Testifying before the Senate Health, Education, Labor, and Pensions (HELP) Committee on Thursday, President Donald Trump’s nominee for FDA Commissioner Martin A. Makary, MD, sought to assure senators that if confirmed, he would support efforts to expedite reviews of new drugs indicted for rare diseases, as well as tailor to individual diseases the agency’s regulatory review-to-approval pathways designed to advance drugs to treat them.
“We have to customize the regulatory process to the condition that we’re trying to be able to offer hope, so, if a condition affects 19 people in the world as a partial triplication chromosome 15 disorder does, or a disease that affects 52 kids in the world, we cannot require two randomized control trials,” Makary said, responding to a question from Sen. Lisa Murkowski (R-AK), according to a transcript released by her office. “We have to customize the regulatory process to what we’re trying to do if our goal is to try to provide safe and effective therapies.”
Makary, a surgeon and public policy researcher at Johns Hopkins University, was nominated “to course-correct and refocus the agency,” Trump said last November in announcing his choice to helm the FDA. Should he be confirmed, Makary would report to Health and Human Services (HHS) Secretary Robert F. Kennedy Jr., who has targeted the FDA for drastic changes on a host of biopharma and broader healthcare concerns as part of his commitment to “make America healthy again” by “go(ing) wild on health.”
“If confirmed, I hope to ensure the FDA holds to the gold standard of trusted science, transparency, and common sense to rebuild public trust and make America healthy again,” Makary said in his opening statement.
Murkowski noted that Makary has committed to pursuing regulatory decisions that are based on both science and “common sense.”
“How do we define common sense here as it applies to the regulatory decisions of the FDA?” Murkowski asked Makary. “How do we make sure that ALS patients who are looking at a very, very limited time frame, they can’t wait for the traditional approval process, there are some emerging measures using digital technologies, is this in your realm of common sense?”
A renewed focus on speeding up rare disease reviews could shore up the stocks of rare disease drug developers—15 of which have seen their share prices slide so far this year, according to analysts at Jefferies.
Analyst sees “clear +” for stocks
“A clear + [positive] for the broader space,” Jefferies equity analyst Andrew Tsai wrote Thursday in a research note following Makary’s testimony.
The average decline of the stocks tracked by Jefferies was 18%, with a median decline of 21%. Falling the furthest since the start of January was Lexeo Therapeutics (NASDAQ: LXEO), which has plummeted 59.5% from $6.67 on January 2 to $2.70 at the closing bell Friday—a slight improvement over the 62% plunge cited by Jefferies as of Wednesday.
Lexeo late last year reached an agreement with the FDA on key elements of a registrational development plan for LX2006, an AAV-based gene therapy delivered intravenously for the treatment of Friedreich’s ataxia (FA) cardiomyopathy. The plan includes an accelerated approval pathway that sets as co-registrational endpoints both left-ventricular mass index (LVMI) and frataxin protein expression. Target levels include 10% reduction in LVMI and 40% frataxin positive area as measured by immunohistochemistry.
In January at the J.P. Morgan 43rd Annual Healthcare Conference, Lexeo said it expected to release data in mid-2025 from patients given the highest of three dosages of LX2006 in the current Phase I/II trial (NCT05445323), with plans to potentially launch a registrational study by the end of this year or early 2026.
Lexeo has also generated positive interim Phase I/II data for another program, LX1001 for the treatment of APOE4-associated Alzheimer’s disease, presented last fall at the Clinical Trials on Alzheimer’s Disease (CTAD) conference. But by January, the company said continued development of LX1001 would hinge on its ability to find a partner—a development that set Lexeo’s stock on a downward path this year.
The second biggest decline was the 47% nosedive by shares of Dyne Therapeutics (NASDAQ: DYN) from $25.46 on January 2 to $12.40 on Friday. That decline was kicked off when the company reported data from its ongoing Phase I/II ACHIEVE trial (NCT05481879) assessing one of its two lead candidates, DYNE-101, in patients with myotonic dystrophy type 1 (DM1).
While Dyne showed splicing correction and robust and sustained functional improvements in DM1 patients dosed with DYNE-101, the extent of improvement was less than investors hoped, and shares tumbled 31% on January 10 as a result. Dyne has since enrolled patients in a registrational expansion cohort of ACHIEVE that is expected to achieve full enrollment by mid-2025, and whose data will support a planned accelerated approval submission to the FDA.
