Five Key FDA Drug Approvals to Watch in Q2 2021: Aducanumab, Avalglucosidase Alfa, AZD1222, 20vPnC, and Pimavanserin

This article firstPublished by: Sina Medicine, Author:newborn，Authorized for republication by VCBeat.

Recently, the foreign biopharmaceutical website BiopharmaDive released noteworthy updates on U.S. FDA drug approvals for the second quarter of 20215 Key Highlights。

Despite extensive research, Alzheimer’s disease (AD) remains one of the most challenging areas in drug development. Promising therapies have failed time and again, leaving patients with only a few drugs for symptomatic treatment.

But treatment options for Alzheimer’s disease (AD) are poised to change soon. The U.S. Food and Drug Administration (FDA) is expected to decide by June 7 whether to approve Biogen’s monoclonal antibody drug, aducanumab, which is regarded as the most closely watched drug across the entire biotechnology sector. If granted regulatory approval, aducanumab would become the first marketed therapy designed to slow the progression of Alzheimer’s disease, with Wall Street analysts projecting its annual sales to reach billions of dollars.

However, approval is far from certain. Statisticians within the FDA and an external advisory committee have raised concerns about the data on aducanumab and Biogen’s analytical methods. At a meeting last November, members of the advisory committee voted almost unanimously against approving the drug. Moreover, just recently, three members of this advisory committee published an article in JAMA expressing their opposition and questioning whether Biogen had engaged in “shooting first and drawing the target afterward.” Although the FDA is not bound to follow these recommendations, it typically does so.

However, industry analysts have not yet concluded that aducanumab is doomed. The reason is that the FDA is not only under immense pressure to provide patients with more Alzheimer’s disease (AD) therapies, but the agency’s clinical staff have also shown unusual support for Biogen’s application.

When regulators recently decided to extend the review of aducanumab, some analysts viewed this as a sign that they were scrutinizing additional data to support approval. Umer Raffat, an analyst at Evercore ISI, stated that the extended review period would raise his estimated probability of approval from below 50% to 70%. Meanwhile, the investment bank Stifel predicted a 60% likelihood of aducanumab gaining approval.

Avalglucosidase alfa is a long-acting enzyme replacement therapy developed by Sanofi, designed to improve the delivery of acid alpha-glucosidase (GAA) to muscle cells. The Biologics License Application for this drug in the treatment of Pompe disease is undergoing priority review by the U.S. FDA, with a target action date of May 18, 2021.

For many years, the primary treatment for Pompe disease has been long-term enzyme replacement therapy with Lumizyme. Sanofi acquired this therapy a decade ago when it purchased Genzyme, a developer of rare disease medications. However, the company aims to establish a new standard of care by developing an upgraded version of Lumizyme. This next-generation therapy is designed to deliver more acid alpha-glucosidase (GAA) into muscle cells, particularly skeletal muscle cells, to enhance efficacy. Compared with Lumizyme, avaloglucosidase alfa contains approximately 15 times more mannose-6-phosphate (M6P), with the goal of improving cellular uptake of the enzyme and clearance of glycogen in target tissues.

However, Sanofi has not yet substantiated this hypothesis. In the Phase 3 study, the efficacy of avalglucosidase alfa was comparable to that of Lumizyme, as measured by improvements in respiratory function, which was the primary endpoint of the study. Nevertheless, the “clinical relevance” of the differences in the mechanisms of action between these two drugs has not been confirmed.

Nevertheless, the approval of Sanofi’s avalglucosidase alfa may raise the bar for other therapies under development, including an oral drug from Amicus Therapeutics and several gene therapies being developed by Roche, Bayer, and Avrobio.

To date, the FDA has approved three COVID-19 vaccines for use in the United States, with little controversy surrounding them. However, the AZD1222 vaccine developed by AstraZeneca and the University of Oxford presents a more complex situation. The vaccine is scheduled to be submitted to the U.S. FDA for review in April, seeking Emergency Use Authorization (EUA). Nevertheless, a series of communication missteps and safety setbacks have damaged AstraZeneca’s credibility and dampened public expectations for AZD1222.

Positive results from early studies in the United Kingdom and elsewhere have failed to confirm the vaccine’s efficacy in the elderly. Meanwhile, larger-scale trials conducted by AstraZeneca in the United States and South America were delayed by nearly two months. More recently, rare cases of thrombosis occurred during the vaccine rollout in Europe, prompting many countries to temporarily suspend vaccination campaigns.

