SUBSPECIALTY NEWS

Genentech Delays Halting Avastin Sales to Compounding Pharmacies

Company Responds to AAO/ASRS Concerns.

JERRY HELZNER, SENIOR EDITOR

■ After a high-level meeting with representatives of the American Academy of Ophthalmology (AAO) and the American Society of Retinal Specialists (ASRS), Genentech agreed to continue sales of Avastin to compounding pharmacies until the end of this year. Earlier, Genentech had created deep concerns in the retina community by announcing that it would end all Avastin sales to compounding pharmacies as of Nov. 30.

In a joint AAO/ASRS statement released on Oct. 30, the two organizations said they were "encouraged" by the results of the meeting, which included Arthur D. Levinson, PhD, the CEO and chairman of Genentech. Discussions are expected to continue on the issue of Avastin availability.

Many retina specialists have been using the cancer drug Avastin instead of Genentech's FDA-approved Lucentis to treat wet AMD, especially for patients who are not on Medicare or who do not have health insurance. Avastin, an anti-VEGF agent that is closely related to Lucentis, becomes a relatively inexpensive therapy (approximately $50 to $100 an injection) when repackaged by a compounding pharmacy in the small amounts required for ophthalmic use.

Genentech conceded that the decision it announced on Oct. 11 to end sales to compounding pharmacies was "not made lightly" and certain to draw the ire of the retina community. The company had provided some initial assurance to retina specialists that Avastin would still be available for ophthalmic use through hospital pharmacies and direct sales to physicians.

A spokesperson for the biotech giant had also said that compounding pharmacies would probably continue to play a role in Avastin use, with the most likely scenario being that doctors would buy the drug from Genentech and send it to the compounders to break down vials into individual doses.

But those assurances had not been enough. The AAO and ASRS continued to press Genentech on the issue of Avastin availability, which resulted in the late October meeting. At the meeting, Genentech agreed to:

► delay the Avastin sales embargo to compounding pharmacies until Jan. 1, 2008, which allows the AAO and ASRS more time to help their members find work-around solutions

► not impede physicians or other legal agents (eg, group purchasing agents) from ordering Avastin or using compounding pharmacies after the embargo is in place

► seek advance comment from the Academy and ASRS on any direct-to-patient or direct-to-physician communications on Avastin vs Lucentis

► work with appropriate parties to make anti-VEGF therapy available for eligible low-income or underinsured patients

► ensure that an anti-VEGF agent (Avastin or Lucentis) can be made rapidly available for patients with time-critical needs in a way that minimizes in a legally appropriate manner the financial risk to the physician

► communicate directly with ophthalmologists on the issue of Avastin availability, beginning with the AAO meeting in New Orleans in November and at future ASRS meetings as well

Genentech has cited 3 major reasons for deciding to end its relationships with compounders:

► The company has an effective, FDA-approved therapy for wet AMD in Lucentis. The drug is available to uninsured patients as part of a program called Lucentis Commitment.

► Avastin is not formulated as an ophthalmic drug and has not been formally studied for ophthalmic indications. (The head-to-head CATT study comparing Lucentis and Avastin, funded by the National Institutes of Health, will begin soon.)

► The FDA has expressed concerns about the repackaging of Avastin for ophthalmic use, noting that repackaging an already sterile drug is not consistent with the role of compounding pharmacies.

The FDA also caused Genentech to destroy 350,000 vials of Avastin that were deemed unsuitable for ophthalmic use but suitable for the drug's FDA-approved cancer indication.

Genentech said it would reinstate sales to compounders if the FDA gave it "legal and regulatory authorization" to do so, a hint that the FDA is the key to resolving the Avastin issue.

VEGF-Trap Meets All Phase 2 Endpoints

A Phase 3 Study Has Begun.

■ Regeneron Pharmaceuticals, Inc. and partner Bayer HealthCare AG announced positive results from the full analysis of the primary 12-week endpoint of a phase 2 study evaluating VEGF Trap-Eye in the treatment of wet AMD.

In this double-masked, prospective, randomized, multicenter phase 2 trial, 157 patients were randomized to 5 groups and treated with VEGF Trap-Eye in 1 eye. Two groups received monthly doses of 0.5 or 2 mg of VEGF Trap-Eye and 3 groups received quarterly doses of 0.5, 2, or 4 mg of VEGF Trap-Eye (at baseline and week 12). Patients were monitored for safety, retinal thickness, and visual acuity (VA).

All 5 dose groups showed an improvement in retinal thickness and an increase in mean letters read vs baseline at all time points through week 12. There were no drug-related ocular or systemic serious adverse events reported. Treatment with VEGF Trap-Eye was generally well tolerated. The most common adverse events were those typically associated with intravitreal injections.

VEGF Trap-Eye met the primary study endpoint of a statistically significant reduction in retinal thickness after 12 weeks of treatment compared with baseline. All 5 dose groups combined showed a mean decrease of 119 μm, (P<.0001). The mean change from baseline in VA, a key secondary endpoint of the study, also demonstrated statistically significant improvement. All groups combined showed a mean increase of 5.7 letters, (P<.0001).

