5 FDA decisions to watch in the fourth quarter

Though 2022 has been a down year for the biotechnology sector, notable decisions from the Food and Drug Administration have provided a few bright spots.

Two gene therapies came to market, providing a lift for a field that’s been slowed by recent setbacks. The cancer drug Enhertu was approved for a newly defined tumor type known as “HER2-low.” The regulator also cleared a new medicine for ALS and a first-of-its-kind inflammatory disease drug.

The fourth quarter could yield some other medical milestones. An Alzheimer’s drug that unexpectedly succeeded in a large trial last week is under review. So are what could be the first treatment for a common form of vision loss, a closely watched HIV drug, and a type of anemia pill the FDA has already turned back twice.

Here are 5 FDA decisions to watch:

Covis’ Makena for prevention of preterm births

In the decade since the FDA made Makena available for the prevention of preterm births, the treatment has become a flashpoint in the debate over speedy drug approvals.

Makena was developed by AMAG Pharmaceuticals and granted accelerated approval in 2011 based on a study showing it reduced the risk of preterm births — which can jeopardize a baby’s health — in women with a history of delivering early.

A study meant to confirm Makena’s benefits took years to complete, however. When the results did arrive in 2019, Makena didn’t perform meaningfully better than a placebo.

Since then, the fate of Makena has been the subject of a fight between the FDA, AMAG and the drug’s current owner, Covis Pharma, which acquired AMAG in 2020. After an FDA advisory panel in 2019 recommended the regulator pull Makena from the market, the agency proposed doing so, arguing “the available evidence does not show Makena is effective” for its approved use.

Its developers, as well as some patient advocates and outside experts, have countered that doing so would be a mistake, claiming the drug still may help Black women at high risk of early births, who made up a larger portion of participants in the original trial than the confirmatory study.

A hearing on the issue has been delayed several times amid legal wrangling, extending the drug’s time on market while its benefit remains unclear. The FDA specifically cited the case as “an example of how lengthy and burdensome the withdrawal process may be” when a company disagrees with the agency, according to a report on accelerated approvals published last week by the U.S. Department of Health and Human Services.

The back-and-forth could come to a conclusion this quarter. A three-day hearing of an FDA advisory panel will begin on Oct. 17 and feature discussions on the available confirmatory evidence as well as “whether FDA should allow Makena to remain on the market.”

GSK’s daprodustat for anemia from kidney disease

GSK’s daprodustat is the third anemia drug of its kind to be reviewed by the FDA. If the rejections of the first two are any indication, daprodustat could have a tough time when the agency’s expert advisers meet to review it on Oct. 26.

Daprodustat is intended to be an oral alternative to injectable biologics like Epogen and Aranesp that boost red blood cell production and are used to treat anemia in patients with damaged kidneys. Those medicines have been standard treatments for years, but their use has been restricted because of the risk of heart problems.

GSK’s drug is also meant to increase red blood cell levels, but by tricking the body into thinking it’s in a low-oxygen environment. The approach is meant to be both safer and more convenient for patients, and has spawned daprodustat as well as drugs from FibroGen and Akebia Therapeutics. All three are approved in Japan, and FibroGen’s is cleared for use in Europe.

But none are available in the U.S., where regulators have taken a tougher stance. In a meeting last year, the FDA and its expert reviewers challenged claims that FibroGen’s drug is safer than its injectable competitors. The agency rejected that medicine and demanded another trial. It then did the same to Akebia’s treatment in March.

GSK believes it has a better case. Unlike its rivals, daprodustat didn’t perform worse than injectable drugs on measures of heart safety in the key studies supporting its application. There are still concerns, however. An editorial published in the New England Journal of Medicine alongside GSK’s two large studies flagged the risk of cancer, and questioned the drug’s benefit in patients who aren’t on dialysis, a group that makes up the majority of people with chronic kidney disease.

Apellis’ pegcetacoplan for geographic atrophy

People with the “wet” form of age-related macular degeneration, a leading cause of vision loss, have many effective treatment options. The estimated 5 million people across the globe with geographic atrophy — an irreversible eye disease that results from AMD — don’t. That could change if the FDA approves Apellis Pharmaceuticals’ pegcetacoplan later this year, however.

Pegcetacoplan is an injectable drug that blocks activation of the complement system, a part of the body’s innate immune response. In clinical testing, it’s shown the potential to slow growth of the lesions, or scar tissue, found in the eyes of people with geographic atrophy.

