Abstract
The U.S. Department of Health and Human Services (HHS) has issued a draft guidance promoting innovation for rare disease therapies like the one developed by a groundbreaking partnership that successfully treated K.J. Muldoon, or “Baby KJ,” in a milestone for the development of N-of-1 gene editing therapies.
The Food and Drug Administration’s (FDA’s) Plausible Mechanism Pathway draft guidance consists of a series of initiatives designed to increase regulatory flexibility and spur the development of bespoke gene-editing therapies for rare and ultrarare disorders, which collectively affect about 30 million individuals in the United States.
“The Agency anticipates that substantial evidence of effectiveness for individualized therapies could be established based on a single adequate and well-controlled clinical investigation with confirmatory evidence,” the draft guidance stated. 1
The draft guidance was unveiled in a briefing held at HHS headquarters in Washington, DC, hosted by HHS Secretary Robert F. Kennedy, Jr., and the Commissioner of the U.S. FDA, Martin Makary, MD, MPH. In attendance were dozens of families and patient advocates impacted by rare disorders.
In his opening remarks, Kennedy hailed the K.J. Muldoon story as a medical miracle that should not remain a one-time miracle.
“Every child deserves the same kind of treatment,” Kennedy said. “For decades, families heard the same thing: not enough patients, approvals take too long. That ends today… A disease with 100 distinct mutations in the same gene will no longer require 100 clinical trials… Individualized medicine is no longer theoretical.” 2
Kennedy and Makary were joined at the briefing by two Philadelphia-based physician scientists—Kiran Musunuru, MD, PhD, of Perelman School of Medicine at the University of Pennsylvania (Penn), and Rebecca Ahrens-Niklas, MD, PhD, of Children’s Hospital of Philadelphia. It was largely the Baby K.J. clinical breakthrough last year, led jointly by Musunuru and Ahrens-Niklas, that provided the impetus for the release of the Plausible Mechanism Pathway plan.
In May 2025, a research consortium led by Ahrens-Niklas and Musunuru announced the successful treatment of K.J. Muldoon, an infant born with a rare metabolic disorder. A rapidly assembled private-public partnership designed and tested a bespoke base editing treatment that was able to engineer a single-base substitution in the defective gene. K.J. was discharged last June, receiving a police escort home, before his parents undertook a flurry of national television interviews. Nine months later, Musunuru said, K.J. is now thriving, growing well, and full of unbridled joy.
Last June, at an historic roundtable of cell and gene therapy researchers and clinicians hosted by the FDA, base editing pioneer David Liu, PhD stated, “With sufficient organization and federal support and partnership with the FDA, I believe it will be possible by 2030 to treat at least 1,000 patients with personalized genetic treatments.” 3
But making strides towards that goal, as FDA leaders acknowledged at the time, would require numerous regulatory steps and accommodations to adapt to the new reality of rare disease therapeutics, which has traditionally been at odds with the economics of drug development.
Addressing the families of children with rare diseases, Kennedy pledged to end the delays in regulatory approval for rare disease therapies. In rare disease situations where randomized clinical trials are simply not feasible, Kennedy said that moving forward, “one well-controlled clinical investigation can support approval.”
Liu is the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare, vice chair of the faculty at the Broad Institute of MIT and Harvard, the Thomas Dudley Cabot Professor of the Natural Sciences at Harvard University, and a Howard Hughes Medical Institute investigator.
FEDERAL CIRCUIT SIDES WITH REGENXBIO
The U.S. Court of Appeals for the Federal Circuit (CAFC) has overturned a 2024 U.S. District Court summary judgement favoring Sarepta Therapeutics in a patent dispute with REGENXBIO and the Trustees of Penn, declaring that claims directed at an undisputedly human-made host cell containing recombinant nucleic acid molecules are patent eligible under Title 35 of the U.S. Code, Section 101.
