Keith Gottesdiener, MD, president and CEO of Prime Medicine

Prime Medicine said it has gained FDA clearance for the first human trials of a prime editing therapy as the agency has approved an investigational new drug (IND) application for the company’s first candidate to enter the clinic.

Prime Medicine’s PM359 is a candidate designed to target the p47phox variant of chronic granulomatous disease (CGD). PM359 consists of autologous hematopoietic stem cells modified ex vivo using prime editors that have been designed to correct a high percentage of cells containing the disease-causing mutation.

Mutations that cause CGD, a rare inherited blood disorder, have been estimated to occur between one in 100,000 and one in 200,000 births in the United States, according to studies cited in a 2022 retrospective review published in Journal of Clinical Immunology by researchers from Ann & Robert H Lurie Children’s Hospital of Chicago and Northwestern University Feinberg School of Medicine.

Prime Medicine plans to assess PM359 through a multinational, first-in-human Phase I/II trial designed to assess the safety, biological activity, and preliminary efficacy of PM359 in adults and children.

Initial participants in the Phase I/II trial will be adults with stable disease. If PM359 shows safety and biological activity in that cohort, Prime Medicine plans to enroll participants with active infection or severe inflammation, as well as adolescent and pediatric participants in the trial.

Prime Medicine said the study will follow participants for safety, including engraftment and reconstitution of the hematopoietic system—both early biological markers of restored immune function—as well as long-term resolution and prevention of infectious and inflammatory complications of CGD.

Initial clinical data from the study is expected to be reported in 2025, Prime Medicine said.

“We are thrilled to achieve this important milestone for our first product candidate, PM359, which represents the first-ever IND clearance for a Prime Editor product candidate and a significant advancement in the field of next-generation gene editing,” Keith Gottesdiener, MD, Prime Medicine’s president and CEO, said in a statement.

Positive response

Investors responded positively to the news, as Prime Medicine shares jumped 15%, from Friday’s closing price of $4.43 to $5.11 as of 12:49 p.m.

“Based on data from our preclinical studies, we believe PM359 has the potential to sufficiently correct a prevalent disease-causing mutation of CGD, leading to amelioration of disease for these patients,” Gottesdiener said. “We look forward to the planned initiation of our Phase I/II trial and further determining the potential therapeutic impact of PM359 in patients with this devastating disease.”

In a February presentation to investors, Gottesdiener said the clinical trial for PM359 would consist of three cohorts of CGD patients—one of adults ages 18+, one of adolescents ages 12–17, and one of children ages 6–11. To be eligible, patients must have a nucleotide GT deletion (delGT) mutation in their NCF1 gene, dihydrorhodamine (DHR) combined with CGD, and recent or ongoing infectious/inflammatory CGD complications.

The trial’s key outcome measures, he said, would include DHR >20% normal neutrophil function; resolution of pre-existing infectious/inflammatory CGD complications; and frequency of new infectious/inflammatory CGD complications.

PM359 heads Prime Medicine’s hematology and immunology specialty—one of four therapeutic area specialties or “pillars” around which the company has organized its pipeline. Within the pillar, Prime has discovery phase programs for Fanconi anemia and cell shielding, according to its pipeline posted on its website.

The other three pillars are:

  • Liver—Programs to treat Wilson’s disease and glycogen storage disease 1b are in lead optimization phases, while a program with an undisclosed liver indication is in discovery phase. All three apply lipid nanoparticle (LNP) delivery.
  • Ocular—A retinitis pigmentosa/rhodopsin candidate targeting eye tissue and using adeno-associated virus (AAV) vector delivery, is also in lead optimization phase. Other discovery programs are proceeding in retinitis pigmentosa/Usher syndrome, and Fuchs’ endothelial corneal dystrophy.
  • Neuro and muscular—A candidate for Friedreich’s ataxia also delivered via AAV, also in lead optimization phase; a myotonic dystrophy type 1 program using viral and nonviral delivery is in discovery phase. Other discovery programs are proceeding in amyotrophic lateral sclerosis, Huntington’s disease, Fragile X syndrome, oculopharyngeal muscular dystrophy, and Duchenne muscular dystrophy.

Partnership opportunities

Not included among the pillars are programs that Prime Medicine is advancing as potential partnership opportunities—a category that includes the company’s cystic fibrosis program (LNP delivery, discovery phase), for which initial research funding has been provided by the Cystic Research Foundation; a CAR-T program for oncology/autoimmune indications (ex vivo delivery; discovery phase); and two discovery programs focused on ear disorders, Usher syndrome (Type 3); and non-syndromic hearing loss targeting GJB2.

Addressing investors at the 42nd Annual J.P. Morgan Healthcare Conference, Gottesdiener said Prime Medicine supported its IND filing with data that showed:

  • No off-target editing detected in healthy human donor CD34+ cells, according to a targeted in vitro analysis of 550 potential off-target sites of off-target editing.
  • No large deletions or translocations in bone marrow engrafted Prime-Edited LT-HSCs, according to data from an in vivo analysis from mouse bone marrow harvested 16 weeks after engraftment was complete.
  • Translocation positive control: Cas9 nuclease-edited cells, generated by transfecting HEK293T cells with single guide RNA (sgRNA) targeting NCF1 and Streptococcus pyogenes Cas9 (SpCas9) mRNA.

Prime Medicine said it plans to present additional preclinical data at three upcoming meetings: the 3rd Annual LNP Formulation and Process Development Summit; the American Society of Cell & Gene Therapy (ASGCT) 27th Annual Meeting; and TIDES USA Oligonucleotide & Peptide Therapeutics Conference.

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.

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