Recent stories on bisphosphonate side effects might be signaling the advent of a new, superior drug, but will Halozyme’s rHuPH20 enzyme solve the problem of jaw necrosis?

Drug development companies operate within the overall consumer culture. We all want better drugs, better everything. Generic Fosamax (alendronate) now costs just $4 at Wal-Mart, Kroger and other retail pharmacies. What might make right now a better than usual time to get word out to the masses that Fosamax carries some dreadful, if quite rare, risks?

As we just reported, U.S. Food and Drug Administration official Diane Wysowski reveals in the current New England Journal of Medicine that the FDA has received 23 reports of esophageal cancer possibly linked to Fosamax between its October 1995 debut and May 2008. Of these patients, according to her report, so far 8 have died. Is there any ulterior reason in the fact that the FDA is publicizing this risk just now? Is anything better on the horizon?

Checking our good friend SEARCH, indeed there is. Just last month, December 2008, a Texas company, Healthcare Discoveries, began recruiting patients for a Phase I clinical trial of a new, subcutaneously injectable bisphosphonate drug made by Halozyme Therapeutics. Halozyme’s bisphosphonate uses an enzyme called rHuPH20 (recombinant human hyaluronidase PH20). Searching “bisphosphonate” at clinicaltrials.gov, brings up rHuPH20 top of a list of 195 bisphosphonate trials.

Halozyme Therapeutics’s immediate need as of December is for 72 people at risk for osteoporosis, who have not taken a bisphosphonate in the past 6 months and are willing to take a new type of osteoporosis drug. Some of these people would receive bisphosphonate alone, and some would receive it with rHuPH20. The company reported results of preclinical animal studies of rHuPH20 in April 2008.

Let’s step back a moment from cynicism — not a good spirit in which to start a new year. Or maybe turn it around. The question is not just why is FDA publicizing 23 cases of esophageal cancer now. It’s, what took them so long to report this as a rare side effect of Fosamax? And how sure can they be that just 23 people developed this cancer out of the millions who take Fosamax or other oral drugs in the same family (Boniva and Actonel)?

In May 2004, Salvatore Ruggiero, DMD, MD, reported 63 cases of another serious side effect of bisphosphonates, necrosis of the jaw. Dr. Ruggiero has continued to work on this problem since. In an article scheduled for publication January 9, he writes:

Bisphosphonate therapy has been considered standard therapy in the management and care of cancer patients with metastatic bone disease and patients with osteoporosis. The efficacy of these drugs is due to their ability to inhibit osteoclast-mediated bone resorption. However, the postmarketing experience with intravenous and, to a much lesser extent, oral bisphosphonates has raised concerns about potential side effects related to profound bone remodeling inhibition and osteonecrosis isolated to the jaws. We review the risk factors, incidence, pathogenesis, prevention strategies, and management of this new complication.

Every new drug development brings a ray of hope and a whole new set of questions. Halozyme’s enyzme treated bisphosphonate is designed, as an injectable, to bypass 2 obstacles to patients’ treatment with this class of drugs: risk from taking the pill form and inconvenience or hardship of reaching a center to receive infusion. The company writes:

Bisphosphonates are a class of molecules that bind to mineralized bone matrix and inhibit bone resorption. Currently, there are oral and intravenous bisphosphonates. Oral Bisphosphonates often cause gastrointestinal side effects and require a cumbersome dosing regimen. The gastrointestinal side effects of oral bisphosphonates is a significant cause of patient non-compliance to prescribed therapy. Certain bisphosphonates are indicated for the treatment of osteoporosis and skeletal metastases, but can only be administered today by intravenous infusion. As such, patients often have to travel to an infusion center or see a specialist to receive their intravenous bisphosphonate infusion. Subcutaneous injections of bisphosphonates are not considered feasible due to injection site toxicity in the skin and/or impractical injection volumes.

The recombinant protein, rHuPH20, is a human hyaluronidase enzyme that increases the dispersion and systemic absorption of locally injected drugs by temporarily degrading hyaluronan under the skin.

This new injectable format will likely completely resolve the problem of gastrointestinal effects and also any risk of cancer of the espohagus. The injection will not irritate or involve any part of the digestive tract. But whether this investigational drug will help in any way with the other problem, of bisphosphonates’ anti-healing effects on injured bone (such as the jaw after dental extraction) remains to be seen.