In late March, AstraZeneca reported that its vaccine was safe and highly effective in preventing COVID-19 in a Phase 3 clinical trial conducted in the United States, laying the groundwork for FDA review. However, the good news was overshadowed by controversy. The independent data monitoring committee overseeing the trial publicly questioned the company’s preliminary results—an unusual and startling accusation.

The advisory committee meeting held this month may reflect these twists and turns. A briefing document outlining the FDA’s own findings could clarify the discrepancies between AstraZeneca and its Data Monitoring Committee. This meeting will provide scientific experts with an opportunity to question AstraZeneca executives on this topic and several other pending issues.

20vPnC is a 20-valent pneumococcal vaccine developed by Pfizer, currently undergoing priority review by the U.S. FDA, with a target action date of June 2021. The vaccine is indicated for adults aged 18 years and older to prevent invasive disease and pneumonia caused by the Streptococcus pneumoniae serotypes included in the vaccine. Previously, the FDA had granted Breakthrough Therapy Designation to this vaccine.

In addition to covering the 13 serotypes included in the existing standard vaccine product Prevnar 13, 20vPnC also covers seven serotypes associated with high mortality, antibiotic resistance, and/or meningitis. Prevnar 13, a blockbuster pneumococcal vaccine from Pfizer, generated global sales of $5.85 billion in 2020, making it Pfizer’s best-selling product; however, the product will lose patent protection in 2026.

If approved for market launch, the new vaccine 20vPnC will help strengthen Pfizer’s franchise. The FDA is scheduled to issue a review decision in June this year on the application for 20vPnC in adults aged 18 years and older—a relatively smaller population compared with Prevnar 13, which is indicated for children and infants as young as 6 weeks of age. However, Pfizer aims to ultimately extend its use to younger populations, and the company has already released Phase 2 clinical data for 20vPnC in infants and children.

Currently, Merck & Co.’s 15-valent pneumococcal vaccine, V114, is also undergoing priority review by the U.S. FDA for the prevention of invasive pneumococcal disease in adults aged 18 years and older, with a target action date of July 18, 2021. The design of V114 follows that of the company’s older 23-valent vaccine, Pneumovax 23. Like Pfizer’s new vaccine, V114 can be used to prevent several key serotypes that cause invasive pneumococcal disease and are not included in currently marketed vaccine products.

Pimavanserin is Acadia Pharmaceuticals’ key asset and the active pharmaceutical ingredient in its only marketed product, Nuplazid. Approved in April 2016, Nuplazid became the first medication indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. As the first drug to selectively target the 5-HT2A receptor, pimavanserin’s unique pharmacology has established a novel drug class—selective serotonin inverse agonists (SSIAs). This agent preferentially targets the 5-HT2A receptor while avoiding the dopamine receptor activation and other off-target effects commonly associated with most antipsychotic medications.

In 2020, Nuplazid’s sales increased by 30%. In recent years, Acadia Pharmaceuticals has been striving to drive further growth of Nuplazid by expanding its therapeutic indications. Last year, the company submitted a supplemental New Drug Application (sNDA) to the U.S. FDA for the treatment of hallucinations and delusions associated with dementia-related psychosis (DRP), with a target action date of April 3, 2021.

According to Acadia’s announcement, the FDA has issued a Complete Response Letter (CRL) regarding the aforementioned sNDA. This indicates that the agency has completed its review and determined that the sNDA cannot be approved in its current form. Although the company had previously reached an agreement with the FDA’s Division of Psychiatry Products on the design of the pivotal Phase 3 HARMONY study, which analyzed a broad patient population with dementia-related psychosis (DRP) as a single group, the CRL noted that certain dementia subgroups lacked statistical significance. Furthermore, there were insufficient numbers of patients with certain less common dementia subtypes, resulting in inadequate efficacy data to support approval.

The HARMONY study met its pre-specified primary and secondary endpoints: robust and compelling data confirmed the clinical and statistical superiority of Nuplazid over placebo in treating dementia-related psychosis (DRP)-associated hallucinations and delusions, which is a pre-agreed prerequisite for the DRP indication. However, statistical separation by dementia subgroups and by minimum specific patient numbers was not within the pre-specified requirements.

Acadia Pharmaceuticals has voiced strong objections to the FDA’s decision. The company stated that throughout the review process, the Agency raised no questions regarding the agreed-upon study protocols, including those cited in the Complete Response Letter (CRL). Acadia will immediately request a Type A meeting to collaborate with the FDA in addressing the CRL issues and to establish an expedited pathway for the approval of Nuplazid for the treatment of dementia-related psychosis (DRP).

Reference source: 5 FDA approval decisions to watch in the second quarter