FDA Drug Approval Marks a First for a Disease — But It’s Not Autism

The FDA made waves with its recent announcement a single well-controlled Phase 3 study would suffice for a drug submission, replacing the previous standard of two pivotal studies. This past week, the FDA granted a drug approval without any new clinical data — and not for the autism indication the agency initially touted.

FDA approval of the drug, leucovorin, makes it the first treatment for cerebral folate deficiency, an inherited disorder in which patients lack folate, a vitamin essential for brain health. Patients with this deficiency experience developmental delays and movement disorders, among other neurological complications. The exact prevalence of this ultra-rare disorder is unknown, but fewer than 20 cases have been documented in medical literature, according to the National Organization for Rare Disorders.

When FDA Commissioner Marty Makary announced last September that the agency was trying to make leucovorin available for treating autism, he said during a news conference that the drug might be able to help hundreds of thousands of children. The agency said at the time its analysis of literature published between 2009 and 2024 found that leucovorin calcium can help patients who have cerebral folate deficiency. The FDA added that those who have this deficiency have been observed to have developmental delays with autistic features.

Leucovorin, a small molecule designed to serve as a folate analog, was initially developed to reduce side effects from cancer treatments. From 1983 to 1997, GSK marketed it under the brand name Wellcovorin. Though GSK no longer makes this drug, it remains available from generic drug manufacturers. But because GSK submitted leucovorin’s initial new drug application, the FDA needed the pharmaceutical company to submit an application seeking to expand the drug’s label. GSK did so at the agency’s request.

The FDA said its review of the leucovorin supplemental application was based on published literature, including case reports with patient-level information. There was no new clinical trial, but with so few cerebral folate deficiency patients, it would have been difficult for any company to conduct such a study.

The FDA’s announcement of leucovorin’s expanded approval said nothing about autism. In a prepared statement, Tracy Beth Hoeg, acting director of the FDA’s Center for Drug Evaluation and Research, said the drug’s review “provides a good example of how observational or ‘real world’ evidence can lead to an FDA approval when the product is shown to provide clear clinical benefit compared with what is seen with the natural history of the disease.”

There’s plenty of news on the regulatory front. Here’s a recap of recent highlights:

More Developments in Rare Disease

—Ascendis Pharma’s navepegritide, brand name Yuviwel, received FDA approval for treating achondroplasia, the most common form of dwarfism. The Ascendis drug was developed for weekly dosing, which is an advantage over daily injections of Voxzogo, the BioMarin Pharmaceutical product that was the first FDA-approved achondroplasia therapy. Ascendis expects to launch Yuviwel early in the second quarter of this year. In connection with the approval, Ascendis was also awarded a rare pediatric disease priority review voucher that the drugmaker may apply to another product or sell to another company.

—Acadia Pharmaceuticals’ trofinetide received a negative opinion in Europe as a treatment for Rett syndrome, a rare inherited neurological disorder. The drug met the goals of its pivotal study, but the European Commission’s Committee for Medicinal Products for Human Use said the treatment effect after 12 weeks was limited. The committee also said the study did not capture all of the disease’s core symptoms and assessment of long-term outcomes was influenced by patient discontinuations over time. Acadia plans to seek a re-examination of the opinion. Trofinetide won FDA approval in 2023 and is marketed in the U.S. as Daybue.

—The FDA awarded accelerated approval to Immedica Pharma’s pegzilarginase, brand name Loargys, for treating arginase-1 deficiency (ARG1-D) in patients age 2 and older. The ultra-rare disease is an inherited deficiency of the enzyme needed to break down arginine, an amino acid. High arginine blood levels lead to central nervous system problems, such as seizures and developmental delays. Loargys is the first FDA-approved treatment for ARG1-D.

Regulatory Approvals

—The GSK respiratory syncytial virus (RSV) vaccine Arexvy expanded its label to include use by adults age 18 to 49 who are at risk of lower respiratory tract disease, broadening the addressable market for this shot. The FDA’s 2023 approval of Arexvy covered patients age 50 to 59. Arexvy competes with RSV vaccines from Pfizer and Moderna.

—Johnson & Johnson’s Tecvayli is now approved as a second-line multiple myeloma treatment when used alongside Darzalex Faspro, an injectable J&J therapy that is a standard treatment for this blood cancer. Tecvayli is a bispecific antibody designed to target BCMA on multiple myeloma cells. The FDA initially awarded Tecvayli accelerated approval in 2022 as a fifth-line multiple myeloma treatment.

