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Keith Gottesdiener, MD, former president and CEO of Prime Medicine
Prime Medicine is eliminating 25% of its workforce—about 50 jobs—in a restructuring that includes the company pivoting its prime editing-based pipeline focus to liver disease and programs funded by external collaboration partners, following the resignation of Keith Gottesdiener, MD, as president, CEO, and board member.
Succeeding Gottesdiener is Prime Medicine’s CFO Allan Reine, MD, who was promoted immediately to CEO and appointed to the company’s board. Reine said Prime was exploring options for its lead clinical candidate PM539, a treatment for the p47phox (also called neutrophil cytosol factor 1) variant of autosomal recessive chronic granulomatous disease (CGD), accounting for 25% of patients with CGD, according to the NIH’s National Library of Medicine. Prime estimates that CGD causative mutations occur in between one in 100,000 and one in 200,000 births in the United States.
PM359 is the first prime editor-based therapy to be administered in humans. Prime’s effort to outlicense PM359 comes after it announced positive initial data—the first-ever clinical data supporting safety and efficacy of prime editing in humans—following infusion of ex vivo prime edited autologous CD34+ hematopoietic stem cells (HSCs) in the first patient dosed in its ongoing Phase I/II trial (NCT06559176) assessing PM359 in CGD, launched last year as the first-ever clinical phase prime editing therapy.
The patient, identified as an 18-year-old male, experienced complete restoration of NADPH oxidase activity in 58% of neutrophils by Day 15 and 66% of neutrophils by Day 30 following treatment with a single dose of PM359, administered by intravenous infusion. Those results exceeded the anticipated 20% minimum threshold for clinical benefit from PM359, which showed no serious adverse events attributable to the treatment, Prime Medicine said.
The patient also experienced rapid engraftment of his autologous transplant following myeloablative conditioning, confirmed in neutrophils on Day 14 and in platelets on Day 19. Those results were nearly twice as fast as approved gene editing technologies, where median engraftment has been reported to occur on Days 27 and 35 across these same measures, Prime Medicine noted.
NADPH oxidase activity was measured by the dihydrorhodamine (DHR) assay.
“DHR data is the best we’ve seen in the CGD space,” Jefferies equity analyst Maury Raycroft, PhD, declared in a research note.
Raycroft cited data from Orchard Therapeutics showing a >15% DHR improvement confirmed in neutrophils at one month, as well as a 16% to 46% improvement with lentivirus gene therapy in X-linked CGD over 12 months. “Vignette suggests prime editing (no DSBs [double-stranded breaks]) may be better tolerated in HSCs w/ rapid engraftment of neutrophils on D14 and platelets on D19,” Raycroft added.
“Landmark moment”
Allan Reine, MD, new CEO of Prime Medicine
“The first-in-human data for PM359 announced today represent a landmark moment for the industry and for our company, demonstrating the unequivocal power of Prime Editing to change patients’ lives, with a single dose of PM359 providing potentially curative benefit in a matter of weeks,” Reine said in a statement. “These data also reinforce the critical importance of ensuring Prime Medicine is positioned to withstand the challenges of the current environment, so that we can one day deliver the tremendous promise of Prime Editing to address a wide spectrum of genetic diseases.”
For investors, however, the dazzling clinical success of prime editing was overshadowed by the commercial setback of pipeline pruning and cuts to Prime Medicine’s workforce, which numbered 214 employees as of December 31, 2024, according to the company’s Form 10-K annual report for last year, filed February 28. A 25% reduction would equal 53 jobs.
Prime Medicine said the job cuts will reduce its cash requirements by half through 2027, though the company maintained earlier guidance that its cash runway was sufficient to fund operations into the first half of 2026. Prime finished the first quarter with $158.3 million in cash, cash equivalents, investments, and restricted cash, down 23% from $204.5 million as of December 31, 2024.
Prime Medicine shares tumbled 18% Monday as of 2:55 p.m. ET, from $1.59 to $1.31, slowly climbing from the day’s low of $1.26 at 9:48 a.m. (a 21% decline).
Prime editing was first described in a 2019 paper published in Nature by Andrew Anzalone, MD, PhD, and colleagues in the Broad Institute lab of genome editing pioneer David Liu, PhD, whose lab a few years earlier developed another genome editing approach without double-stranded breaks in DNA called base editing. Anzalone discussed the technology and the company on GEN’s “Close to the Edge” video interview series. Anzalone is Prime’s lead developer of prime editing, and the company’s scientific co-founder.
