Ranibizumab (Lucentis) and Bevacizumab (Avastin)

Lucentis

The FDA announced on June 30, 2006, that it has granted approval to Ranibizumab (Lucentis) for the treatment of wet macular degeneration. Ranibizumab is an anti-VEGF antibody fragment that is administered as a monthly intravitreal injection. Clinical trials have shown that around 95% of patients treated with ranibizumab maintain and 40% improve their vision over the course of therapy. This clearly is the most efficacious FDA-approved treatment to date and may become a first line therapy in many patients. As of July 15, 2006, Lucentis has been available at our clinic and has been approved for coverage by Medicare (AdminaStar Federal) in Indiana.

Possible Increased Risk for Stroke with Lucentis

On January 30, 2007, Genentech, Inc, warned healthcare professionals regarding the potential increased risk for stroke associated with use of ranibizumab (Lucentis) in the treatment of neovascular (wet) age-related macular degeneration in elderly patients.

The warning was based on interim data from an ongoing safety study (SAILOR) showing that the risk for stroke was significantly higher in patients receiving the recommended dose of ranibizumab (0.5 mg) compared with a 0.3 mg dose (1.2% vs 0.3%; P = .02) at an average follow-up of 230 days. Patients with a history of stroke appeared to be at increased risk for subsequent stroke, the company said.

The 0.3- and 0.5-mg doses were not statistically different in terms of incidence of heart attack (myocardial infarction) or vascular death, and their overall safety appeared to be consistent with that observed in phase 3 studies submitted as part of the drug approval process.

In light of this interim data, we will offer patients with previous strokes or patients at high risk for a stroke the option of the lower 0.3 mg dose or alternative treatment (Avastin or photodynamic therapy).

Avastin

This anti-VEGF antibody has been used at our clinic on an “off-label” basis since the fall of 2005. It is the “parent” molecule from which Lucentis is derived. Although it has not been through the FDA for ocular use, it is felt that there is enough evidence of efficacy that this is also covered by Medicare in Indiana. This is not limited to macular degeneration and this may be used in diabetic retinopathy, retinal vein occlusions, ocular histoplasmosis, and pathologic myopia. Because of its much lower cost and less frequent administration, this is used as a first line treatment in most macular degeneration patients.

Lucentis vs. Avastin

With the availability of two excellent anti-VEGF agents, a common question posed to physicians is which agent (Avastin or Lucentis) is “better.” The National Eye Institute is currently sponsoring a randomized study comparing the two drugs, but results may be years away. Based on our experience, the drugs appear equivalent in terms of clinical response. It is also our experience that both have been extremely well-tolerated. Despite the recent announcement about the possible increased risk of stroke with Lucentis, we have not seen any systemic side effects definitely attributable to an intraocular injection. The biggest difference between the two agents is cost. The cost per dose (in a form ready for intraocular injection), is approximately $2000 for Lucentis and $75 for Avastin. Because there seems to be no difference in efficacy and a major difference in cost, we treat most patients with Avastin. The decision to continue treatment, switch to another agent, or combine with photodynamic therapy is based on the patient's clinical response.

PrONTO Study and Implications for Today's Practices

With different agents and different dosing schedules, it is clear that one protocol may not be optimal for all patients.

Dr. Philip Rosenfeld, from the Bascom Palmer Eye Institute in Miami, designed the Prospective OCT imaging of patients with Neovascular AMD Treated with IntraOcular Lucentis (PrONTO) study to prospectively evaluate variable dosing of ranibizumab using OCT. Patients with wet AMD received 3 monthly injections with Lucentis (ranibizumab) and then only as needed, using predetermined criteria. The average number of injections at the 12-month time point was 5.6. An average gain in visual acuity of 9.3 letters was noted at 12 months -- better than the results of the MARINA trial. And in results similar to those of the MARINA trial at 12 months, 95% of patients maintained visual acuity (less than 15-letter loss) and 35% of patients gained 3 or more lines. Rosenfeld noted a tendency for OCT to show return of fluid before loss of vision, allowing re-treatment with ranibizumab without loss of vision.

For most patients, I currently use the following schedule:

• 3-4 monthly injections with Avastin (sometimes Lucentis). OCTs done every 1-2 months to determine response
• Occasional fluorescein angiography to determine leakage
• Once lesion becomes “dry” dosing can be less frequent. Additional injections are given if vision decreases or if fluid recurs