Lead therapeutic candidate, PEGPH20, is based on Halozyme’s proprietary rHuPH20 enzyme. rHuPH20 is a recombinant human hyaluronidase enzyme, which temporarily degrades hyaluronan (HA), a glycosaminoglycan or chain of natural sugars that accumulate around certain tumors.
Preclinical studies have shown that removal of HA from tumors improves the ability of chemotherapies or immunotherapies to penetrate the tumor, inhibiting its growth.
How Does It Work?
Certain cancers, including pancreatic, breast, lung, colon and prostate, have been shown to accumulate high levels of hyaluronan (HA). This accumulation creates a unique microenvironment that fosters the growth of tumor cells and generates barriers to drug delivery, inhibiting the potential effectiveness of many anti-cancer agents.
Breaking through the HA component of the tumor microenvironment opens previously constricted vessels, which may increase blood flow and access of co-administered therapies to the tumor.
Halozyme initiated a Phase 1 clinical trial 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.
Today, Halozyme is conducting multiple clinical trials of PEGPH20 in patients with a range of previously treated or untreated solid tumor malignancies in combination with both chemotherapies and immunotherapies.
Key Events and Data Timeline for PEGPH20
- In January 2017, Halozyme reported topline results from the combined analysis of Stages 1 and 2 and Stage 2 alone of its HALO-202 study as of December 2016. HALO-202 is a Phase 2 randomized, multi-center clinical trial of lead investigational drug PEGPH20 in combination with ABRAXANE® (nab-paclitaxel) and gemcitabine in stage IV pancreas cancer patients. Among the findings, the primary endpoints were achieved, showing a statistically significant increase in progression-free survival (PFS) for the efficacy evaluable population and by demonstrating a reduction in the rate of thromboembolic events in Stage 2 of the study in the PEGPH20 arm.
- The combined study population showed a statistically significant increase in PFS in the targeted HA-High patient population. Patients with high levels of hyaluronan (HA-High) treated with PEGPH20 plus ABRAXANE and gemcitabine (PAG arm) when compared to HA-High patients receiving ABRAXANE and gemcitabine (AG arm) alone.
- Stage 2 of the study, which completed enrollment in February 2016, showed a 91% improvement in median PFS for HA-High patients. PFS in the PAG arm was 8.6 months vs. 4.5 months in the AG arm, hazard ratio with a 95% confidence interval of 0.63 (0.21, 1.93).
- In Stage 2, the overall survival (OS), an exploratory endpoint, showed a 50% improvement in HA-High patients in the PAG arm was 11.7 months vs. 7.8 months in the AG arm, hazard ratio with a 95% confidence interval of 0.52 (0.22, 1.23).
- In June 2016, Halozyme announced results from a analysis as of February 2016 in 135 patients with metastatic pancreatic cancer who were treated in Stage 1 of HALO 109-202, a Phase 2 clinical study of its investigational new drug PEGPH20 in combination with ABRAXANE® (nab-paclitaxel) and gemcitabine (PAG arm) as compared to ABRAXANE and gemcitabine alone (AG arm). This final analysis of Stage 1 secondary and exploratory endpoints was conducted using the Ventana companion diagnostic assay to retrospectively identify high levels of HA. The key results based on a February 2016 data cut-off showed in the HA-High patient population are as follows:
- Median progression-free survival (PFS) was 9.2 months in the PAG arm vs. 6.0 months in the AG arm, hazard ratio with a 95% confidence interval of 0.46 (0.15, 1.40);
- Overall response rate (ORR) was 50%, including one complete response in the PAG arm vs. 33% and all partial responses in the AG arm;
- Median duration of response was 8.1 months in the PAG arm vs. 3.7 months in the AG arm;
- The exploratory analysis of median overall survival was similar between the treatment arms -- 11.8 months vs. 10.9 months in the PAG vs. AG arms, respectively. Factors potentially having an impact on these results include less aggressive disease among patients in the AG arm and a greater than 40% discontinuation rate of PEGPH20 treatment at the time of the clinical hold, resulting in all patients receiving AG alone in both arms;
- The rate of thromboembolic events reduced from 43% to 9% in the PAG arm and from 25% to 6% in the AG arm with the introduction of prophylaxis with low molecular weight heparin (enoxaparin) from Stage 1 to Stage 1 of the study.
- In May 2015, Halozyme presented interim findings from the ongoing Phase 2 clinical study of its investigational new drug PEGPH20 in combination with ABRAXANE® (nab-paclitaxel) and gemcitabine 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 HA.
- In December 2014, the European Commission, acting on the recommendation from the Committee for Orphan Medicinal Products of the European Medicines Agency (EMA), designated PEGPH20 as an orphan medicinal product for the treatment of pancreatic cancer.
- In October 2014, the FDA granted Orphan Drug designation for PEGPH20 for the treatment of pancreatic cancer.
- In August 2014, the FDA granted Fast Track designation for the treatment of patients with metastatic pancreatic cancer using PEGPH20 in combination with ABRAXANE® (nab-paclitaxel) and gemcitabine.
- In September 2013 at the European Cancer Congress, Halozyme 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 better to PEGPH20 has resulted in our effort to develop a companion diagnostic to enable pre-selection of these patients.
- In June 2013 at the American Society of Clinical Oncology (ASCO) Annual Meeting, Halozyme presented 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). The 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 three weeks, followed by no PEGPH20 treatment in Week 4 (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% (10 of 24 patients, 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.