Prime Medicine (NASDAQ: PRME) has had a lot to celebrate in recent months, explaining a surge that has seen the prime editing therapy developer’s stock more than double this year, including a 22% jump this past week.
Prime’s lead candidate generated positive initial data in May—an announcement overshadowed by the company chopping 15% of its workforce. A month later, Prime basked in the glow of Eli Lilly (NYSE: LLY) acquiring Verve Therapeutics for up to $1.3 billion, a deal that bolstered the buyer’s cardiovascular treatment pipeline with Verve’s gene edited therapies.
David R. Liu, PhD, a professor at Harvard University, the Broad Institute of MIT and Harvard, and the Howard Hughes Medical Institute
More recently, Prime enjoyed favorable attention from investors after its namesake editing technology was written up in Wired. The article by Emily Mullin summed up remarks made at the magazine’s Wired Health summit by genome editing pioneer David R. Liu, PhD, whose Broad Institute lab developed both prime editing and base editing technologies over more than a decade.
The article also revealed that later this year, Liu’s lab plans to report on an editing approach that could enable a single composition of matter to treat multiple unrelated genetic diseases—an approach Liu calls disease-agnostic therapeutic genome editing.
“I believe that there are certain ways to use a prime editor, for example, in which a single prime editing agent, one prime editor plus one prime editing guide RNA (pegRNA), one composition of matter, and one syringe of stuff, so to speak, can actually permanently treat multiple different patients with different diseases,” Liu shared in August on the podcast “Behind the Breakthroughs” hosted by Jonathan D. Grinstein, PhD, North American editor of Inside Precision Medicine, a sister publication of GEN.
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 (HHMI) investigator.
“This hasn’t been a way that people have used gene editing before, even though I think this kind of approach could benefit many more patients more quickly than the current approach of correcting one or a small handful of mutations at a time per gene editing drug,” Liu added. “There’s more than one solution that fits this area. But we hope to report the first.”
Liu is co-founder of Prime Medicine, which was formed to commercialize prime editing by developing treatments based on applying the technology’s “search and replace” approach to genome editing.
Prime stock jumps
Following publication of the Wired article on September 15, Prime’s shares soared 28% in the first four days of this past week, from $4.01 to $5.12 on Thursday, before sliding 4.5% to $4.89 on Friday. Over the past six months, shares of Prime have more than doubled, zooming 144.5% from $2 on March 19.
More importantly, Prime has also enjoyed stock buying surges by investors and insiders. Investors have ranged from the management entity for Google Ventures (GV), which has backed Prime stretching back to its concurrent Series A and B financings totaling $315 million in 2021, to an exchange transfer fund of ARK Investment Management (ARK Invest), the high-profile firm led by chief investment officer and portfolio manager Catherine D. (Cathie) Wood.
In the most recent transaction, disclosed by Prime in a regulatory filing (Form 4) filed August 5, an entity of GV (GV 2021 GP, LLC) acquired 1.5 million shares at $3.30 a share, raising its stake in Prime to 3,262,440 shares. As of June 30, according to Prime’s definitive proxy statement filed July 14, all GV-affiliated entities owned 15,062,498 shares of Prime, 11.2% of the company’s total shares.
According to that proxy statement, GV was the third largest shareholder in Prime behind Liu (20,334,460 shares, 15.12%) and entities affiliated with ARCH Venture Partners (15,456,594 shares, 11.49%)
On September 10, ARK Invest’s ARK Genomic Revolution ETF (ARKG) added 230,755 shares of Prime Medicine valued at more than $950,710, increasing its total investment in the company to $19 million. That investment has since grown to $24,427,560.96 as of Friday, consisting of 4,771,008 shares, the 19th largest holding accounting for 2.22% of the ARKG portfolio.
Among insiders, Prime CEO Allan Reine, MD, owned 646,875 shares as of June 30, according to the proxy statement. In August, Reine disposed of options to buy 850,000 shares at an exercise price of $6.80, then acquired an equal number of options for the same number of shares at $4.04, after Prime shareholders approved a one-time repricing of outstanding stock options to reflect its August 1 closing price.
Reine was promoted from CFO to lead the company and join its board in May after his predecessor, Keith Gottesdiener, MD, resigned as president, CEO, and board member.
Job cuts, pipeline pivot
Under Reine, Prime eliminated 25% of its workforce—about 50 jobs—in a restructuring that included the company pivoting its prime editing-based pipeline focus to liver disease and programs funded by external collaboration partners.
Allan Reine, MD, CEO of Prime Medicine
Prime has slashed its pipeline, which once numbered 18 programs, to four, all of them preclinical. Two are internally developed in vivo programs designed to treat two liver diseases with large patient populations representing potentially 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.
The other two pipeline programs are externally funded:
An 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.
A program 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).
At the time, Reine said Prime was exploring options for its lead clinical candidate PM359, the first prime editor-based therapy to be administered in humans. PM359 is 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.