The appeals court ruling reverses a 2024 summary judgment by the District Court for the U.S. District of Delaware, which held that the claims in U.S. Patent No. 10,526,617 (“Method of Detecting and/or Identifying Adeno-Associated Virus (AAV) Sequences and Isolating Novel Sequences Identified Thereby”), licensed by REGENXBIO from Penn, were patent ineligible because they were directed at naturally occurring subject matter.
“The claims here are not merely directed to repackaging products of nature,” the CAFC concluded in a decision written by Kara Farnandez Stoll, a circuit judge of the appeals court appointed in 2015 by President Barack Obama. “Genetically engineering two nucleic acid sequences from separate species into a single molecule and then transforming a host cell in order to incorporate that new molecule into it—thus fundamentally creating a cell containing a molecule that could not form in nature on its own—is materially different from growing more than one naturally occurring bacteria strain in a culture where none of the bacteria undergo any change from their natural state.” 4
Stoll heard the case along with CAFC circuit judges Timothy B. Dyk, who was appointed by President Bill Clinton in 2000, and Todd M. Hughes, who was appointed by Obama in 2013. The CAFC remanded the case (1:20-cv-01226-RGA) to the Delaware District Court, whose Judge Richard G. Andrews, also an Obama nominee (in 2011), initially heard the dispute.
REGENXBIO and Penn sued Sarepta in 2020, alleging that Sarepta used an improperly patented adeno-associated virus (AAV) vector platform in the gene therapy that the company markets as Elevidys® (delandistrogene moxeparvovec-rokl), for which Sarepta first won approval in 2023. Elevidys is indicated for the treatment of patients 4 years of age and older with Duchenne muscular dystrophy (DMD) who are ambulatory and have a confirmed mutation in the DMD gene.
AFTER FAILING TO FIND A BUYER, BIOMARIN WITHDRAWS ROCTAVIAN
BioMarin Pharmaceutical said it will voluntarily pull Roctavian® (valoctocogene roxaparvovec-rvox or “val rox”) from the market after trying but failing to find a company willing to in-license the marketed hemophilia A gene therapy.
“BioMarin undertook a comprehensive effort to identify a potential buyer. Despite these efforts, BioMarin was unable to identify a qualified buyer and has made the decision to voluntarily withdraw Roctavian from the market,” the company stated. 5
BioMarin announced the withdrawal 4 months after embarking on plans to find a buyer or licensee to enable it to divest of Roctavian, after sales of the marketed hemophilia A gene therapy fell short of forecasts.
Roctavian generated $36 million in net product revenues during 2025, up 38% from $26 million a year earlier. During the fourth quarter, Roctavian racked up $13 million, up 18% from $11 million in Q4 2024. Analyst forecasts called for between $2.2 billion and $4 billion in 2027 sales. 6
The withdrawal accounts for BioMarin reporting declines in quarterly income.
The company reported a $47 million generally accepted accounting principles (GAAP) net loss during the fourth quarter of 2025, compared with net income of $125 million in Q4 2024. BioMarin said the quarterly net loss was primarily due to the withdrawal of Roctavian from the market, resulting in charges of approximately $240 million during the quarter. Those charges mostly consisted of a $119 million inventory write-off that was included in the cost of sales and $118 million of long-lived asset impairments that the company included as part of its selling, general, and administrative expense.
Non-GAAP income for the fourth quarter of 2025—which excludes amortization of intangible assets, stock-based compensation expense, and other specified items—decreased to $89 million in Q4 2025 compared with $180 million in the year-ago quarter, also primarily due to the Roctavian inventory write-off included in cost of sales.
FDA ADVISES UNIQURE TO CONDUCT
uniQure has acknowledged receiving a strong recommendation from the U.S. FDA to conduct a prospective, randomized, double-blind, sham surgery-controlled study to support a future marketing application for its Huntington’s disease (HD) gene therapy candidate AMT-130.
The FDA concluded that data from uniQure’s Phase I/II studies, which compared AMT-130 to an external control, were not sufficient to provide the primary evidence of effectiveness needed for the agency to approve AMT-130.
uniQure said it plans to request a Type B meeting with agency officials in the second quarter to further discuss potential study design approaches and intends to continue its engagement with the FDA regarding Phase III development of AMT-130.
