mAbs have provided new, effective treatments for patients with multiple diseases ranging from cancer to autoimmune disorders. More than 20 monoclonals including murine, chimeric, humanized, and human antibodies have been approved by the FDA. Estimates of total worldwide antibody sales in 2008 range from $25.1 billion to $32 billion, and mAbs now command between 25% to 30% of the global biologic drug market.
Monoclonals continue to pay off handsomely for the companies that develop them. For example, Roche’s Herceptin, sanctioned for Her-2 neu positive breast cancers, raked in about $4.8 billion (CHF 5.1 million) in global sales during 2008. Even at the development stage, mAbs are great assets to leverage in deal-making; GenMab received $459 million up front through cash and an equity investment from GlaxoSmithKline in December 2006 for its then late-stage mAb. The total value of the deal was $2.1 billion, and GenMab received a $23 million milestone fee most recently when Arzerra gained accelerated approval for chronic lymphocytic leukemia.
The financial potential of mAbs may, however, be limited most by delivery-related issues. Large doses are often required, particularly for chronic conditions. Couple this with the fact that mAbs can only be delivered intravenously and you get a recipe for potential administration-related side effects. Not to mention that pricing for these drugs is staggering.
Improved administration could enhance uptake and compliance, in turn padding a company’s bottom line. With the complete takeover of Genentech, which focused on mAbs, Roche seems to have turned its attention to facilitate deliverability of these drugs.
Earlier this month the company decided to spend $181 million or so (CHF 190 million) on two European manufacturing facilities to develop a patient-friendly device that could allow the subcutaneous (SC) self-administration of its biological anticancer drugs. Additionally, it paid Halozyme Therapeutics $20 million up front and agreed to another $581 million in milestones in December 2006 for exclusive, global rights to the firm’s delivery technology.
Herceptin Dosing and Pricing
The market for Herceptin has already expanded beyond breast cancer. On January 28, Roche won EC approval of the drug in Her2-positive metastatic stomach cancer. About 16% of patients with stomach cancer have tumors expressing high levels of Her-2, according to the company.
In general, mAbs require the delivery of between 100 mg and 1 g of protein per dose. Because the high end of formulation concentrations for mAbs is in the range of 50 mg/mL, treatments commonly require the administration of 2–20 mL through IV infusion, which has to be performed in a clinical or hospital setting.
For breast cancer treatment, a year’s course of Herceptin costs over $38,000, dosing generally takes 60–90 minutes, with follow up and maintenance administration sessions requiring 30-minute sessions twice weekly. Herceptin carries a black box warning partly related to its mode of administration, which can result in infusion reactions including anaphylaxis, angioedema, and acute respiratory distress syndrome.
Exploring the Subcutaneous Route
Roche has thus been conducting Phase III studies to determine the efficacy of subcutaneously administered Herceptin to provide both convenient administration and potentially avoid reactions associated with infusions. The formulation was developed using Halozyme’s Enhanze technology. Dosing of the first patient, in October 2009, triggered a $5 million fee to Halozyme.
Halozyme’s Enhanze technology is based on recombinant human PH20 (rHUPH20), a recombinant version of human hyaluronidase. This naturally occurring enzyme degrades hyaluronic acid, a space-filling, gel-like substance that is a major component of tissues throughout the body, such as skin and cartilage. The PH20 enzyme digests hyaluronic acid to temporarily break down the gel and facilitate the penetration and diffusion of other drugs and fluids that are injected under the skin or in the muscle.
Halozyme says that co-injection of a drug with rHUPH20 allows administration of up to five times more volume than normally feasible with subcutaneously injected drugs, or 5–10 mL versus 1–2 mL. This may “allow the conversion of intravenously administered pharmaceuticals to more desirable local routes,” making it possible for patients with chronic diseases to self-administer these medicines.
The current clinical trial will not use the device that Roche is also working on, but the company plans to have the device available for use with the new SC formulation, assuming it gets approved. The production line in Kaiseraugst, Germany, will provide the supply for clinical studies and market launch. A full-scale automated production line in Mannheim will deliver commercial supply to markets.
Halozyme investor relations director, Robert Uhl, told GEN that the subcutaneous delivery device would be “about the size of a cell phone.” He said that it would come preloaded with the Herceptin-PH20 mixture for one-time use and would then have to be returned for re-fill and re-use. “The patient can put it on the abdomen, push a button, and the infusion is complete within five minutes,” Uhl explained.
The technology would allow subcutaneous administration of up to 5–20 mL without causing discomfort to the patients, according to Uhl. He pointed out that trips to infusion centers can be very difficult and emotionally trying for patients who often have to wait to be paged for their infusions, adding to their anxiety.
To date, one preclinical study in mice supports the use of PH20 to facilitate subcutaneous antibody delivery. This mouse study compared intravenous and subcutaneous administration of Remicade alone to its subcutaneous administration with PH20. Remicade, an anti-TNF antibody approved for Crohn disease, rheumatoid arthritis, and psoriatic arthritis, is currently delivered to patients intravenously at one to three month intervals. Study results showed that subcutaneous administration with PH20 dramatically improved the bioavailability of the antibody and exhibited pharmakokinetic profiles more similar to intravenous dosing.
Should the Herceptin/PH20 clinical trial prove successful, the PH20 drug-delivery enhancing technology may overcome clinical risks and inconvenience associated with intravenous antibody infusions for cancer treatment and facilitate antibody use in chronic diseases where repeated administration is required.