Preliminary analyses at 16 weeks showed that VEGF Trap-Eye, dosed monthly, achieved a mean gain in VA of 9.3 to 10 letters (for the 0.5 and 2 mg dose groups, respectively). In additional exploratory analyses, VEGF Trap-Eye, dosed monthly, reduced the proportion of patients with BCVA of 20/200 or worse (a generally accepted definition for legal blindness) from 14.3% at baseline to 1.6% at week 16; the proportion of patients with BCVA of 20/40 or better was likewise increased from 19.0% at baseline to 49.2% at 16 weeks.

Preliminary week 16 results showed that retinal thickness for all groups combined continued to improve, with a mean decrease of 159 μm vs baseline (P<.0001). The mean change from baseline in VA also continued to improve. All groups combined showed a mean increase of 6.6 letters vs baseline (P<.0001).

Patients receiving monthly doses of VEGF Trap-Eye, either 0.5 or 2 mg, achieved mean decreases in retinal thickness of 160 and 183 μm, respectively, and mean improvements in VA of 9.3 and 10 letters, respectively, at week 16. While quarterly dosing improved retinal thickness and VA vs baseline at 12 and 16 weeks, the effect was not as robust as with monthly dosing. A single 2-mg dose maintained similar effect on VA as 2 mg dosed monthly out to 8 weeks (5.8 vs. 6.2 letters gained at 8 weeks, respectively).

"We are particularly encouraged by the decrease, following monthly treatment, in the proportion of patients with vision at the legally blind level of 20/200 or worse, as well as the proportion of patients whose vision improved to 20/40 or better," said George D. Yancopoulos, MD, PhD, president of Regeneron Research Laboratories. "Our large phase 3 program will help us determine the full impact of VEGF Trap-Eye on visual acuity in these patient populations with significant unmet clinical needs."

"These results reaffirm the decision to study both the 0.5 mg and 2 mg monthly doses in the phase 3 program," stated Jeffrey Heier, MD, a clinical ophthalmologist at Ophthalmic Consultants of Boston, a primary investigator in the phase 2 study, and chair of the steering committee for the phase 3 VIEW 1 trial. "The quarterly dosing arms seemed to sustain their effect on visual acuity out to 8 weeks, providing the rationale for exploring an 8-week dosing schedule in the phase 3 program."

Regeneron and Bayer HealthCare AG initiated a phase 3 global development program for VEGF Trap-Eye in wet AMD in August of this year. In the first phase 3 trial, the companies will evaluate VEGF Trap-Eye using 4- and 8-week dosing intervals in direct comparison with Lucentis administered every 4 weeks according to its label. The phase 3 wet AMD study is currently being enrolled.

Regeneron and Bayer HealthCare are collaborating on the global development of VEGF Trap-Eye for the treatment of wet AMD, diabetic eye diseases, and other eye diseases and disorders.

Bayer HealthCare will market VEGF Trap-Eye outside the United States, where the companies will share equally in profits from any future sales of VEGF Trap-Eye. Regeneron maintains exclusive rights to the drug in the United States.

Top Retina Specialists Take New Posts

Drs. Haller, Olsen, and Puliafito Move Up.

■ Three prominent retina specialists have accepted prestigious new positions with increased professional responsibilities. For Julia Haller, MD, and Timothy Olsen, MD, the moves are from professor to department chairman. For Carmen Puliafito, MD, the move is from department chairman to dean of a highly regarded school of medicine.

► Dr. Haller has confirmed that she is moving from her post as Katharine Graham Professor of Ophthalmology at the Wilmer Eye Institute of John Hopkins University to ophthalmologist-in-chief at the Wills Eye Hospital and professor and chairman of the department of ophthalmology at Jefferson Medical College in Philadelphia.

► Dr. Olsen will move to Emory University in Atlanta on Jan. 1 to become chief of the department of ophthalmology and director of the Emory Eye Center. He is currently director of retina at the University of Minnesota School of Medicine, holding the William H. Knobloch Chair in ophthalmology. At Emory, Dr. Olsen will replace Thomas Aaberg Sr., who has been chairman of the department of ophthalmology for the past 20 years and who is retiring.

► On Nov. 1, Dr. Puliafito became the dean of the Keck School of Medicine at the University of Southern California. He previously served as director of the Bascom Palmer Eye Institute and chairman of the department of ophthalmology at the University of Miami Miller School of Medicine. Dr. Puliafito won acclaim in recent years for leading the resurgence of Bascom Palmer and restoring it to a position as the top-rated eyecare center in the United States. Under Dr. Puliafito's stewardship, Bascom Palmer has expanded its faculty from 33 members to 70, built 2 satellite eye centers, and opened a $22 million, 7-acre facility in palm Beach Gardens that has been called the most technologically advanced eyecare center in the country. Eduardo Alfonso, MD, a specialist in corneal and external disease, is currently serving in the positions relinquished by Dr. Puliafito. A search for a new director for Bascom Palmer will soon get under way.