trials with PEGPH20 in the treatment of solid tumors. In these trials, a dose of oral dexamethasone, a steroid, is administered to all patients prior to and subsequent to intravenous administration of PEGPH20 to minimize the side effects of PEGPH20. Our Phase 2 clinical trial, with a Phase 1b run-in period, for patients with metastatic pancreatic cancer is currently ongoing, and the enrollment of the run-in phase is complete. We have identified our intended Phase 2 dose of PEGPH20 in combination with gemcitabine, a chemotherapeutic drug. The preliminary efficacy and safety results were presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting. In this single-arm Phase 1b trial, the overall response rate (complete response + partial response) by RECIST 1.1 criteria was 42 percent (95% CI 22 - 62) for those treated at therapeutic dose levels of PEGPH20 (1.6 and 3.0 µg/kg) as assessed by an independent radiology review (n=24). Additionally, in subjects with high levels of hyaluronan (HA), a substance found in a protective matrix that surrounds many pancreatic cancers, the overall response rate was 64 percent (7 of 11 subjects with available biopsy). Moreover, 43 percent (6 of 14 subjects) saw a reduction of at least 70 percent in serum carbohydrates antigen 19-9 (CA 19-9), a biomarker which often correlates with tumor cell burden. As a result, we have initiated a new Phase 2 multicenter, randomized clinical trial evaluating PEGPH20 as a first-line therapy for patients with stage IV metastatic pancreatic cancer wherein approximately 124 patients will participate in the study and receive gemcitabine and nab-paclitaxel either with or without PEGPH20. The primary outcome will be to measure progression-free survival between patients administered PEGPH20 to those who are not.