Pledging ‘Radical Transparency,’ FDA Reveals Drug Rejection Letters — With Limits

When the FDA turns down a drug application, it has historically been up to the drug company to reveal it. These FDA complete response letters, or CRLs, have not been considered public documents. Companies do disclose these negative regulatory decisions, but they usually reveal little else about the what the agency said regarding the submission.

Debate has continued for years about whether CRLs should be made public. While companies want to ensure that proprietary information stays private, investors want transparency. The FDA is moving toward more transparency. Last Thursday, the FDA revealed more than 200 CRLs in what it said is a first batch of these letters spanning 2020 to 2024.

The FDA said the practice of keeping CRLs private enabled companies to misrepresent the agency’s rationale for a regulatory decision. According to an FDA analysis, drug companies’ public announcements about negative FDA decisions avoided mentioning 85% of the agency’s concerns about safety and efficacy.

“Moreover, when FDA calls for a new clinical trial for safety or efficacy, that critical information is not disclosed approximately 40% of the time,” the agency said. “Lessons learned from non-approvals are also not shared within the industry, leading companies to repeatedly make similar mistakes.”

The FDA described the publishing of the letters as “radical transparency,” but it comes with some restrictions. The letters are redacted to protect trade secrets and confidential commercial information. The letters published so far are also only for drugs that eventually overcame the deficiencies spotted in their applications, enabling them to go on to secure regulatory approval. That means the latest letters don’t make the cut.

On Friday, the FDA turned down Capricor Therapeutics submission for Deramiocel, a cell therapy for the cardiovascular complications of Duchenne muscular dystrophy. Capricor said the FDA asked for more clinical data showing efficacy. After Friday’s market close, Ultragenyx Pharmaceutical revealed a CRL for its gene therapy for the rare neurodegenerative disorder Sanfilippo syndrome. Ultragenyx said the FDA’s questions were about chemistry, manufacturing, and controls issues that are addressable.

There’s plenty of other regulatory news for the summer so far. Here’s a recap of some recent regulatory developments:

Cancer Drug Approvals

—Dizal Pharmaceutical’s Zegfrovy received an accelerated FDA approval for non-small cell lung cancer driven by exon 20 insertion mutations to EGFR proteins. Johnson & Johnson’s Rybrevant has approval for treating NSCLC driven by this genetic signature, but as a bispecific antibody must be administered as an intravenous infusion. Zegfrovy is a once-daily pill.

—Incyte drug Monjuvi expanded its label to include the treatment of follicular lymphoma. The monoclonal antibody, designed to target the cancer protein CD19, was initially approved in 2020 for relapsed or refractory diffuse large B cell lymphoma for use alongside the Bristol Myers Squibb drug Revlimid. Monjuvi’s new approval covers its use alongside Revlimid and the Roche drug Rituxan. Incyte had commercialized Monjuvi in partnership with MorphoSys. MorphoSys had U.S. rights to the drug while Incyte had rest of world rights. Incyte acquired MorphoSys’s rights last year after that company reached a deal to be acquired by Novartis.

—Datroway expanded its label to include treatment of advanced cases of non-small cell lung cancer (NSCLC) driven by EGFR mutations. It was first approved in January for treating HR positive and HER2 negative breast cancer. The antibody drug conjugate, developed by partners AstraZeneca and Daiichi Sankyo, targets the cancer protein TROP2. The new regulatory decision for the drug is an accelerated approval. Additional clinical studies are underway evaluating Datroway alone and in combination with the AstraZeneca cancer drug Tagrisso for the treatment of advanced cases of EGFR-mutated NSCLC.

—Merck immunotherapy Keytruda added a new FDA approval in head and neck cancer as a neoadjuvant, a treatment administered to shrink tumors before surgery. The FDA said it’s the first approval in head and neck squamous cell carcinoma in six years and the first overall perioperative (before and after surgery) approval for this type of cancer that is locally advanced.

