A few days ago, the biopharmaceutical website BiopharmaDive released 5 highlights that deserve attention in the US FDA drug approval in the second quarter of 2021.

1, aducanumab

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

But treatment options for AD will soon change. The FDA should decide before June 7 whether to approve Bojian's monoclonal antibody drug aducanumab, which is considered to be the most concerned drug in all biotechnological fields. If approved by regulatory agencies, aducanumab will become the first drug to be marketed to slow the progression of Alzheimer's disease, and Wall Street analysts expect annual sales of the drug to reach billions of dollars.

However, approval is far from certain. Statisticians within the FDA and an external advisory committee questioned the aducanumab data and Biogen's analysis methods. At a meeting in November last year, members of the advisory committee voted almost unanimously against approval of the drug. And just recently, three members of the advisory committee expressed their objections in the JAMA journal and questioned Bojian’s suspicion of “shooting first, then drawing the target”. Although the FDA does not need to follow these recommendations, it usually does.

However, industry analysts have not yet determined that aducanumab will be sentenced to death. The reason is that the FDA is not only facing tremendous pressure to provide more AD drugs to patients, but also the agency's clinical staff have been unusually supporting Bojian's application.

When the regulator recently decided to extend the review of aducanumab, some analysts saw this as a sign that the regulator was combing through more data to support the approval. Evercore ISI analyst Umer Raffat has said that extending the review period will increase his estimate of the probability of approval from less than 50% to 70%. At the same time, investment bank Stifel predicts that there is a 60% chance that aducanumab will be approved.

2. Avalglucosidase alfa

Avalglucosidase alfa is a long-acting enzyme replacement therapy developed by Sanofi to improve the delivery of acid alpha-glucosidase (GAA) to muscle cells. The application for a biological product license for the drug to treat Pompe disease is undergoing priority review by the US FDA, and the target action date is May 18, 2021.

For many years, the main treatment for Pompe disease has been long-term treatment with Lumizyme, an enzyme replacement therapy. Sanofi acquired this therapy when it bought Genzyme, a rare disease drug developer, 10 years ago. But the company's goal is to develop a new standard of treatment by developing an upgraded version of Lumizyme. This new escalation therapy aims to deliver more enzymes (GAA) to muscle cells, especially skeletal muscle muscle cells, to increase effectiveness. Compared with Lumizyme, the mannose-6-phosphate (M6P) content of avaloglucosidase alfa is increased by about 15 times, the purpose is to help improve the absorption of enzymes by cells and the clearance of glycogen in target tissues.

However, Sanofi has yet to prove this hypothesis. In the phase 3 study, the efficacy of avalglucosidase alfa was comparable to Lumizyme as measured by the improvement of respiratory function, which was the main goal of the study. However, the "clinical relevance" of the difference between the modes of action of these two drugs has not been confirmed.

Nevertheless, the approval of Sanofi avalglucosidase alfa may raise the threshold of other treatments being developed, including an oral drug from Amicus Therapeutics, and some gene therapies developed by Roche, Bayer, and Avrobio.

3. AZD1222

Up to now, the FDA has approved 3 COVID-19 vaccines for use in the United States, and there is not much controversy about these vaccines. But the situation of the vaccine AZD1222 of AstraZeneca and Oxford University is more special. The vaccine will be submitted to the US FDA for review in April, seeking emergency use authorization (EUA). However, a series of communication errors and safety setbacks damaged AstraZeneca's credibility and lowered public expectations for AZD1222.

Positive results from early studies in the UK and elsewhere cannot confirm that the vaccine is effective in elderly people. At the same time, AstraZeneca’s larger trials in the United States and South America have been postponed for nearly two months. Recently, in the process of promoting vaccines in Europe, rare thrombotic events have occurred, causing many countries to temporarily stop vaccination.

In late March, AstraZeneca reported in a phase 3 clinical study conducted in the United States that this vaccine is safe and very effective in preventing COVID-19, laying the foundation for the FDA's review. But the good news was overshadowed by the controversy. The independent expert committee overseeing the trial publicly questioned the company’s preliminary results, which is an unusual and shocking accusation.

