Transthyretin familial amyloid polyneuropathy: Vyndaqel, first therapy approved in the European Union


European Commission has approved Vyndaqel ( Tafamidis ) for the treatment of transthyretin familial amyloid polyneuropathy ( TTR-FAP ) in adult patients with stage 1 symptomatic polyneuropathy. TTR-FAP is a rare, progressive and fatal neurodegenerative disease that affects approximately 8,000 patients worldwide.

Mutations of the transthyretin ( TTR ) gene can result in the production of unstable TTR proteins which can accumulate as amyloid fibrils. Amyloid fibrils can deposit in a variety of organs including the nerves, heart and kidneys, interfering with normal function.
Vyndaqel is a novel specific transthyretin stabilizer designed to prevent the formation of these misfolded proteins and the subsequent amyloid deposits that induce neurodegeneration and decline of neurologic function.
In the pivotal trial ( Fx-005 ), transthyretin stabilization ( as demonstrated by an in vitro assay ) was observed in 98% of patients on Vyndaqel, and in no patients on placebo, at 18 months.

The approval is based on results from a pivotal clinical trial ( Fx-005 ) and an open-label, 12-month extension study ( Fx-006 ), which evaluated the long-term safety and efficacy of Vyndaqel in patients with TTR-FAP. Across these clinical studies, Vyndaqel showed efficacy in delaying peripheral neurologic impairment. Additional data from these studies showed 51 to 81 percent less deterioration in neurologic function, large fiber function ( measure of motor strength ) and small fiber function ( measure of sensation ) compared with patients treated with placebo. Vyndaqel resulted in improved nutritional status ( modified body mass index or mBMI ); decline in mBMI was shown to correlate with disease progression in the pivotal 18-month study.

The adverse drug reactions reported in the pivotal study of Vyndaqel were diarrhea, upper abdominal pain, urinary tract infection and vaginal infection.

Mutations of the transthyretin ( TTR ) gene can result in the production of unstable TTR proteins which can accumulate as amyloid fibrils. Amyloid fibrils can deposit in a variety of organs including the nerves, heart and kidneys, interfering with normal function. Patients with TTR-FAP experience significantly diminished quality of life due to symptoms including polyneuropathy characterized by sensory loss, pain and weakness in the lower limbs; as well as severe impairment of the autonomic nervous system commonly manifesting as erectile dysfunction, alternating diarrhea and constipation, unintentional weight loss, orthostatic hypotension, urinary incontinence, urinary retention and delayed gastric emptying. As the disease progresses, patients often lose the ability to walk, needing wheelchair assistance, and eventually become bedridden and unable to care for themselves. TTR-FAP typically occurs during active adult years with onset as early as the 30s, followed by disease progression that reaches the terminal stage in approximately 10 years on average.

Fx-005 - The pivotal study of Vyndaqel was an 18-month, multicenter, randomized, double-blind, placebo-controlled study that evaluated the safety and efficacy of once-daily 20 mg Vyndaqel in 128 patients with TTR amyloid polyneuropathy with the V30M mutation and primarily stage 1 disease. The primary outcome measures were the Neuropathy Impairment Score - Lower Limb ( NIS-LL ) and the Norfolk Quality of Life - Diabetic Neuropathy ( Norfolk QOL-DN ). Other outcome measures included composite scores of large nerve fiber and small nerve fiber function and nutritional assessments utilizing the modified body mass index ( mBMI ).
While the pivotal study missed its co-primary endpoints, it did meet statistical significance in a predefined secondary analysis, which was designed to adjust for the impact of patient attrition due to liver transplantation. Following 18 months of treatment, more Vyndaqel-treated patients were NIS-LL responders ( showed less deterioration in neurologic function as measured by the NIS-LL ), and the secondary end points demonstrated that Vyndaqel treatment resulted in less deterioration of neurologic function and improved nutritional status ( mBMI ) compared with placebo. Transthyretin stabilization ( as demonstrated by an in vitro assay ) was observed in 98% of patients on Vyndaqel, and in no patients on placebo, at 18 months.
The adverse drug reactions reported in the pivotal study of Vyndaqel were diarrhea, upper abdominal pain, urinary tract infection and vaginal infection.

Fx-006 ( open-label extension study ) - In a 12-month, open-label, single-treatment arm extension of the 18-month, double-blind, placebo-controlled trial, investigators evaluated the longer-term effect of Vyndaqel as a treatment for TTR-FAP. In this study, all patients were treated with Vyndaqel. The study evaluated groups identified by the treatment sequence patients received in the respective trials ( Vyndaqel-Vyndaqel or placebo-Vyndaqel ).
In the open-label extension study, the rate of change in the NIS-LL during the 12 months of treatment was similar to that observed in those patients randomized and treated with Vyndaqel in the previous double-blind18-month period. No new safety issues were identified in this open-label extension study.

Source: Pfizer, 2011

XagenaMedicine2011


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