“While we did not reach alignment on a submission pathway based on the Phase I/II data, we believe the totality and durability of our data warrant continued substantive dialogue regarding how the FDA’s stated commitment to regulatory flexibility may be appropriately applied in this setting,” uniQure CEO Matt Kapusta said. “We remain committed to engaging with the FDA to determine a clear, scientifically grounded, and efficient path forward for AMT-130.” 7
The FDA stunned uniQure in November 2025 by telling the company that what it called game-changing data showing significant slowing of HD progression in patients treated with AMT-130 may not be enough to secure FDA approval.
The about-face, uniQure asserted, reversed earlier guidance from the FDA supporting the company’s collection of data from the Phase I/II studies compared with an external control—guidance that was reflected in prespecified protocols and statistical analysis plans shared with the FDA before the company carried out its analyses.
PRIME MEDICINE PLANS BIOLOGICS LICENSE APPLICATION
Prime Medicine said it plans to submit a Biologics License Application (BLA) for PM359, a prime editing therapy candidate designed to treat the p47phox (phagocyte oxidase 47 kDa protein) variant of Chronic Granulomatous Disease (CGD), though the treatment has only been given to two patients.
“Prime Medicine continues to engage with the U.S. FDA to explore ways to make PM359 available to patients with CGD. Based on recent interactions, Prime Medicine believes clinical data generated to date may be sufficient to support an accelerated approval of PM359,” the company stated in announcing fourth-quarter and full-year 2025 results. 8
In December 2025, researchers from Prime Medicine and its clinical partners published what they called positive proof-of-concept data in The New England Journal of Medicine (NEJM) from two participants in a Phase I/II clinical trial (NCT06559176) of PM359. The data showed rapid neutrophil and platelet engraftment, as well as durable restoration of nicotinamide adenine dinucleotide phosphate oxidase activity and early clinical benefit, without any safety concerns.
The data—which was also presented in a poster session at the 67th American Society of Hematology Annual Meeting—showed results from the first peer-reviewed clinical use of prime editing to treat human patients.
“Prime editing of autologous CD34+ cells corrected the molecular defect in p47-CGD and restored neutrophil function to near-healthy levels in the two participants,” the researchers wrote. “These results establish that prime editing can result in high levels of precise correction and, along with the clinical data, provide support for the development of this approach as a therapeutic platform for CGD and other genetic diseases.” 9
PM359 consists of autologous hematopoietic stem cells (HSCs) modified ex vivo using an all-RNA-based prime editor that has been designed to correct a high percentage of cells containing the disease-causing mutation. The modified HSCs are designed to correct the deletion of two base pairs, a guanine followed by a thymine (delGC), in NCF1, which is the primary cause of p47phox-deficient CGD (p47-CGD).
BOEHRINGER INGELHEIM SCRAPS INHALED CYSTIC FIBROSIS CANDIDATE
Boehringer Ingelheim has ended development of BI 3720931, an inhaled, lentiviral vector-based gene therapy candidate being developed to treat adults with cystic fibrosis who are not eligible for cystic fibrosis transmembrane conductance regulator modulator therapy (CFTR-MT).
The decision followed the failure of BI 3720931 in the Phase I/II Lenticlair™ 1 trial (NCT06515002), which Boehringer Ingelheim has since terminated. Lenticlair 1 was designed to assess how well BI 3720931 was tolerated and whether it improved lung function in people with cystic fibrosis.
Lenticlair 1 was a two-phase study that began in November 2024 and enrolled five patients. The primary outcome measure for Phase I was the occurrence of any drug-related, treatment-emergent adverse events up to Week 24 after drug administration. For Phase II, the primary outcome measure was absolute change from baseline in forced expiratory volume in 1 s and percent of predicted value (FEV1pp) at Week 8 after drug administration.
