Lucentis Shines In Diabetic Eye Disease, But Competition Looms From Cheap, Off-Label Avastin

Clinically speaking, Roche/Genentech’s injectable Lucentis (ranibizumab) looks well-positioned for a role in diabetic macular edema after the full release of Phase III trial data.

However, the good news could wind up spurring use of Roche’s Avastin (bevacizumab), which is already being used off-label in DME and other eye diseases at a fraction of the cost.

Two pivotal trials show that Lucentis, given as a monthly injection, significantly improves vision and slows disease progression compared to a placebo injection.

Genentech plans to submit an sBLA for diabetic macular edema this fall.

Lead investigator David Boyer, a clinical professor at the University of Southern California Keck School of Medicine, presented the full results of these 24-month, Phase III studies, known as RIDE and RISE, at the American Diabetes Association meeting on June 28 in San Diego. Top-line results had been announced in March.

Lucentis is a monoclonal antibody fragment derived from the vascular endothelial growth factor inhibitor bevacizumab, which is approved for a number of cancers but is also used widely off-label in eye disease.

The only FDA-approved therapy for diabetic macular edema is laser treatment, which prevents further vision loss but does not improve sight. As a result, Avastin, steroids and other drugs are used off-label. Lucentis is currently FDA-approved for macular edema after retinal vein occlusion and wet age-related macular degeneration. Genentech plans to submit an sBLA to FDA for diabetic macular edema this fall.

Pushback On Price

In the U.S. Lucentis costs about $2,000 per injection, compared to Avastin, which is compounded in pharmacies in microdoses and available at a cost of about $50 per injection, also typically given monthly. Because of the price differential, Avastin is often used off-label instead of Lucentis for certain eye diseases – although it is unclear how much of Avastin’s total use comes from off-label ophthalmic applications, including DME.

In Europe, where rights to the drug are owned by Novartis, Lucentis already won approval for diabetic macular edema this year, but governments are pushing back on price .

Setting price aside, in an interview after the presentation, David Kendall, the ADA’s chief medical and scientific officer, said that the RIDE/RISE data are exciting because they demonstrate that the drug not only prevents further loss of sight but actually improves it. The results will have “very practical implications” for patients if FDA approves the drug.

Two doses of Lucentis were tested in the identical RISE and RIDE trials. The percentage of people able to achieve vision of greater than 20/40, which is required for driving, was 37.8% for placebo, compared to 60% and 63.2% with Lucentis in RISE. And in RIDE, the placebo rate was 34.6% vs. 54.4% and 62.2% for Lucentis.

In an interview at the meeting, Boyer acknowledged that as with other diseases, clinicians may think they can substitute Avastin for Lucentis based on the results. However, evidence does not support interchangeability in DME.

“It would be nice to have a head-to-head study to see if Avastin is safe in this population and if the results are equal,” Boyer said. “Unless you have a head-to-head study, it’s just anecdotal as to whether it [Avastin] works.

Roche/Genentech has no plans to perform a head-to-head study.

Results, published this spring from the high-profile Comparison of Age Related Wet Macular Degeneration Treatment Trial (CATT), showed little difference in efficacy between the two drugs (Also see "Lucentis And Avastin Stack Up In CATT, Forcing Genentech/Novartis To Play Defense" - Pink Sheet, 28 Apr, 2011.). But these results cannot be extrapolated to diabetic macular edema, Boyer said.

Roche is not planning on doing anything to discourage use of Avastin off-label instead of Lucentis in this indication, according to Tony Adamis, Roche/Genentech’s global head of ophthalmology. Doctors and their patients will make a choice based on the evidence, he said.

Full Results For RISE And RIDE

Asked to comment on the commercial opportunity for Lucentis in the U.S., Adamis noted the “substantial unmet medical need” in diabetic macular edema.

DME occurs when damaged blood vessels leak into the retina, causing swelling and impairing vision. Striking 10% of people with diabetes, or about two million people in the U.S., diabetic macular edema can lead to blindness if left unchecked. About 75,000 new cases are diagnosed each year in the U.S.

Results from the RISE and RIDE studies, with 377 and 382 participants respectively, suggest that Lucentis improves vision and delays progression, with sustained effects. The primary endpoint for each was the percent of patients able to read at least 15 additional letters, or three lines, on an eye chart, compared to baseline. Two doses of the drug were tested: 0.3 mg and 0.5 mg.

In RISE, 18.1% of those on placebo were able to read the additional 15 letters, compared to 44.8% and 39.2% for the two doses of Lucentis. In RIDE, the placebo rate was 12.3% compared to 33.6% and 45.7%.

Whereas with laser treatment it may take three to five months to see the benefits, with Lucentis, anatomic and visual changes are noted within a week of treatment, Boyer said in the interview.

The percentage of patients who progressed to proliferative diabetic retinopathy, a secondary endpoint along with the 20/40 vision results, was 15% for placebo in RISE, compared to 1.6% and 5.6% in RISE. In RIDE the placebo rate for progression to proliferative diabetic retinopathy was 11.5% for placebo, vs. 3.2% and 3.9% for Lucentis.

Although patients in the studies were treated for two years, in real-world clinical practice it’s possible that some patients will need fewer injections, Boyer said.

In terms of safety, the drug’s profile is in keeping with what is known about VEGF inhibitors. Incidence of severe adverse effects in the studies was low and often related to the procedure, the company reported. These included traumatic cataracts (0 for placebo in both studies vs. 0.8% in RISE and 0.4% in RIDE). Investigators also reported cases of bacterial infection, increased intraocular pressure, retinal detachment and inflammation inside the eye.

There were fewer reports of adverse events related to diabetic retinopathy, such as abnormal growth of new blood vessels, for those taking Lucentis compared to placebo.

By Emily Hayes