The advisory board meeting held this month may reflect these twists and turns. A briefing document summarizing the results of the FDA's own investigation may shed light on the differences between AstraZeneca and its data monitoring committee. This meeting will give scientific experts the opportunity to ask AstraZeneca executives questions on this topic and several other outstanding issues.

4. 20vPnC

20vPnC is a 20-valent pneumococcal vaccine developed by Pfizer. It is currently undergoing priority review by the US FDA. The target date of action is June 2021. The vaccine is used in adults aged 18 and over to prevent invasive diseases and pneumonia caused by the serotype of Streptococcus pneumoniae in the vaccine. Previously, the FDA has granted the vaccine breakthrough drug designation.

In addition to the 13 serotypes in the existing standard vaccine product Prevnar 13 (Prevnar 13), 20vPnC also covers 7 serotypes related to high mortality, antibiotic resistance and/or meningitis. Prevnar 13 is Pfizer’s overweight pneumococcal vaccine. With global sales of US$5.85 billion in 2020, it is Pfizer’s best-selling product, but the product will lose patent protection in 2026.

If the new vaccine 20vPnC is approved for marketing, it will help consolidate Pfizer’s franchise rights. The FDA will make a review decision on the application of 20vPn for adults aged 18 and over in June of this year. This is a relatively small group compared to Prevnar 13, which can be used for children and infants as young as 6 weeks. . But Pfizer's goal is to eventually apply it to young people. The company has released phase 2 clinical data for 20vPnC in infants and children.

At present, Merck’s 15-valent pneumonia vaccine V114 is also undergoing priority review by the US FDA. The vaccine is used to prevent invasive pneumococcal disease in adults aged 18 and above. The target action date is July 18, 2021. The design of V114 follows the company's older 23-valent vaccine Pneumovax 23 (Neumovax). Like Pfizer's new vaccine, V114 can be used to prevent some key serotypes that cause invasive pneumococcal disease, and these key serotypes have not been included in the vaccine products already on the market.

5. pimavanserin

Pimavanserin is a key asset of Acadia Pharmaceuticals and the active pharmaceutical ingredient of its only marketed product Nuplazid. The product was approved for marketing in April 2016 and became the first drug to treat psychiatric symptoms such as hallucinations and delusions experienced by Parkinson’s disease patients. . As the first drug that selectively targets 5-HT2A receptors, pimavanserin's unique pharmacology has created a new drug category—selective serotonin inverse agonists (SSIA), which not only preferentially target 5-HT2A receptors. The HT2A receptor can also avoid the side effects of dopamine receptor and other receptor activation that most psychiatric drugs have.

In 2020, Nuplazid's sales have increased by 30%. In recent years, Acadia has been trying to promote further growth of Nuplazid by expanding its therapeutic indications. Last year, the company submitted a Supplemental New Drug Application (sNDA) for Nuplazid to the US FDA for the treatment of hallucinations and delusions related to dementia-related psychosis (DRP), with a target action date of April 3, 2021.

According to the Acadia announcement, the FDA has issued a complete response letter (CRL) to the aforementioned sNDA. This indicates that the agency has completed the review and determined that the sNDA cannot be approved in its current form. Although the company previously reached an agreement with the FDA Psychiatric Products Department on the design of the key Phase 3 HARMONY study, the broad DRP patient population was analyzed as a single group. However, the CRL pointed out that certain subgroups of dementia lack statistical significance, and certain less common subtypes of dementia have insufficient numbers of patients and lack sufficient efficacy data to support approval.

The HARMONY study reached the pre-specified primary and secondary endpoints: in the treatment of DRP-related hallucinations and delusions, strong and convincing data confirmed the clinical and statistical superiority of Nuplazid over placebo, which is An agreed prerequisite for DRP indications. The statistical separation according to the minimum number of dementia subgroups and specific patients is not within the pre-specified requirements.

Acadia Company expressed a strong protest against the FDA's decision. The company said that during the entire review process, the agency did not raise any questions about the agreed research agreement, including the issues raised in the CRL. We will immediately request a Class A meeting to work with the FDA to resolve the CRL problem and determine a fast way to approve the application of Nuplazid in the treatment of DRP.

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