FDA Advisory Panel to Discuss Genzyme’s Myozyme BLA on Tuesday
News Oct 20, 2008
This product is intended for the treatment of Pompe disease, a progressive, debilitating and life-threatening inherited disorder affecting approximately 2,000 people in the United States. The meeting will focus on the clinical outcomes of the Late Onset Treatment Study (LOTS), including statistical analyses of the study results, safety and the indication for alglucosidase alfa.
Genzyme’s LOTS study was a randomized, double-blind, placebo-controlled clinical trial that enrolled 90 patients. The co-primary efficacy endpoints were the Six-Minute Walk Test (6MWT) and percent-predicted Forced Vital Capacity (FVC). These co-primary endpoints were prospectively agreed upon with the FDA and are considered the most clinically relevant measures of walking ability and pulmonary function, respectively, for patients with late-onset Pompe disease. The co-primary endpoints achieved statistical significance according to the statistical analysis plan for the primary efficacy endpoints.
The results showed that, at 18 months, patients treated with alglucosidase alfa increased their distance walked in six minutes by an average of 28 meters, as compared with the placebo group, which did not show any improvement from baseline (ANCOVA; p<0.035). Percent-predicted FVC, the co-primary endpoint, increased in the treated group by one percentage point at 18 months. In contrast, FVC declined by approximately three percentage points in the placebo group over the same period (ANCOVA; p<0.0055). The results for both efficacy endpoints were consistent across various prospectively defined subgroups.
Earlier this week, Genzyme learned that the FDA will use a sensitivity analysis as the primary analysis for the 6MWT for discussion at the panel meeting. Genzyme believes that the application of this sensitivity analysis is not appropriate for this trial. Genzyme believes that the pre-specified primary analysis demonstrates the efficacy of the 2000 L product.
Additionally, the LOTS safety data demonstrate that alglucosidase alfa produced at the 2000 L scale has an acceptable safety profile in late-onset patients. The number of patients with serious and treatment-emergent non-serious adverse events was similar in the alglucosidase alfa and placebo groups. Twenty-eight percent of patients in the treatment group compared to 23 percent in the placebo group experienced infusion-associated reactions. Allergic symptoms were more frequent during infusion-associated reactions in the treatment group. Similar to the 160 L experience, five percent of patients experienced anaphylaxis and two thirds of these were able to continue treatment. There was one death in the Myozyme group unrelated to treatment.
“Genzyme believes that the LOTS safety and efficacy data, in combination with additional clinical and post-marketing safety data, support a full approval of alglucosidase alfa produced at the 2000 L scale for patients with late-onset Pompe disease,” said Genzyme Senior Vice President Alison Lawton. “We look forward to a productive discussion of these data at the advisory committee to facilitate a successful first-cycle approval for the 2000 L process and thereby assure a continued supply of alglucosidase alfa, the only treatment for patients with Pompe disease.”
Genzyme currently has U.S. approval to sell Myozyme, manufactured at the 160 L scale, and the company has been seeking clearance from the FDA for 2000 L-scale production. Genzyme submitted a separate BLA for alglucosidase alfa produced by the 2000 L manufacturing process on May 30th, following a determination by the FDA that alglucosidase alfa produced at the 160 L and 2000 L scales should be considered as two separate products because of comparability differences.
Genzyme is proposing the following indication for the product produced at the 2000 L scale: “Alglucosidase alfa is indicated for long-term use in patients with late-onset Pompe disease (GAA deficiency). Alglucosidase alfa has been shown to improve distance walked and stabilize pulmonary function in patients with late-onset Pompe disease.” Late-onset patients are currently defined for the clinical studies as patients who develop clinical manifestations of the disease after two years of age, and who have no cardiac involvement.
Formal FDA action is expected on Genzyme’s BLA by November 29, 2008. Genzyme anticipates that the FDA review process will culminate in the availability of two commercial versions of alglucosidase alfa in the United States: one produced at the 160 L scale and the other produced at the 2000 L scale. Production of Myozyme at the 2000 L scale has been approved for the use in all patients with Pompe disease in more than 40 countries. Approximately 1000 patients worldwide are on treatment.
To ensure that severely affected adults with Pompe disease in the United States have access to treatment, Genzyme, in collaboration with the FDA, created the Myozyme Temporary Access Program (MTAP) in May 2007. Through this program, the company is currently providing Myozyme produced at the 2000 L scale free of charge to approximately 160 patients. U.S. demand for alglucosidase alfa has now increased to the extent that it is no longer feasible for Genzyme to supply product to additional adult patients under the MTAP program. FDA approval of 2000 L production scale is needed to provide broader access to treatment for adult patients in the United States. There are approximately 50 – 100 patients identified who are waiting for access to treatment.
FDA and Genzyme briefing documents for Tuesday’s advisory committee meeting are available on the FDA’s Website.
Prior to the public advisory committee meeting, Genzyme and the FDA will meet with the advisory panel members in closed session to discuss proprietary manufacturing information. During this morning session, the discussion will focus around the biochemical characteristics of alglucosidase alfa produced at the 2000 L scale and its comparability to product produced at the 160 L scale.