"These findings clearly demonstrate the activity of our long acting PEGPH20 enzyme candidate against HA-rich tumors in combination with chemotherapy," said Gregory Frost, PhD, Halozyme's Vice President and Chief Scientific Officer. "By targeting tumors that overproduce the HA matrix component, PEGPH20 may selectively attack tumor interstitial fluid pressure and combined with chemotherapy, reduce tumor burden for a significant number of patients."
Halozyme is continuing its pharmacology, manufacturing and toxicology studies as part of its PEGPH20 development program in oncology. The company is making preparations for a pre-IND meeting with the FDA later this year to seek advice with regard to the design of its first-in-human clinical trial and plans to initiate studies in cancer patients with PEGPH20 during the first half of 2009.
Study Details and Background
This study utilized three widely accepted animal cancer models: xenograft PC3, xenograft Du145luc, and PC3-M-luc bone metastases. For the HA-producing xenograft PC3 model, animals received an intramuscular inoculation with PC3 prostate carcinoma cells in the hind leg in order to generate tumors with high IFP. When tumor volume reached 400-500 mm(3), a high tumor burden, animals were randomized to receive one of four possible treatments: PEGPH20 alone, chemotherapy alone, chemotherapy plus PEGPH20, or placebo. Two chemotherapeutic agents, docetaxel and liposomal doxorubicin, were tested in this model. The non-HA-producing xenograft Du145luc model was utilized in a similar manner with docetaxel. Finally, an HA-producing PC3-M-luc disseminated bone metastasis model was used to test PEGPH20 alone and in combination with docetaxel.
Xenograft PC3 results
-- Tumor volume growth suppressed significantly. Tumor volume growth over time was significantly lower in the PEGPH20 plus docetaxel (p<0.01) and PEGPH20 plus liposomal doxorubicin (p<0.05) groups compared to chemotherapy alone. These results clearly indicate a synergistic effect with the addition of PEGPH20 to the docetaxel regimen. Furthermore, a significant reduction in tumor volume was observed following administration of PEGPH20 alone.
-- Survival for combination treatment was significantly increased. Docetaxel plus PEGPH20 increased life span by 225% while docetaxel alone increased life span by 59% relative to control. Furthermore, the survival benefit produced by the combination treatment was significantly better than docetaxel alone (p=0.003).
Xenograft Du145luc results -- Tumor volume growth unaffected by combination treatment, as expected. Human Du145luc prostate tumor cells do not produce hyaluronan, and no change in interstitial fluid pressure was observed following PEGPH20 treatment. Therefore, treatment with an HA-reducing treatment regimen would not be expected to provide a therapeutic benefit. Results demonstrated no meaningful difference in tumor volume between the docetaxel alone and PEGPH20 plus docetaxel treatment groups. In addition, unlike the HA-producing PC3 tumors, tumor growth curves in the control and the PEGPH20 groups were virtually superimposable. These findings support the proposed mechanism of action that only HA-producing tumors would be most susceptible to PEGPH20.
PC3-M-luc bone metastases results
-- Survival benefit demonstrated. Two different combination dosage regimens of PEGPH20 plus docetaxel demonstrated improved survival compared to the control group. For this model, tumor cells are injected directly into the left ventricle and migrate to bone tissue.
Hyaluronan is a dominant constituent of the extracellular matrix in subsets of many solid tumor types, including prostate, breast, ovarian, pancreatic, and gastric, where it may increase the resistance to chemotherapeutic agents. Previous studies presented by Halozyme (Thompson et al. Proceedings AACR Annual Meeting, Volume 49, April 2008) demonstrated significant reductions of HA around the tumor, IFP, and tumor water content after intravenous administration of PEGPH20. Elevated tumor IFP is believed to limit the response to cytotoxic treatment regimens in many solid tumors. Removal of peritumoral HA and the lowering of IFP may potentially lead to improved responses to chemotherapy and a more rapid reduction of tumor volume that could potentially improve patient survival.
Pegylation refers to the covalent attachment of polyethylene glycol to a molecule, usually a drug or therapeutic protein. A pegylated molecule may be masked from the immune system and have a prolonged circulatory time due to a reduction in renal clearance. The pegylation of rHuPH20 increases its plasma half-life to greater than 24 hours compared to less than one minute for the unpegylated enzyme, therefore resulting in a longer duration of action.
About Halozyme Therapeutics, Inc.
Halozyme is a biopharmaceutical company developing and commercializing products targeting the extracellular matrix for the drug delivery, metabolism, oncology and dermatology markets. The company's portfolio of products and product candidates is based on intellectual property covering the family of human enzymes known as hyaluronidases. The company's Enhanze(TM) Technology is a novel drug delivery platform designed to increase the absorption and dispersion of biologics. Its key partnerships are with Roche to apply Enhanze Technology to Roche's biological therapeutic compounds for up to 13 targets and with Baxter to apply Enhanze Technology to Baxter's biological therapeutic compound, GAMMAGARD LIQUID 10%. In addition, the company has received FDA approval for two products: Cumulase®, for use in in-vitro fertilization, and HYLENEX, for use as an adjuvant to increase the absorption and dispersion of other injected drugs and fluids. HYLENEX is partnered with Baxter International Inc. The Company also has a number of different enzymes in its portfolio that are targeting significant areas of unmet need.
Safe Harbor Statement
In addition to historical information, the statements set forth above include forward-looking statements (including, without limitation, statements concerning the safety and efficacy of PEGPH20 in animal models) that involve risk and uncertainties that could cause actual results to differ materially from those in the forward-looking statements. The forward-looking statements are also identified through use of the words "believe," "enable," "may," "will," "could," "intends," "estimate," "anticipate," "plan," "predict," "probable," "potential," "possible," "should," "continue," and other words of similar meaning. Actual results could differ materially from the expectations contained in forward-looking statements as a result of several factors, including regulatory approval requirements and competitive conditions. These and other factors that may result in differences are discussed in greater detail in the company's reports on Forms 10-K, 10-Q, and other filings with the Securities and Exchange Commission.
Halozyme Contact Media Contacts Robert H. Uhl Karen Sparks / Joleen Schultz Senior Director, Investor Relations Mentus (858) 704-8264 (858) 455-5500, x275/x215 ruhl@halozyme.com karen@mentus.com jschultz@mentus.com
Source: Halozyme Therapeutics, Inc.
