5 FDA decisions to watch in the third quarter

 The Food and Drug Administration made one of the most controversial decisions in its history early last month, when the agency decided to clear Biogen's Alzheimer's drug despite contradictory evidence from clinical trials.

Few forthcoming actions can match that approval's impact, but the FDA still faces a slate of critical decisions in the months ahead. Looming largest are expected full approvals for Pfizer's and Moderna's coronavirus vaccines, which remain only cleared for emergency use more than six months after their initial authorizations. While the outcome is not in doubt, calls have grown for the FDA to speed its review as news of a standard approval may help convince vaccine hold-outs and skeptics. 

The FDA will also need to decide whether the bar it set with Aduhelm's approval holds for other drugs like it, as Eli Lilly has said it will apply for an accelerated OK of a treatment called donanemab later this year. An approval decision likely wouldn't come until well into 2023, but the FDA first has to agree Lilly's study data are enough to merit a review. 

Important questions on the safety of several new arthritis drugs, a closely watched anemia drug and an unusual diabetes treatment are also set to be decided. Read on for details on all five: 

Full approval of Pfizer's and Moderna's coronavirus vaccines

The two coronavirus vaccines from Pfizer and BioNTech, and Moderna, are the most widely used and powerful tools in the COVID-19 response in the U.S. Since their initial clearances in December, the two shots have accounted for about 96% of the roughly 328 million doses administered to date to Americans. Real-world use has affirmed both to be safe and strongly effective, helping drive down infections, hospitalizations and deaths. 

But six months after their initial clearances, both vaccines are still distributed under emergency use authorization, a regulatory pathway meant to speed critical treatments during a public health crisis, rather than a standard drug approval. 

Transitioning each to full approvals could be important to re-energizing a U.S. vaccination campaign that has slowed considerably since April. Full approvals could help counter persistent vaccine hesitancy and would give employers backing to mandate vaccinations. The urgency to grant them is growing, as the Delta variant is fast becoming the dominant strain in the U.S. Research has shown Delta to be more transmissible and potentially more resistant to immune responses, although full vaccination with Pfizer's and Moderna's shots still appears protective .

Pfizer and BioNTech filed an approval application in May, and Moderna followed in early June. Though the FDA typically takes up to six months to review an application, both developers submitted "rolling" submissions, enabling the agency to review paperwork as it is filed and streamline the process. 

Acceptance of Eli Lilly's Alzheimer's drug application

Any doubts about whether the FDA set a precedent with approval of Biogen's Aduhelm were quickly dispelled by Eli Lilly, which two weeks after the agency's decision declared it would seek approval for its similarly acting drug donanemab. 

The announcement was a reversal from just two months earlier, when a top Lilly R&D executive said the company did not think it had enough evidence to ask for an OK. 

That assessment apparently changed when the FDA surprisingly decided to base its approval of Aduhelm not on the drug's purported clinical benefit, but rather its ability to clear the brain of toxic plaques. Donanemab does that job, too, and data from a small Phase 2 study released earlier this year showed it does so quite well. 

It's unclear whether the FDA confirmed that Lilly's results were sufficient to move forward. But the company was confident enough to announce it would file an approval application later this year. The agency has two months after Lilly submits to decide whether it will accept and start a review. 

Other Alzhiemer's drugs could soon follow donanemab. A report from analysts at Jefferies said Roche will take a similar approach with its drug gantenerumab, although the company would not confirm its plans. 

Warning for arthritis drugs from Pfizer, AbbVie and Lilly

Pfizer's Xeljanz is one of the company's top-selling medicines, widely used for rheumatoid arthritis and three other inflammatory conditions. 

So it was notable news when, in late January, Pfizer said a large safety study found patients taking the drug were more commonly affected by major heart complications and cancer than those who received another type of drug.

The results raised alarm bells, including at the FDA, which has since pushed back decisions to expand approvals for drugs from AbbVie and Eli Lilly that work the same way as Xeljanz. In its announcement of the latest delay, AbbVie said the regulator had cited an ongoing review of data from Pfizer's safety study. 

The concern over side effects linked to the drugs, known collectively as JAK inhibitors, isn't the first safety red flag. All carry the FDA's strictest warning for the risk of serious infection, malignancy and blood clots. 

Analysts expect a new warning label as the most likely outcome of the FDA's review, but other options, including limiting certain drugs to lower doses, could be possible, albeit less likely. 

Several other JAK approval decisions are expected in July and September, meaning more delays might be forthcoming.

The advisory committee meeting on Fibrogen's anemia drug

Much has changed since last year when FibroGen first sought FDA approval of roxadustat, an anemia pill for people with chronic kidney disease that could become the first drug of its kind in the U.S. 

First, the FDA's review of FibroGen's application was delayed from December to March. Then, company executives expressed surprise after the agency revealed plans to consult an advisory committee, pushing a decision back even further and seeding doubt about the drug's prospects.

But the most significant twist came in April, when FibroGen made the stunning disclosure that cardiovascular safety data it had touted in press releases and medical conferences since 2019 — numbers used to claim roxadustat was as good or better than injectable drugs or placebo at reducing heart risk — were misleading. 

FibroGen updated the results, and executives argued there was "no change" in the drug's efficacy data and stressed confidence in its safety. Since then, FibroGen won a key endorsement as Europe's drug regulator recommended approval. But the FDA advisory committee meeting represents the company's stiffest test yet, as FibroGen's data are set to be publicly scrutinized by FDA scientists and outside experts. 

Geoffrey Porges, an analyst at SVB Leerink, wrote recently he expects votes supporting the drug's use in both potential indications — chronic kidney disease patients who are or aren't on dialysis — along with "cautionary language" in the drug's label.

The meeting is set for July 15. The FDA hasn't yet announced a target decision date for FibroGen's drug, though it has set a March 22 deadline to complete a review of a rival treatment from Akebia Therapeutics. 

Approval of Provention Bio's diabetes drug

Friday is a critical date for the future of Provention Bio, a small biotech that took a chance on a diabetes drug with a checkered past. 

Three years ago, Proventin bought rights to a drug called teplizumab that had been shelved by Macrogenics and partner Eli Lilly in 2010 after a trial setback in Type 1 diabetes. Academic studies continued, however, and eventually showed signs teplizumab might delay the disease's onset. 

Provention went public with a pitch to prove that benefit, and sought an approval after results from a Phase 2 study showed a 14-day course delayed insulin-dependent, clinical-stage disease in patients who hadn't yet developed symptoms. If approved, the drug would be the first therapy cleared to prevent the disease, at least temporarily.  

But Provention has had a bumpy ride since then. The FDA found "deficiencies" in its approval application and asked for more data, dimming the drug's approval prospects. And while an advisory committee in May recommended approval of teplizumab, the vote was close. Several panel members were concerned about the severe side effects seen with treatment, and recommended a narrower group of patients be eligible for the drug. 

All of which has injected considerable uncertainty into the FDA's imminent decision, which could result in a delay, rejection, or "unexpected approval," SVB Leerink analyst Thomas Smith recently wrote.  

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