—UroGen Pharma’s Zusduri became the first FDA-approved treatment for recurrent low-grade intermediate-risk non-muscle invasive bladder cancer. The product consists of the chemotherapy mitomycin and UroGen’s proprietary sustained release hydrogel. Delivered to tumors by a catheter, Zusduri offers a non-surgical way to treat tumors. In its Phase 3 test, results showed a 78% complete response; 79% of responders were event free 12 months later. UroGen landed the regulatory approval despite a 4 to 5 vote FDA advisory committee vote in May on the question of whether the benefits of Zusduri outweigh its risks. The product’s label warns of the risks of serious adverse effects if administered to patients who have a perforated bladder.

—Nuvation Bio’s taletrectinib, brand name Ibtrozi, landed FDA approval for the treatment of advanced cases of non-small cell lung cancer driven by the ROS1 mutations. It’s a rare mutation, but ROS1-driven cancer can be aggressive. Ibtrozi will compete against established ROS1 inhibitors Xalkori from Pfizer and Rozlytrek from Roche as well as Augtyro, an FDA-approved ROS1 inhibitor that Bristol Myers Squibb obtained from its $4.1 billion acquisition of Turning Point Therapeutics.

Immunology & Inflammation Approvals

—Sobi drug smapalumab, brand name Gamifant, received FDA approval for treating macrophage activation syndrome (MAS), a severe and potentially fatal complication of rheumatic diseases. The regulatory nod specifically covers MAS in patients with Still’s disease, a rare autoinflammatory disorder. Gamifant is an antibody designed to bind to and neutralize interferon gamma, a signaling protein that plays a key role in immune responses.

—The blockbuster Sanofi and Regeneron Pharmaceuticals drug Dupixent expanded its label again with an FDA approval that makes it the first targeted therapy for bullous pemphigoid, a rare immunological skin disease. This regulatory nod comes two months after Dupixent notched FDA approval for a different inflammatory skin disorder called chronic spontaneous urticaria. Dupixent’s label now spans eight indications.

—The FDA approved an autoinjector for administering Benlysta to children age 5 and older who have lupus nephritis. The autoinjector will enable children to take the GSK drug at home. Intravenously infused Benlysta was first approved in 2011 as a treatment for lupus in adults. A self-injectable formulation for adults won FDA approval in 2017.

Approvals in Infectious Disease

—Moderna received FDA approval for its next-generation messenger RNA Covid-19 vaccine. Known in development as mRNA-1283, Moderna will market this new vaccine as mNEXSPIKE. In the key clinical trial supporting the application, mNEXSPIKE showed a 9.3% higher relative vaccine efficacy compared to SpikeVax, Moderna’s first approved Covid-19 vaccine. The approval for mNEXSPIKE covers its use in all adults age 65 and older as well as those age 12 to 64 who have at least one underlying risk factor that puts them at greater risk of severe disease from Covid-19 infection.

—The FDA also granted full approval to Moderna’s SpikeVax for children ages 6 months to 11 years old who are at increased risk of disease from Covid-19. This vaccine was previously available to this age group under emergency authorization.

—A new formulation of Novartis malaria drug Coartem won regulatory approval in Switzerland, making it the world’s first antimalarial therapy for newborns and infants. Following the approval in Novartis’s home country, eight African countries are expected to approve the drug. Novartis said it will supply Coartem on a not-for-profit basis in regions where malaria is endemic.

Other Approvals of Note

—The ultra-rare metabolic disorder alkaptonuria now has its first FDA-approved drug, Cycle Pharmaceuticals’ nitisinone (brand name Harliku). Aalkaptonuria leads to buildup of urine homogentisic acid, which in turn leads to osteoarthritis, ochronosis, and kidney and heart complications. Cycle said it expects to launch Harliku, a once-daily pill, in July.

—CSL Behring received FDA approval for Andembry for preventing the swelling attacks caused by the rare disease hereditary angioedema (HAE). The company already markets two drugs for the disorder, Berinert for acute treatment of HAE attacks and Haegarda for preventing them. Both are injectable medicines that inhibit a protein called C1 esterase. Andemby blocks a different protein called factor XIIa. This once-monthly injection is approved for HAE patients age 12 and older.

