SAN FRANCISCO—Prime Medicine is on track to file the first IND/CTA application for human trials of a prime editing therapy to the FDA during the first half of this year, with the first clinical data expected as soon as 2025, president and CEO Keith Gottesdiener, MD, told attendees at the 42nd Annual J.P. Morgan Healthcare Conference.

Prime Medicine’s first candidate poised to enter the clinic is PM359, a blood-targeting candidate for chronic granulomatous disease (CGD) now in the IND-enabling phase. PM359 consists of autologous hematopoietic stem cells modified ex vivo using prime editing.

Prime Medicine plans to assess PM359 through a clinical trial consisting 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 include: DHR > 20% normal neutrophil function; resolution of pre-existing infectious/inflammatory CGD complications; and frequency of new infectious/inflammatory CGD complications.

“This now is our moment, because Prime Medicine brings together the right people and the right technology at the right time,” Gottesdiener said.

Investors showed less apparent enthusiasm, as shares of Prime Medicine inched up about 1% in trading Monday, closing at $9.05 from $8.96 on Friday.

During 2023, Prime Medicine held pre-IND and INTERACT meetings about PM359 and its prime editing platform with the FDA, whose recommendations the company has aligned with regarding preclinical data, toxicology, CMC [chemistry, manufacturing, and controls], off-target edits, and clinical development plans. Prime Medicine also said it had held multiple formal and informal interactions with regulatory agencies outside the United States, one of which had what the company called “highly positive” interactions to date.

Meetings with two additional global regulatory agencies are pending for early 2024.

To support its IND/CTA filing, Gottesdiener said, Prime Medicine has generated data showing:

  • 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

“It’s our hypothesis that prime editing goes in, and does a precise therapeutic edit. It doesn’t muck around with the rest of your DNA. And then it gets out and leaves patients with a genetic cure,” Gottesdiener added. “That’s going to be the kind of message that’s going to allow doctors and patients to decide that prime editing therapeutcs truly are something special, and allow their widespread use.”

Pipeline “pillars”

While Gottesdiener shied away from referring to PM359 as Prime Medicine’s lead candidate, the CGD candidate heads the company’s hematology and immunology specialty—one of four therapeutic area specialties or “pillars” around which Prime Medicine has now organized its pipeline. 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. Other discovery programs are proceeding in Fanconi anemia and cell shielding.
  • 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.

“Frankly, many investors have come to us and said, ‘That’s an awful lot of programs. Can you help us to understand what’s most important in your pipeline?’” Gottesdiener said.

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); CAR-T program (ex vivo delivery; discovery phase); and other discovery programs that include Usher syndrome (Type 3); and non-syndromic hearing loss targeting GJB2.

No detectable off-target activity has been seen in the CGD program as well as the company’s programs to treat Wilson’s disease, glycogen storage disease 1b (GSD1b), and retinitis pigmentosa/rhodopsin. That favorable safety profile, Gottesdiener said, “is going to become an important differentiation from other gene editing approaches.”

Reflecting on its transition into a clinical-phase company, Prime Medicine has appointed Allan Reine, MD, as CFO, effective January 17. Reine will oversee the company’s financing strategy and investor relations, as well as all financial operations. Reine previously held the same position at Foghorn Therapeutics and, before that, at Pieris Pharmaceuticals.

2019 paper 

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.

Elements of prime editing plus CRISPR were incorporated into a genome editing technology first patented in February 2023 under the name PASTE (programmable addition via site-specific targeting elements), along with a pair of enzymes designed to enable the integration of large segments of DNA without incurring double-stranded DNA breaks.

“We married advances in programmable CRISPR-based gene editing, such as prime editing, with precise site-specific integrases,” PASTE developers Omar Abudayyeh, PhD, and Jonathan Gootenberg, PhD, and more than two dozen co-authors wrote in a study describing the technology that was published last year in Nature Biotechnology.

Since then, PASTE has been enhanced and improved into a platform called programmable genomic integration (PGI) by a company formed to commercialize that approach, Tome Biosciences.