The new regulatory decision makes Tecvayli the third product to receive an approval under an FDA pilot program that accelerates regulatory review of medicines deemed important for public health or the national interest. It also converts the drug’s status to full FDA approval as a monotherapy in the later-line of treatment.

—The FDA granted full approval to Pfizer’s Braftovi as a first-line colorectal cancer treatment when used alongside standard therapies. The drug, which addresses the BRAF V600E mutation, received accelerated approval in this indication in 2024. Phase 3 data supporting full approval were presented last year during the annual meeting of the American Society of Clinical Oncology.

—Bristol Myers Squibb’s Sotyktu added active psoriatic arthritis as a new FDA-approved indication for the drug. The small molecule TYK2 inhibitor was initially approved in 2022 for the treatment of plaque psoriasis.

—Allergic fungal rhinosinusitis, an intense hyperallergic reaction to fungi that leads to inflamed nasal passages and nasal polyps, now has its first therapy. The FDA approved the Sanofi and Regeneron Pharmaceuticals drug Dupixent for treating patients age 6 and older who develop this disorder. It’s the ninth overall FDA approval for the blockbuster biologic, including a prior regulatory nod for chronic rhinosinusitis with nasal polyps.

—Optune Pax, a wearable Novocure medical device, received FDA pre-market approval for treating locally advanced pancreatic cancer when used alongside standard chemotherapies. Novocure develops and markets devices that deliver alternating fields of electricity the company calls tumor treating fields, or TTFields, to destroy tumors. In Phase 3 testing, Optune Pax led to a statistically significant improvement in overall survival. Results also showed treatment with the device significantly extended the time to pain progression. Optune Pax joins a Novocure portfolio that includes TTField devices approved for non-small cell lung cancer, glioblastoma, and mesothelioma.

—The blockbuster Merck cancer immunotherapy Keytruda expanded its list of approved indications with an FDA nod that makes it a second- or third-line treatment for ovarian cancers that express PD-1, the checkpoint protein addressed by this targeted drug. The new FDA approval covers use of Keytruda alongside chemotherapy with or without Avastin, a Roche drug whose approved uses include ovarian cancer. The regulatory decision also covers Keytruda Qlex, the injectable formulation of the drug approved by the FDA last fall.

—The European Commission approved the Cytokinetics drug Myqorzo for the treatment of symptomatic obstructive hypertrophic cardiomyopathy. The drug, a cardiac myosin inhibitor, received FDA approval in December.

—GSK’s Exdensur, a long-acting antibody drug developed for severe asthma, received European Commission approval. The GSK drug offers six-month dosing for treating patients whose severe asthma is driven by a type of white blood cell called an eosinophil. The European regulatory decision follows FDA approval of Exdensur in December.

Regulatory Setbacks

—Incyte received a complete response letter for its application seeking to expand the FDA approval of its biologic drug Zynyz to include metastatic non-small cell lung cancer. No safety or efficacy concerns were raised. In a regulatory filing, Incyte said the FDA letter cited inspection findings, unrelated to Zynyz, at the Indiana site of contact manufacturer Catalent, which Novo Nordisk acquired in 2024. Incyte said it is working with the FDA and Catalent Indiana to address the matter.

—The FDA placed a clinical hold on PepGen’s Phase 2 test of PGN-EDODM1, an oligonucleotide in development for myotonic dystrophy type 1. According to the company, the trial pause stems from FDA questions about previously submitted preclinical data. PepGen said it will address the matter by submitting additional analyses, including recently unblinded data from the clinical trial.

—Following serious adverse events in four patients, including complications that led to one patient fatality, the FDA placed a partial clinical hold on Macrogenics’s Phase 2 test of lorigerlimab in gynecologic cancers. Lorigerlimab is a bispecific molecule designed to target the proteins PD-1 and CTLA-4. The partial hold means no new patients may be enrolled in the study, but current clinical trial participants may continue to receive the experimental Macrogenics drug.

—Disc Medicine received a complete response letter for bitopertin, a drug developed for the rare blood disorder erythropoietic porphyria. The company said the FDA wants to see more data from another clinical trial to show evidence of patient benefit. The Phase 3 trial intended to be the confirmatory study for the drug is underway, but the rejection was a surprise considering bitopertin was one of the first nine drugs selected by the FDA for a new pilot program intended to speed up the regulatory review of new medicines deemed critical for public health.

—PTC Therapeutics withdrew its FDA resubmission for Duchenne muscular dystrophy drug Translarna. The company said it cannot resolve differences it has with the FDA in interpreting the clinical data for the drug. The decision comes nearly a year after the European Commission declined to renew Translarna’s conditional marketing authorization.