Prime editing can introduce targeted insertions, deletions, and all 12 possible base-to-base substitutions. Liu told GEN at the time that of the roughly 75,000 cataloged pathogenic mutations in human genetic diseases, prime editing had the versatility and potential to correct the majority (89%) of them.
Liu co-founded Prime Medicine in 2020 to commercialize prime editing based on Anzalone’s groundbreaking work when he was a postdoctoral fellow, by developing treatments based on applying the technology’s “search and replace” approach to genome editing. The company went public in 2022.
In a post on X Monday, Liu said the trial of PM359 in p47phox CGD was one of at least 19 base editing and prime editing clinical trials that have begun evaluating treatments in a wide variety of diseases. At least seven of those trials have reported clinical outcomes.
Developed in the U.S., but most trials overseas
“While the U.S. support for science is now in crisis, that there are more base editing and prime editing clinical trials serving patients outside of the U.S. (13) than within the U.S. (9), [has occurred] despite the fact that these technologies were developed in our lab in the U.S.,” Liu wrote.
In addition to seeking a partner for continuing development of PM359, Prime Medicine said it will focus its internal R&D efforts on developing in vivo programs designed to treat two liver diseases with large patient populations representing more lucrative commercial opportunities, Wilson’s Disease and Alpha-1 antitrypsin deficiency (AATD).
The Wilson’s disease program targets prevalent mutations in the ATP7B gene through a lipid nanoparticle (LNP) prime editor. The AATD program is designed to treat the disease by using a universal liver LNP to edit the PiZ mutation (also known as Pi*Z or E342K) in SERPINA1. Prime said in March that LNP delivery of its prime editors showed up to 72% precise correction of the SERPINA1 gene in the hepatocytes of fully humanized mice, restoring over 95% of serum AAT to the corrected isoform, with healthy M-AAT protein in the serum at levels “well above” 20 µM.
The AATD program falls under a collaboration and license agreement Prime signed in 2019 with base editing therapy developer Beam Therapeutics. Prime disclosed today that it recently engaged in binding arbitration proceedings with Beam to resolve a conflict over which company can pursue AATD using prime editing.
Prime Medicine’s current pipeline is a far cry from the 18 candidates that once crowded its pipeline. The company trimmed its roster of preclinical and clinical candidates last September, combining its hematology, immunology, and oncology disease areas into a single area of focus.
Prime Medicine said it expects to file an investigational new drug (IND) and/or clinical trial application (CTA) for its Wilson’s Disease program in the first half of 2026, to be followed in mid-2026 by an IND and/or CTA for its AATD program now in lead optimization phase. The company expects to release initial clinical data from both programs in 2027.
Prime Medicine also said it plans to halt an internal discovery phase CGD program focused on treating the most common form of the disease, X-linked CGD, which is caused by mutations in the CYBB gene that encodes the p91-phox protein, and represents approximately 65% of CGD cases.
That program used Prime Medicine’s Prime Assisted Site-Specific Integrase Gene Editing (PASSIGE) platform technology. PASSIGE combines Prime Editing with an integrase or other site-specific recombinase to introduce large gene-sized cargo into the genome for stable cargo expression. PASSIGE is delivered through an entirely non-viral manufacturing process without introducing double-stranded DNA breaks or off-target edits—features which, according to Prime, may enable more precise and effective genetic modification.
As for externally funded programs, Prime Medicine said it plans to continue its in vivo cystic fibrosis treatment program, a PASSIGE-based discovery phase program which is supported through the up to $15 million committed to the company by the Cystic Fibrosis Foundation.
Prime also plans to continue its efforts to develop Prime Edited chimeric antigen receptor T-cell (CAR-T) products for hematology, immunology, and oncology, through an up-to-$3.5 billion-plus collaboration with Bristol Myers Squibb (BMS). Last September, Prime Medicine received $110 million upfront from BMS after agreeing to partner on developing and commercializing an unspecified number of reagents for ex vivo T-cell therapies, also based on PASSIGE.
Prime Medicine also named another board member, Jeff Marrazzo, as executive chair. Marazzo co-founded Spark Therapeutics and served as its CEO from 2013 to 2022, three years after Spark was acquired by Roche for $4.8 billion. Marazzo is also a trustee of Children’s Hospital of Philadelphia and chairs the board of nChroma Bio, the epigenetic editing therapy developer formed last December by the merger of Chroma Medicine and nVelop Therapeutics. nVelop emerged from stealth last year to develop in vivo genetic cargo delivery approaches developed by Liu and another gene editing pioneer, J. Keith Joung, MD, PhD.
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