Brain drain fears
In addition to overall macroeconomic conditions, the analysts said, the rare disease stock declines reflect fears of a brain drain by industry professionals (and thus investors) that numerous officials will exit the FDA in coming weeks, including experienced reviewers specializing in studying rare disease drugs.
That fear was heightened last month when Patrizia Cavazzoni, MD, resigned as director of the FDA’s Center for Drug Evaluation and Research (CDER), and returned to Pfizer to become its chief medical officer. “We are not sensing FDA review/meeting delays but are certainly monitoring for noticeable changes,” Tsai wrote Wednesday in a second research note.
Tsai noted that if confirmed, Makary could name a permanent successor to Cavazzoni at CDER, which is now helmed by an acting director, Jacqueline Corrigan-Curay, JD, MD. CDER is one of two FDA centers that oversee rare disease reviews, the other being the Center for Biologics Evaluation and Research (CBER).
Since 1992, CDER has granted 328 accelerated approvals—21 of them last year alone—while CBER granted 24 accelerated approvals between 2000 and 2022.
“Many public sources have indicated many more staff at the FDA are considering resignation or various buyout offers, etc., putting risk on FDA capacity and resources especially ahead of increasing numbers of drug filings and reviews, i.e., PDUFAs this year,” Jefferies equity analyst Michael J. Yee wrote in a March 5 research note. Yee used the acronym for the Prescription Drug User Fee Act, the regulation through which the FDA sets target decision dates for its reviews of new drugs and biologics.
Policy questions
In his testimony, Makary touched on numerous topics raised by HELP committee senators, including probationary employee layoffs at the FDA (he committed to assessing the agency’s staffing and personnel levels), the postponement of a Vaccines and Related Biological Products Advisory Committee meeting (he did not commit to rescheduling), and clinical trial diversity (while saying he was supportive, he added he was unfamiliar the agency’s removal of website pages focused on diversity, equity, and inclusion).
But Makary also signaled he intends to delve into big-picture policy questions going beyond drug development in rare diseases and other indications—from the length of reviews, to whether new treatments and devices should require prescriptions.
“We can use some common sense to ask some big questions we’ve never asked before at the FDA. Why does it take 10 years for a drug to get approved?” Makary said. “Why does a college student who suffers from chronic abdominal pain for years, and we have no idea what’s going on, and they go to Italy for a summer and they are suddenly cured of their abdominal pain? Why does a peanut allergy medication that’s been safe with data for decades get approved in Europe before the United States when nearly 10% of our population has a food allergy”
“I do think there’s a lot of areas where we can ask, does a drug need to be prescription, when it could be over the counter?” Makary continued. “Why are we requiring continuous glucose monitors to have a doctor’s prescription when it’s good for people to use these monitors and learn about what they’re eating? We don’t just want to limit continuous glucose monitoring to people with diabetes. We want to prevent diabetes when 30% of our nation’s children have diabetes or pre-diabetes or some form of early insulin resistance. Why are we holding these tools to help people, empower them about their health, until after they’re sick? Same with continuous blood pressure monitoring.”
Leaders and laggards
- Moderna (NASDAQ: MRNA) shares climbed 16% from $30.37 to $35.21 Wednesday after president Stephen Hoge, MD, said a late-stage trial assessing mRNA-4157/V940, the adjuvant melanoma vaccine Moderna is co-developing with Merck & Co. (NYSE: MRK) was fully enrolled, and restated that the companies were aiming to receive full FDA approval in 2027. “Having it fully enrolled and knowing the natural history of when we’d expect those events to be, we’re cautiously optimistic. ’27 is right on path,” Hoge told attendees Wednesday at the TD Cowen 45th Annual Health Care Conference 2025, held in Boston, as reported by Seeking Alpha. mRNA-4157/V940 is a messenger RNA (mRNA)-based individualized neoantigen therapy (INT) for which the companies last fall projected approval in 2027, followed by launch in 2028.
- Plus Therapeutics (NASDAQ: PSTV) shares more than quadrupled, zooming 311% from 35 cents to $1.44 Thursday after the developer of targeted radiotherapeutics with advanced platform technologies for central nervous system cancers announced that the FDA granted its Orphan Drug Designation to Rhenium (186Re) Obisbemeda for the treatment of leptomeningeal metastases (LM) in patients with lung cancer. The designation Plus’ completion of the ReSPECT-LM Phase I single-dose trial (NCT05034497), which established a recommended dose for Phase II studies. Plus is advancing a Phase II single-dose expansion trial and a Phase I multiple-dose trial and said it is actively engaging the FDA to define an optimal pivotal trial strategy.