—The FDA rejected Regenxbio’s RGX-121, a gene therapy developed to treat mucopolysaccharidosis type II (MPS II), a rare enzyme deficiency also known as Hunter syndrome. According to the company, the complete response letter said the FDA is uncertain about the study eligibility criteria to adequately define a population with of patients with neuronopathic diseases verses attenuated disease. The agency also has questions about the comparability of the natural history external control and the appropriateness of measuring cerebrospinal fluid levels of HS DS26 as a surrogate endpoint for assessing brain disease associated with MPS II.

The FDA’s suggested paths forward include a new clinical trial, treating more patients and conducting longer-term follow up, and using an untreated control arm. Regenexbio said all of these options are challenging in an ultra-rare disease like MPS II. The company plans to request a meeting with the FDA to discuss the letter.

—The FDA turned down Pharming Group’s application seeking to expand the approval of leniolisib, brand name Joenja, to children age 4 to 11 with activated phosphoinositide 3-kinase delta syndrome (APDS), a rare primary immunodeficiency. According to Pharming, the FDA is concerned about potential underexposure of the drug in lower-weight pediatric patients. The agency is asking for more pediatric pharmacokinetic data. Joenja’s approval in children age 12 and older is unaffected.

—Aquestive Therapeutics received a complete response letter for Anaphylm, a sublingual film that administers dibutepinephrine to treat type 1 allergic reactions. According to the company, the FDA’s concerns focus on administration of the product and labeling guidance. To address these issues, Aquestive said it has modified the pouch opening, instructions for use, and package labeling. The company also plans to conduct a new human factors study with these modifications.

—AstraZeneca received a complete response letter for the subcutaneously injected version of antibody drug Saphnelo for the treatment of systemic lupus erythematosus. The company said it has provided the FDA with the information requested in the letter and a regulatory decision based on the updated application is expected in the first half of this year. Intravenous Saphnelo, which was approved for lupus in 2021, remains available to patients.

—The FDA asked Amgen to voluntarily withdraw from the market Tavneos, a drug that came from the pharma giant’s 2022 acquisition of ChemoCentryx. Tavneos was approved in 2021 for treating ANCA-associated vasculitis, a group of autoimmune disorders that leads to inflammation and damage to small blood vessels.

According to Amgen, the FDA raised concerns about ChemoCentryx re-adjudicating results for nine of the 331 patients in Tavneos’s pivotal study. The agency also said there is a risk of liver toxicity. Amgen said it is unaware of any issue with the data from the clinical trial conducted by ChemoCentryx or with real-world evidence for Tavneos. Amgen said it is confident of the drug’s benefit-risk profile and the company told the FDA it does not intend to withdraw Tavneos from the market. But the company said it is evaluating next steps with the FDA.

Regulatory Reprieves

—The FDA has resumed review of a Capricor Therapeutics cell therapy for the cardiomyopathy caused by Duchenne muscular dystrophy. Last July, the agency rejected the company’s application for the therapy, Deramiocel, and asked for more data from another clinical trial. Capricor said its response to the FDA included supporting information from a Phase 3 study. The agency set an Aug. 22 target date for a regulatory decision.

—The FDA lifted its clinical hold on the Phase 3 test of Intellia gene therapy nexiguran ziclumeran (nex-z) as a treatment for cardiomyopathy caused by the rare genetic disorder hereditary transthyretin amyloidosis. Last October, the FDA placed holds on the cardiomyopathy study and a separate Phase 3 test in polyneuropathy caused by the disease after liver complications were reported in a patient in the cardiomyopathy study. The FDA cleared the company to proceed with the polyneuropathy study in late January. Changes for both studies include enhanced monitoring for signs of liver problems.

—In an about-face, the FDA said it will review Moderna’s mRNA vaccine for seasonal influenza. The agency initially refused to even review the application, telling the company last month that the vaccine lacked an adequate and well-controlled study and the clinical trial comparator does not reflect the standard of care. After Moderna met with the FDA, the agency agreed to a review based on age: an application seeking full approval for adults age 50 to 64 and accelerated approval for adults 65 and older. An approval in the older age group would come with a requirement for post-marketing study.

—The FDA granted Vanda Pharmaceuticals’ request for an evidentiary public hearing for Hetlioz, a drug the company is trying to expand to the treatment of jet lag disorder. Hetlioz is already approved for treating non-24-hour sleep-wake disorder and nighttime sleep disturbances associated with Smith-Magenis syndrome. In January, the FDA turned down Vanda’s submission for the jet lag indication, telling the company that a trial that shifted bedtimes is insufficiently analogous to actual jet travel.

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