FDA approves fomivirsen for CMV
WASHINGTON - The Food and Drug Administration (FDA) has approved fomivirsen sodium injectable for treating cytomegalovirus (CMV) retinitis. Marketed as Vitravene, it was developed by Isis Pharmaceuticals (Carlsbad, Calif.) and Ciba Vision Corp. (Atlanta).
Vitravene, which applies antisense technology, underwent a priority review process because it may substantially delay the progression of CMV. According to Daniel L. Kisner, MD, president and chief operating officer of Isis Pharmaceuticals and head of the clinical program, it was reviewed and approved in only 5 months.
The agent is indicated for use in patients with AIDS who are intolerant of or have a contraindication to other treatments for CMV retinitis or who were insufficiently responsive to previous treatments. The recommended dosage consists of an induction dose on days 1 and 15 followed by a monthly intravitreal injection of 330 µg.
The highly active anti-retrovirus therapies (HAART) caused patient recruitment in the fomivirsen studies to dwindle to as low as one new patient a month, said Dr. Kisner. HAART therapies caused a 75% drop in new cases of CMV retinitis.
However, the antivirals are causing resistance in some patients. Without enough patients to fully study the drug, the FDA had to accept the small patient pool when considering whether to approve the drug. Antisense drugs such as fomivirsen stop the formation of the proteins active in CMV retinitis replication. The drug is 10 to 30 times more potent than ganciclovir, Dr. Kisner said.
According to John W. Chandler, MD, of Bellingham, Wash., who presented the data to the advisory committee, "The other CMV drugs have a similar mechanism of action and have cross-resistance patterns to them. This offers an alternative to avoid systemic resistance." Dr. Chandler headed the clinical trials of fomivirsen.
The study presented 433 eyes that received two dosing regimens. For cases of new CMV, researchers injected 165 µg every week for three doses and then every other week for maintenance. Patients who had received previous therapies were given 330 µg in 3 weekly injections, followed by every fourth week for maintenance.
According to Dr. Chandler, fomivirsen has a safety profile that compares favorably with other drugs. Events include intra ocular inflammation, which can be treated with corticosteroids, and a transient elevation of intraocular pressure. The retinal detachment rate has been low, and repeated vitreal infections have not been a problem.
Researchers are applying other available drugs in new ways to combat the existing cases of CMV retinitis.
Glenn J. Jaffe, MD, an associate professor at Duke University Eye Center in Durham, N.C., is participating in four complementary clinical trials with ganciclovir, two apiece by Hoffmann-LaRoche (Nutley, N.J.) and Isis.
Two trials by Hoffmann-LaRoche are testing an oral prodrug of ganciclovir to treat either new cases or cases previously treated with intravenous ganciclovir. The oral prodrug is 10 times more potent than the regular oral form and is thought to of fer the potency of intravenous administration with the convenience of oral dosing.
Two more studies in conjunction with Isis are testing fomivirsen in patients with extensive CMV lesions or those who are unresponsive to standard therapy with ganciclovir. The advantage to these two studies is that patients do not exhibit the cross-resistance to fomivirsen that they do to ganciclovir or cidofovir.
Sally Nuessle associate director for medical information and safety surveillance at Gilead Sciences Inc. in Foster City, Calif., said that trials of cidofovir (Vistide, Gilead Sciences) in pediatrics and herpetic keratitis are under way.
Gilead has also joined with Bausch & Lomb Surgical (St. Louis) to evaluate an ophthalmic formulation of cidofovir for viral keratoconjunctivitis, currently in phase 2 clinical studies.
Left eye of patient with newly diagnosed peripheral CMV retinitis. Baseline photos of patient in immediate treatment group, August 1996. Disk/macula and inferior views.
Same patient in October 1997, extended maintenance week 56, after 30 doses of 165 g fomivirsen. Disk/macula and inferior-nasal views. Photos courtesy Isis Pharmaceuticals.
For Your Information:
- Daniel L. Kisner, MD, can be reached at Isis, (760) 931-9200; fax: (760) 931-9639.
- John W. Chandler, MD, can be reached at (360) 715-3604; fax: (360) 715-3606. Dr. Chandler did not disclose if he has a direct financial interest in the products mentioned in this article. He is a paid consultant for Isis Pharmaceuticals Inc.
- Glenn J.Jaffe, MD, can be reached at (919) 684-4458; fax: (919) 681-6474. Dr. Jaffe has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
- Sally Nuessle can be reached at Gilead, (800) GILEAD5 or (650) 572-6668; fax: (650) 577-5477.