The trial was launched as part of an ongoing collaboration by Boehringer Ingelheim with the UK Respiratory Gene Therapy Consortium and Oxford Biomedica, whose lentiviral technology was incorporated into BI 3720931. 10
BI 3720931 failed to produce clinical data supporting further development, according to Boehringer Ingelheim. 11
FDA GRANTS PRIORITY REVIEW TO
The U.S. FDA has accepted for review Ultragenyx Pharmaceutical’s BLA seeking approval of DTX401 AAV gene therapy (pariglasgene brecaparvovec) for the treatment of glycogen storage disease Type Ia. The FDA granted the BLA Priority Review and assigned a Prescription Drug User Fee Act action date of August 23, 2026.
The BLA is based on data from a clinical development program that included 52 treated patients and up to 6 years of follow-up. Data from the randomized, double-blind, placebo-controlled Phase III GlucoGene study (NCT05139316) showed that patients treated with DTX401 experienced significant and clinically meaningful reductions in both the quantity and frequency of daily cornstarch intake while maintaining low levels of hypoglycemia, improved levels of euglycemia, and improved fasting tolerance.
Ultragenyx said those clinical benefits translated to meaningful improvements in patient-reported quality of life, as measured by the Patient Global Impression of Change (PGIC) scale. DTX401 was well tolerated, with an acceptable safety profile.
“If approved, DTX401 would be the first treatment to address the disease at its root cause. We appreciate the FDA’s timely acceptance of the BLA and will continue to work with the Agency throughout its review process,” said Eric Crombez, MD, chief medical officer at Ultragenyx. 12
If approved, Ultragenyx added, DTX401 will be manufactured entirely within the United States at the company’s new gene therapy manufacturing facility in the Boston suburb of Bedford, MA.
DTX401 is an investigational AAV8 gene therapy designed to deliver stable expression and activity of G6Pase under control of the native promoter to allow the treated liver cells to respond to normal hormonal signals intended to manage glucose, including insulin and cortisol. DTX401 has been granted the FDA’s Rare Pediatric Disease, orphan drug, Fast Track, and regenerative medicine advanced therapy designation, as well as the European Medicines Agency’s orphan drug and PRIority MEdicines designations.
FOUNDATION AND FORGE PARTNER TO
The Progeria Research Foundation (PRF) and Forge Biologics, a member of the Ajinomoto Bio-Pharma Services group, have signed a manufacturing agreement of undisclosed value to support the development and manufacturing of SamPro-2, PRF’s investigational gene therapy for children and young adults with Hutchinson–Gilford progeria syndrome.
The manufacturing agreement is designed to combine the nonprofit PRF’s decades-long progeria research program with Forge’s integrated gene therapy capabilities, including process development, cGMP manufacturing, FUEL™ platform technologies, and regulatory consultation. Forge has agreed to provide manufacturing services for Investigative New Drug-enabling studies with SamPro-2, a gene therapy that uses an AAV to deliver a base editing approach designed to correct the single DNA base mutation in the lamin A gene that causes progeria.
PRF and its partners, collectively known as the Progeria Gene Team, have created SamPro-2, a CRISPR-based gene editing strategy designed to permanently correct the progeria genetic mutation at its source. The effort is led by Leslie Gordon, MD, PhD, PRF’s cofounder and medical director and the mother of Sam Berns (1996–2014), who died of complications from progeria; David R. Liu, PhD, Richard Merkin Professor and Director of the Merkin Institute for Transformative Technologies in Healthcare at the Broad Institute of MIT and Harvard; Francis S. Collins, MD, PhD, senior research advisor to the PRF and a former director of the National Institutes of Health (NIH); and Sammy Basso (1995–2024), an Italian biologist and progeria patient advocate who died of complications related to the disease.
“Behind every program like this are patients and families who have waited a long time for progress,” said John Maslowski, Forge Biologics president and CEO. “The Progeria Research Foundation and its Gene Team have shown extraordinary dedication to advancing this science, and we are honored to partner with them. At Forge, we bring that same level of care, expertise, and technical rigor to our manufacturing work as we help advance this program for patients.” 13