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Pfizer's Vyndaqel (tafamidis 61mg) Receives Positive CHMP Opinion for First-Ever Treatment of ATTR-CM in the EU

Dec 16, 2019 14:44 CST Updated 14:44
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European Medicines Agency

The European Medicines Agency (EMA) is a decentralized agency of the European Union (EU), located in London. It began operations in 1995. The agency is responsible for the scientific evaluation, supervision, and safety monitoring of medicines developed by pharmaceutical companies for use in the EU. By ensuring that all medicines available on the EU market are safe, effective, and of high quality, the EMA protects public and animal health in the 28 EU Member States and countries of the European Economic Area.


December 16, 2019 /BioonBIOON/ -- Pharmaceutical GiantPfizer(Pfizer) recently announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion, recommending approval of Vyndaqel (tafamidis), a once-daily 61 mg oral capsule for the treatment of wild-type orHeredityadult patients with transthyretin amyloid cardiomyopathy (ATTR-CM). The CHMP opinion will now be submitted to the European Commission (EC) for review, which is expected to issue a final decision in the coming months.

ATTR-CM is a rare, life-threatening disease characterized by the accumulation of misfolded proteins known as amyloid in the heart, defined as restrictive cardiomyopathy and progressive heart failure. On average, patients survive only 2–3.5 years after diagnosis.. If approved, Vyndaqel will become the first treatment for ATTR-CM in the European Union.

In 2011, the European Union approved a different formulation of Vyndaqel (tafamidis meglumine) 20 mg capsules for the treatment of transthyretin-mediated amyloidosis in adult patients with stage 1 symptomatic polyneuropathy (ATTR-PN) to delay impairment of peripheral neurological function. For ATTR-CM, the tafamidis 61 mg capsule is equivalent to an 80 mg dose of tafamidis meglumine (four 20 mg capsules). This capsule was developed to enhance patient convenience by enabling once-daily dosing. Although both products contain the same active ingredient, tafamidis, they are not interchangeable due to differences in recommended dosing.

In the United States, Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis) were approved in early May this yearFDAApproved as the first and only drug for the treatment of ATTR-CM. The two drugs are two oral formulations of tafamidis, a first-in-class transthyretin stabilizer.

Brenda Cooperstone, M.D., Senior Vice President and Chief Development Officer of Rare Disease at Pfizer Global Product Development, stated: “The CHMP’s positive opinion on Vyndaqel for the treatment of ATTR-CM reflects our unwavering commitment to improving outcomes for patients with this rare and fatal disease. In the ATTR-ACT trial, Vyndaqel reduced wild-type orHereditymortality and frequency of cardiovascular-related hospitalizations in patients with this type of disease. If approved, Vyndaqel would represent a true breakthrough for patients.”

Jean-Christophe Fidalgo, President of the Amyloidosis Alliance, stated, “For patients with ATTR-CM, there are currently no effective pharmacological treatments. The Amyloidosis Alliance endorses the CHMP’s opinion and hopes that the EC will rapidly approve Vyndaqel for ATTR-CM, so that patients can gain timely access to this medication.”

Vyndaqel’s application for expansion of therapeutic indications in the European Union, based on data from the pivotal Phase III ATTR-ACT clinical study, which is the first and only successfully completed global, double-blind, randomized, placebo-controlled trial investigating a pharmacological therapy for ATTR-CM.Clinical Trials. A total of 441 patients were enrolled in this study, including those with variant or hereditary ATTR-CM and those with wild-type ATTR-CM (referring to those who are notGenetics), but may occur with advancing age).

The primary analysis results showed that during the 30-month treatment period: (1) Compared with placebo, Vyndaqel (tafamidis meglumine) significantly reduced all-cause mortality and cardiovascular-related hospitalization rates in patients with wild-type and hereditary ATTR-CM (p=0.0006). (2) Compared with the placebo group, Vyndaqel reduced all-cause mortality and all-cause hospitalization rates by 30% (p=0.026) and 32% (p<0.0001), respectively. (3) Compared with placebo, Vyndaqel reduced the risk of all-cause mortality across all subgroups (wild-type, hereditary, NYHA functional classes I, II, III): the risk of death was reduced by 29% in the wild-type subgroup (HR=0.71, 95% CI: 0.474–1.052) and by 31% in the hereditary subgroup (HR=0.69, 95% CI: 0.408–1.167). (4) Across wild-type andHeredityIn the subtype subgroup, compared with placebo, Vyndaqel demonstrated a consistent reduction in the decline across all domains of patient functional capacity as assessed by the 6-Minute Walk Test (6MWT) and patient quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). (5) In the study, Vyndaqel was well tolerated and exhibited a safety profile comparable to that of placebo.

This application is also based on an evaluation of tafamidis 61 mg in its free acid form. The primary results of the ATTR-ACT trial were presented at the 2018 ESC Congress held in Munich, Germany, and published online in August 2018 in The New England Journal of Medicine (NEJM).

Tafamidis molecular structure (from Wikipedia)

ATTR amyloidosis is a rare, progressive disease characterized by the abnormal accumulation of amyloid deposits composed of misfolded transthyretin protein in various organs and tissues throughout the body. Amyloidosis can affect multiple organs and systems, including the peripheral nervous system, as well as the heart, kidneys, gastrointestinal tract, and eyes. ATTR-CM and ATTR-PN are two clinical manifestations of this condition.

ATTR-CM is a rare, fatal, and severeDiagnosisdeficiency-related disease, associated with progressive heart failure. ATTR-CM is caused by the instability of a transport protein called transthyretin (TTR), which consists of four identical subunits (a tetramer). In ATTR-CM, the dissociation of unstable tetramers leads to heart failure, resulting in misfolded proteins aggregating into amyloid fibrils and primarily depositing in the heart.

Tafamidis is an oral small-molecule drug that stabilizes TTR. In the United States and the European Union, tafamidis was granted orphan drug designation for the treatment of ATTR-CM in 2011. In 2017, the FDA also granted tafamidis Fast Track designation; in March 2018, Japan’s Ministry of Health, Labour and Welfare (MHLW) granted tafamidis SAKIGAKE designation; in May 2018,FDATafamidis Granted Breakthrough Therapy Designation. (Bioon.com)