The next three months will be among the most consequential in the Food and Drug Administration's modern history.
This fall, at least two of the leading coronavirus vaccine makers could seek emergency approvals, setting up what will be a series of momentous decisions for the regulator. The FDA will face immense pressure to clear a vaccine, but will be forced to make a call with significantly less information than usual to go on, due to the extraordinary speed at which developers have proceeded.
Should the agency authorize an experimental vaccine for emergency use, or grant a full approval, tens of millions of people will likely receive a shot, even under a controlled roll-out to high-risk groups.
Further complicating the agency's task is a U.S. presidential election, in which the Trump administration's response to the COVID-19 pandemic will be a top issue among voters. President Donald Trump has staked much to obtaining a vaccine before Nov. 3, publicly pressuring the FDA with timelines that are at odds with those of his own public health officials.
Amid all of this, the FDA will also be carrying out its usual business. Approval decisions are scheduled for a number of important drugs, including a cancer cell therapy for lymphoma, a combination drug for schizophrenia, a new anemia pill and an antibody treatment for the Ebola virus.
The five experimental therapies are listed in order of the currently scheduled date by which the FDA has agreed to make a decision on approval. There are no scheduled review times for SARS-CoV-2 vaccines. However, the FDA is widely expected to consider granting emergency authorizations prior to a standard review.
Vaccines for SARS-CoV-2 infection
Four drugmakers are testing would-be vaccines for the new coronavirus in large, late-stage trials in the U.S. Two, Pfizer and Moderna, expect to get preliminary data from their studies by, respectively, late October and November.
It's not clear exactly what any early results would look like, but detailed study plans made public by the companies give some sense of how the trials are being conducted and when they might be declared a success (or failure).
Each trial has enrolled tens of thousands of healthy adults, randomizing them to receive either a placebo or the experimental shot being studied. Relatively few cases of COVID-19 will be needed to determine whether vaccination is protective — 164 in Pfizer's trial and 151 in Moderna's.
But the drugmakers have built interim data checks into their trials, allowing independent monitoring committees to review results after as few as 32 and 53 cases, respectively. In either case, the vaccine would need to be highly effective, or clearly ineffective, for the committee to reach a judgment so early.
In guidelines released this summer, the FDA has said it will require a vaccine be at least 50% effective in preventing COVID-19 before it grants an approval. On safety, the agency wants to see data from thousands of study participants followed for at least six months after vaccination.
The FDA could also first grant an emergency use authorization, or EUA, which typically requires less data. Given the potential for widespread use of any cleared vaccine, however, FDA officials have indicated any emergency authorization would be more like an "EUA plus," with a correspondingly higher bar.
Guidelines on the EUA process for coronavirus vaccines were supposed to be made public, but the document has become political because of how it could affect the chances of a vaccine being cleared for use before the Nov. 3 election.
While Pfizer and Moderna are likely to be the first with data, AstraZeneca and Johnson & Johnson could in theory announce results before the end of the year, too. AstraZeneca's U.S. study is currently on hold due to safety concerns, while J&J just began its late-stage test last week.
Regeneron's EB3 for Ebola virus infection
Regeneron is a leader in the race to develop antibody-based drugs for the new coronavirus. Its speedy progress is a product of the roadmap it developed battling another viral threat, Ebola, that could result in a drug approval next month.
Responding to the 2014 Ebola outbreak in West Africa, Regeneron deployed its antibody drug technology - which it's used to make approved medicines for cancer and eye diseases, among others - against a viral infection.
Within months, Regeneron came up with REGN-EB3, a cocktail of three antibodies. But the 2014 outbreak passed, meaning Regeneron had to wait for the virus to return before it could prove the treatment's worth.
Success finally came last year, when REGN-EB3 recorded positive results in a multi-drug trial amid a new flareup in the Democratic Republic of the Congo. The trial was stopped early after the antibody bested a drug called Zmapp at keeping patients alive after 28 days. Regeneron’s drug could be approved on Oct. 25, potentially becoming one of just a few available treatments for the lethal virus.
Despite the scientific achievement, Regeneron's Ebola drug isn't high on the radar screens of Wall Street analysts, who are focused on the company's more lucrative ongoing efforts in oncology and, more recently, COVID-19.