Tome was founded in 2021 by Abudayyeh and Gootenberg while both were McGovern fellows at MIT’s McGovern Institute for Brain Research; the two discussed PASTE technology with GEN Edge earlier this year. Abudayyeh is now a lead investigator at Brigham and Women’s Hospital, while Gootenberg holds the same position at Beth Israel Deaconess Medical Center, both affiliated with Harvard Medical School. Tome emerged from stealth mode in December 2023 with $213 million in financing and plans to create curative cell and “integrative” gene therapies capable of correcting genes in vivo.

Speaking with GEN at the time, Tome’s President and CEO Rahul Kakkar, MD, insisted the company did not need to license prime editing. He said that while PGI was very similar to PASTE, “there are some differences that moved away from the initial PASTE invention and form the basis of much of our IP [intellectual property],” he added.

That IP, Kakkar said, was broader than the three initial patents assigned to MIT for the core PASTE technology invented by Abudayyeh and Gootenberg—Nos. 11,572,556 (published February 7, 2023); 11,827,881 (published November 28); and 11,834,658 (published December 5), all titled “Systems, methods, and compositions for site-specific genetic engineering using PASTE.”

“I think there is clinical room for CRISPR-based technologies, base editing, prime editing and PGI. We all serve different clinical indications, different patient populations, and I wish all of those companies well. I will not comment on their IP directly,” Kakkar said. “We continue to believe we sit on very firm IP grounds. And, at this point in time, we have not sought, nor do we intend to seek licensure from any third party.”

“Absolute clear priority”

During Monday’s presentation, Gottesdiener staked an opposite position without naming Tome or any other genome editing company, declaring that Prime Medicine had “absolute clear priority in the space” of prime editing.

He asserted that Prime Medicine has pursued an aggressive filing strategy for technological advances, and holds broad, enabling, foundational IP for all prime editing technologies—three issued and one allowed patents.

Prime’s three issued patents consist of U.S. Patent Nos. 11,643,652, dated May 9, 2023, and 11,447,770, dated September 20, 2022, both of which cover compositions and methods for conducting prime editing of a target DNA molecule (e.g., a genome) that enables the incorporation of a nucleotide change and/or targeted mutagenesis. The third and most recent issued foundational U.S. patent covering prime editing methods and compositions—No. 11,795,452, dated October 24—includes issued claims to prime editing guide RNAs (pegRNAs) encoding recombinase landing site sequences, and to recombinases that recognize these sequences.

All issued patents have been assigned to the Broad Institute and Harvard College.

“Our position is, for those that truly look like, act like, seem like prime editing, they probably are prime editing, and we’re confident that we have the foundational IP for these technologies,” Gottesdiener said.

“Of course, we continue to be slightly flattered by the imitation and rebranding of PE by others, but I think as one of our more outspoken directors says, we invented it. We own it. And certainly we in Prime Medicine certainly feel that way overall.

Gottesdiener’s presentation capped a day of announcements for Prime Medicine that included Reine’s appointment and what the company called an amicable settlement of competing arbitration claims filed by it and Myeloid Therapeutics, its partner in a multi-million-dollar collaboration launched in 2022 to accelerate development of Myeloid’s RNA-based, LINE-1 retrotransposon mediated gene-insertion technology, (RetroT™). Prime Medicine paid Myeloid $45 million upfront and agreed to pay “significant” milestone and option exercise payments and sales-based royalties.

Prime Medicine terminated the collaboration in September 2023, prompting Myeloid to file an arbitration claim seeking $17.5 million after Prime failed to pay a milestone payment in that amount. Prime countered that Myeloid breached their agreement, and filed its own arbitration claim in October seeking $43.5 million from Myeloid, according to Prime’s Form 10-Q quarterly report for the third quarter of 2023.

“We believe the resolution of our current dispute will permit both companies to advance their scientific and commercial goals, with the ultimate aim of improving patient outcomes,” Myeloid Therapeutics CEO Daniel Getts, PhD, stated.

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