—In other HAE news, the FDA approved KalVista Pharmaceuticals’ Ekterly, making the pill the first oral on-demand treatment for the swelling attacks caused by this rare disease. It’s the biotech’s first commercialized product.

—An Alcon drug developed to stimulate natural tear production has received FDA approval as a new treatment for dry eye disease. The drug will be marketed under the brand name Tryptyr. While the exact way Tryptyr works is unknown, alcotremon, the active pharmaceutical ingredient in the eye drop, activates the TRPM8 receptor. Stimulating this receptor has been shown to activate nerve signaling that increases tear production. Alcon said it expects to launch Tryptyr in the third quarter of this year.

Disappointing Developments

—The FDA issued a complete response letter for Unicycive Therapeutics’ submission for oxylanthanum carbonate (OLC) as a treatment for hyperphosphatemia, excess phosphate in the blood, in patients with chronic kidney disease who are on dialysis. According to Unicycive, the FDA cited manufacturing issues unrelated to OLC at a third party vendor. The company has identified a second vendor that has already produced OLC and could be used to address the issues that the agency had raised.

Hyperphosphatemia is treated with phosphate binders, drugs that bind to phosphate and prevent absorption by the body. But currently available drugs require patients to take many pills. Unicycive makes OLC with nanoparticle technology to boost its phosphate binding potency, reducing the number and size of pills that patients need to take.

—The FDA is investigating two fatalities associated with Elevidys, a Sarepta Therapeutics gene therapy for Duchenne muscular dystrophy. Both fatalities were in non-ambulatory teenagers who developed acute liver failure. That matters because older, heavier patients require a higher dose of the gene therapy, which raises the risk of complications. The FDA safety communication said the agency is investigating the risk of acute liver failure with serious outcomes, including hospitalization and death. Sarepta has already taken steps, such as stopping shipments of Elevidys for non-ambulatory patients and convening a group of Duchenne and liver experts to advise on an immunosuppression regimen to counteract adverse liver effects.

—The FDA turned down Stealth Biotherapeutics application for elamipretide, a drug that the biotech had developed as a treatment for the ultra-rare mitochondrial disorder Barth syndrome. Despite the complete response letter, Stealth said the FDA has agreed to consider knee extensor muscle strength as a potential intermediate clinical endpoint to support accelerated approval. Here’s more about elamipretide and its long clinical trial and regulatory history.

—Savara said the FDA sent a refuse-to-file letter regarding the submission for molbreevi, a potential treatment for the autoimmune pulmonary alveolar proteinosis. This rare disease is characterized by abnormal buildup of proteins and lipids on the alveoli of the lungs. According to Savara, the FDA did not raise any safety questions nor did it ask for additional clinical data. The company said the regulator requested additional information related to chemistry, manufacturing, and controls.

—Axsome Therapeutics received refuse-to-file letter for AXS-14, a drug it developed for managing fibromyalgia. According to the biotech, the FDA said the second of the drug’s two placebo-controlled studies is not adequate and well controlled because its primary endpoint was at eight weeks and it used a flexible-dose paradigm. The first placebo-controlled study was for 12 weeks and used a fixed dose paradigm. Axsome said it will conduct another clinical trial using a fixed-dose paradigm and a 12-week primary endpoint. This study is slated for a fourth quarter 2025 start.

Other FDA Actions

—The FDA eased some restrictions for CAR T-cell therapies for cancer. This drug class no longer requires a safety plan called a Risk Evaluation and Mitigation Strategy. The FDA also removed the requirement that these therapies be administered in specially qualified centers. The agency said these changes should make cancer cell therapy more accessible to a wider range of eligible cancer patients.

—The labels of extended-release stimulants for treating attention-deficit/hyperactivity disorder (ADHD) must now carry a warning for the risk of weight loss in children younger than age 6. While these drugs are not approved for this age group, they are often prescribed off-label for young children. The FDA said its analysis of clinical trial data found that children younger than age 6 have a greater risk of weight loss than older children who take these drugs.

Photo: Getty Images, Sarah Silbiger