But the company has said it took a page from its Ebola work in developing its coronavirus antibody cocktail, a two-drug combination now in late-stage testing. Anticipation of an Ebola redux has led to higher investor expectations, wrote SVB Leerink analysts. Regeneron's shares are up nearly 30% since announcing work on the drug in March, touching all-time highs in July.
Alkermes' ALKS-3831 for schizophrenia and bipolar I disorder
Alkermes has made a concerted effort to transform itself from a drug delivery specialist to drugmaker. Key to that strategy has been a pipeline of experimental neurological and cancer medicines that, so far, has yet to bear fruit.
The company's closest shot, a depression drug called ALKS-5461, was panned by an FDA advisory committee and rejected by the agency in 2018. Alkermes restructured a year later. Shares now trade at less than $20 apiece, lower than in any year since 2012.
Now comes ALKS-3831, a drug Alkermes hopes can help win back investor confidence. The drug is a combination of the antipsychotic Zyprexa and a second compound, samidorphan, that is supposed to help mitigate the weight gain associated with Zyprexa.
Alkermes hasn’t definitively proven that theory, however. In one four-week study, Zyprexa and ALKS-3831 patients gained weight at similar rates. In a second, much longer trial, the Alkermes drug outperformed Zyprexa on measures of weight gain. Alkermes filed for approval in both schizophrenia and bipolar I disorder based on the results.
As with its depression drug, Alkermes will again have to take a mixed set of data to an FDA advisory committee on Oct. 9, which "may be a little unnerving to some after how things played out with '5461," wrote Stifel analyst Paul Matteis. The FDA should make a decision by Nov. 15.
Bristol Myers Squibb's liso-cel for non-Hodgkin lymphoma
Three years ago, executives of Juno Therapeutics predicted an approval for their experimental cancer cell therapy could come as early as late 2018.
Known first as JCAR017 and then as liso-cel, the treatment was a large part of Celgene's decision to buy Juno for $9 billion in January 2018. Liso-cel, which is being studied for use in treating non-Hodgkin lymphoma, has since had its corporate owner change again, when Bristol Myers Squibb acquired Celgene one year later.
With each transaction, the timeline to market has slipped later and later. Bristol Myers filed an application with the FDA in December 2019 and secured a coveted priority review, setting up a possible approval by June. But in May, the regulator delayed its decision, marking Nov. 16 as the date by which it would determine whether liso-cel can be sold as a lymphoma treatment.
For former shareholders of Celgene, a lot is riding on the FDA's decision. Bristol Myers, as part of its acquisition, agreed to pay an additional $9 per Celgene share should three experimental therapies win U.S. approval by certain dates. The first, a multiple sclerosis treatment called Zeposia, met its deadline with an OK in March. Liso-cel is next up.
Should liso-cel gain FDA clearance, it will be the fourth CAR-T treatment to reach market, after Novartis' Kymriah and Gilead's Yescarta and Tecartus. Both Kymriah and Yescarta are approved to treat non-Hodgkin lymphoma.
Fibrogen's roxadustat for chronic kidney disease
For decades, people with anemia and damaged kidneys have been treated with injectable biologic drugs like Amgen's Epogen and Aranesp. But a new group of anemia pills could upend the market. By Dec. 20, FibroGen's roxadustat might be the first of them to win U.S. approval.
Roxadustat is the furthest along among an emerging class of drugs that are meant to trick the body into thinking it's in low-oxygen conditions. This approach stimulates the production of red blood cells, thereby boosting hemoglobin levels in people with anemia. The drug has been shown to be comparable to biologics in patients with chronic kidney disease either on or off or dialysis, and FibroGen has parlayed those findings into approvals in China and Japan.
Reviews are underway in the U.S. and Europe as well, and the outcome of each could tell how broad of a reach FibroGen's drug will have. Though FibroGen's drug hasn't been tripped up by safety issues in large studies of cardiovascular risk — a key concern of treatment with biologics for anemia — a similar, rival drug from Akebia recently was.
Analysts at RBC Capital Markets thought Akebia's failure might heighten FDA scrutiny of FibroGen's drug. But SVB Leerink was more positive, calling it a "goldilocks scenario" that set back a key competitor but didn't undermine the whole class of drugs.