Yet Apellis doesn’t have a clear-cut case. The drug missed statistical significance in one of its two Phase 3 studies. Apellis also hasn’t yet proven that slowing lesion growth directly translates to improved vision. In August, the company reported patients in its late-stage trials didn’t experience a visual acuity benefit after two years of treatment.

Apellis executives have expressed confidence the drug’s benefit will become apparent with longer follow-up. “We have trouble imagining a scenario where lesion size doesn’t inevitably correlate with function,” wrote Evercore ISI analyst Umer Raffat, in a research note.

A green light from the FDA could yield a drug that Jefferies analysts estimate could generate as much as $6 billion in yearly sales at its peak. A rejection or delay, meanwhile, could cost Apellis a chance to be first to market, as Iveric Bio plans to file for approval of a similar drug early next year.

The FDA will make a decision by Nov. 26.

Mirati’s adagrasib for non-small cell lung cancer

For three years, analysts and investors have debated whether a cancer drug developed by Mirati Therapeutics, a small San Diego biotech, can top a rival one from Amgen that’s become the crown jewel of the larger company’s oncology business.

The two companies have traded clinical trial readouts showing their drugs can effectively shrink tumors driven to growth by mutations in a gene, called KRAS, that for decades was considered undruggable. Last spring, Amgen turned its positive data into a first-of-its-kind approval for its drug, now sold as Lumakras.

Now it’s Mirati’s turn in front of the FDA, as its drug adagrasib is under review with a decision deadline of Dec. 14. Should it win approval, Mirati would compete for market share with Amgen, which has the benefit of recent data confirming its drug beat chemotherapy in a larger study of patients with non-small cell lung cancer.

But Lumakras failed to show it could extend patients’ lives, leaving an opening for Mirati to do better. The company is currently enrolling a bigger trial that’s meant to confirm adagrasib’s benefit.

Gilead’s lenacapavir for HIV

By Dec. 27, Gilead Sciences should know whether its second attempt at getting a key HIV drug approved in the U.S. has succeeded.

The first try ended with an FDA rejection because of concerns about potential adverse interactions between the drug, known as lenacapavir, and the specific glass vials in which it was contained. Gilead said it has since addressed those manufacturing-related issues by using vials made from a different glass. The treatment won its first approval in Europe in September.

A similar outcome in the U.S. would bolster the commercial prospects for an important addition to Gilead’s arsenal of HIV medicines. Lenacapavir has a unique way of binding to the protein shell that surrounds the virus, and its benefits appear long-lasting. In a small study, an injection of the drug every six months, in combination with other antivirals, kept the virus in check for heavily pretreated patients who had developed resistance to multiple therapies.

Gilead has been evaluating potential combinations of lenacapavir and other drugs, including Merck & Co.’s islatravir, although that latter therapy has raised safety concerns over the last year. Gilead is also testing whether its drug works as a preventive treatment.

In a note to clients earlier this year, RBC Capital Markets analyst Brian Abrahams wrote that his team expects the FDA to approve lenacapavir for heavily pretreated HIV patients — a “relatively small indication” that could generate peak annual sales of about $200 million in the U.S.

But given lenacapavir’s various advantages, including the ability to be combined with other treatments and administered in multiple ways, the RBC team argues the drug could become “the backbone” of Gilead’s HIV franchise within several years and ultimately achieve more than $4 billion in yearly sales at its apex.

BONUS: Eisai and Biogen’s lecanemab for Alzheimer’s

Will lecanemab, an experimental Alzheimer’s drug that succeeded in a large clinical trial last week, become a backbone therapy for the neurodegenerative disease? Doctors and researchers aren’t yet sure, as only limited data have been disclosed by lecanemab’s developers, Eisai and Biogen.

They’ll get much more information Nov. 29, when the companies present fuller study results at a medical meeting in San Francisco. The results are likely to be pored over and debated, as they represent the first clearly positive data from a Phase 3 trial of a drug meant to treat Alzheimer’s underlying cause.

They’re also likely to help the FDA decide whether to approve lecanemab on an accelerated basis. Using data from an earlier study, Eisai filed an application earlier this year, and a decision is expected by Jan. 6 on the basis of the treatment’s ability to clear toxic plaques from the brain.

The new trial results were meant to confirm those preliminary findings. Now that they’re positive, Eisai has a stronger case and the FDA a potentially easier judgment call.

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