Pfizer's Clinically Urgent Overseas Drug Tafamidis Meglumine Capsules Submitted for Approval in China with Clinical Trial Waiver

On July 29, according to the New Drug R&D Monitoring Database (CPM), Pfizer’s drug for hereditary transthyretin-mediated amyloidosis, "Tafamidis Meglumine Soft Capsules," was granted a clinical trial waiver by the CDE.Li。

Tafamidis, a rare-disease drug developed by Pfizer for the treatment of hereditary transthyretin-mediated amyloidosis (ATTR), is available in two formulations: meglumine salt (VYNDAQEL) and free acid (VYNDAMAX). Due to its breakthrough therapeutic efficacy, it was promptly included in China’s “First Batch List of Overseas New Drugs Urgently Needed for Clinical Use.” Today, it has submitted a marketing application in accordance with the “Technical Guidelines for Accepting Overseas Clinical Trial Data for Drugs,” having not previously conducted clinical trials in China.

According to the Comprehensive Drug Database (PDB), as the number of countries approving VYNDAQEL continues to increase globally, its sales have been steadily rising. To date, VYNDAQEL has been launched in more than 20 countries and regions, including Europe, the United States, Japan, and South Korea. In 2018, it achieved sales of $180 million, representing a year-on-year growth of 25.8%.

Data Source: PDB Comprehensive Drug Database

ATTR is caused by the aggregation of misfolded transthyretin (TTR) into amyloid fibrils within organs and tissues, thereby disrupting their normal function. These protein deposits most commonly occur in the peripheral nervous system and the heart. Involvement of the peripheral nervous system can lead to sensory loss, pain, and weakness in the limbs, as well as autonomic neuropathy; whereas cardiac involvement manifests as restrictive cardiomyopathy and progressive heart failure. Additionally, amyloid deposits can affect the kidneys, eyes, gastrointestinal tract, and central nervous system.

VYNDAQEL (meglumine formulation) and VYNDAMAX (free acid formulation) are oral TTR stabilizers that bind specifically to TTR, stabilize it, slow its dissociation into monomers, and delay the formation of amyloid deposits that cause ATTR.

On November 17, 2011, VYNDAQEL was first approved in the European Union for the treatment of transthyretin amyloidosis with polyneuropathy (ATTR-PN) in adult patients with early symptomatic polyneuropathy to delay peripheral nerve damage.

ATTR-PN is a rare, progressive, and fatal neurodegenerative disorder affecting approximately 8,000 patients worldwide. Currently, VYNDAQEL has been approved for the treatment of ATTR-PN in 40 countries, including Japan, several European countries, Brazil, Mexico, Argentina, Israel, Russia, and South Korea. However, neither VYNDAQEL nor VYNDAMAX has been approved in the United States for the treatment of ATTR-PN. On June 18, 2012, the FDA rejected the New Drug Application (NDA) for VYNDAQEL for the treatment of TTR-FAP due to insufficient clinical evidence. Last year, the FDA approved Onpattro (patisiran), the first siRNA drug, for adult patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis.

Fx–005&Fx–006

The approval of this drug in the European Union is based on the results of a pivotal clinical trial (Fx–005) and an open-label, 12-month extension study (Fx–006). The results of Fx–005 demonstrated that patients in the VYNDAQEL group experienced a 51–81% reduction in the progression of neurological impairment, large-fiber function (measured by activity intensity), and small-fiber function (measured by sensory assessment) compared to those in the placebo group.

As shown in Fx–006, during the 12-month open-label study, the monthly rate of change in NIS-LL was similar to that observed in patients who received VYNDAQEL during the 18-month randomized study period. This indicates that VYNDAQEL slowed neurological progression and maintained quality of life over 30 months. Furthermore, patients who initiated VYNDAQEL treatment early demonstrated better outcomes than those who started treatment after receiving placebo for 18 months.

On May 10 of this year, the U.S. FDA approved VYNDAQEL and VYNDAMAX for the treatment of adults with wild-type or hereditary transthyretin-mediated cardiomyopathy (ATTR-CM) to reduce cardiovascular-related mortality and hospitalization rates. Notably, these are the first and only FDA-approved therapies for ATTR-CM.

ATTR-CM is generally classified into two types: hereditary ATTR-CM, which results from mutations in the TTR gene; and wild-type ATTR-CM, in which patients have no TTR gene mutations but develop cardiac amyloid deposition due to aging. Wild-type ATTR-CM is more commonly observed in men over the age of 60.

Patients with ATTR-CM are typically diagnosed only after symptoms become severe; once diagnosed, the median survival is just 2–3.5 years. Statistics indicate that there are approximately 100,000 patients with ATTR-CM in the United States, yet only 1–2% are diagnosed. Previously, no therapies had been approved for this condition; available treatment options were limited to symptomatic management and, in select cases, heart transplantation (or combined heart-liver transplantation).

ATTR-ACT

The FDA’s approval of VYNDAQEL was based on the results of the pivotal Phase III ATTR-ACT clinical trial. The trial demonstrated that, over the 30-month study period, VYNDAQEL significantly reduced a composite endpoint consisting of all-cause mortality and cardiovascular-related hospitalizations compared with placebo. VYNDAQEL not only reduced the risk of all-cause mortality by 30% and the risk of cardiovascular-related hospitalization by 32%, but also improved other functional measures in patients.

Pfizer’s submission for marketing approval of “Tafamidis Meglumine Soft Capsules” in China brings a life-changing breakthrough innovation to patients with hereditary transthyretin-mediated amyloidosis (ATTR) in the country. For the vast number of patients suffering from this rare, fatal disease who currently have no approved therapeutic options, this milestone undoubtedly promises a transformative improvement in their lives.

Original Title: Filling the Treatment Gap! Pfizer’s Urgently Needed Overseas New Drug Approved for Marketing in China Without Clinical Trials!