“Solid proof of concept”
Prime began efforts to outlicence PM359 after announcing 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, 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. 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, in which he characterized the data as showing “solid proof-of-concept DHR restoration.”
In August, Prime shared data on a second patient treated with PM359 in the trial, which the company identified as a 57-year-old male in a footnote to its September corporate presentation. Consistent with the first patient, the second showed rapid engraftment of PM359-edited HSCs with restoration in 70% of neutrophils at day 15 and 80% of neutrophils at day 30—rates that Raycroft termed “impressive.”
“While leveraging advancements made by earlier-gen players in the gene editing space, the company’s prime editing platform offers a highly differentiated and more versatile approach to the treatment of genetic disorders,” Eric Joseph, PhD, biotech analyst at J.P. Morgan, wrote May 9.
Ten days later, after Prime cut its workforce, Joseph downgraded Prime’s shares from “Overweight” to “Neutral”: “While the strategic prioritization strikes us as prudent, the resulting clinical catalyst outlook does get pushed back beyond the current 1H26 cash runway.”
Joseph also predicted that shares of Prime would trade “range bound,” or within a range defined by its historic high and low prices, “pending better visibility on development timelines and reach within key pipeline programs.”
Roche buys MASH “bargain” with 89bio acquisition
Shares of 89bio (NASDAQ: ETNB) leaped 85% from $8.08 to $14.96 on Thursday, after it announced it was being acquired by Roche (SIX Swiss Exchange: ROG) for up to approximately $3.5 billion.
Driving the deal was 89bio’s lead candidate, pegozafermin, a fibroblast growth factor 21 (FGF21) analog being developed as a potential treatment for moderate to severe metabolic dysfunction-associated steatohepatitis (MASH).
Edward Nash, a managing director and senior biotechnology analyst with Canaccord Genuity, noted that pegozafermin was one of two Phase III FGF21 analogs for MASH that Roche could have acquired. The other was efruxifermin, which is being developed by Akero Therapeutics (NASDAQ: AKRO).
“With basically two acquisition targets available to Roche in the FGF21 space, we believe Roche got a relative bargain for a late-stage Phase III asset,” Nash wrote, given the tough climate for biotech acquisition deals.
Roche investors appeared unfazed, as shares of the pharma giant inched up 0.4% from CHF 260.40 ($327.40) to CHF 261.50 ($328.79) on Thursday, then climbed another 1.4% on Friday to CHF 265.10 ($333.31).
Roche’s acquisition was a surprise, according to Nash, since the company had not been known as a MASH drug developer. The MASH space is the deal’s real winner, Nash commented, since Roche is the second pharma to acquire FGF21 assets in four months. In May, GlaxoSmithKline (GSK) bought efimosfermin alfa from privately held Boston Pharmaceuticals for up to $2 billion ($1.2B upfront, up to $800M in milestone payments).
Pegozafermin is under study in two Phase III trials: The ENLIGHTEN-Fibrosis trial (NCT06318169) in non-cirrhotic (F2-F3) MASH, set to release topline data in the first half of 2027; and the ENLIGHTEN-Cirrhosis trial (NCT06419374) in compensated cirrhotic (F4) MASH, whose data readout is planned for the first half of 2028.
89bio reasons that Roche’s resources as a global pharma giant will help propel pegozafermin through the trials to approvals in MASH and several other liver and cardiometabolic diseases. These include severe hypertriglyceridemia (SHTG), for which pegozafermin is under study in a third Phase III trial, ENTRUST (NCT05852431).
If pegozafermin reaches the market, 89bio shareholders stand to gain. In addition to $2.4 billion ($14.50 per share) cash upfront, Roche agreed to pay shareholders a non-tradeable contingent value right (CVR) to receive up to $6 per share cash, but that extra cash is tied to achieving milestones that include:
The first commercial sale of a pharmaceutical product containing pegozafermin with an approved indication for the treatment of Stage 4 MASH, on or before March 31, 2030 ($2 per share if achieved)
Worldwide net sales of at least $3 billion in a single calendar year on or before December 31, 2033 ($1.50 per share if achieved)
Worldwide net sales of at least $4 billion in a single calendar year on or before December 31, 2035 ($2.50 per share if achieved)
Efruxifermin is under study in three late-stage trials:
SYNCHRONY Outcomes (NCT06528314) in compensated cirrhotic MASH (data readout due first half of 2026)
SYNCHRONY-Real World (NCT06161571) in non-invasively diagnosed MASH and metabolic dysfunction-associated steatotic liver disease (MASLD; first half of 2026)
SYNCHRONY Histology (NCT06215716) in non-cirrhotic, nonalcoholic MASH and fibrosis (first half of 2027)
Nash noted that efruxifermin was supported by strong and positive data from two Phase IIb trials in both F2/F3 MASH as well as in F4 MASH populations.
“We believe Akero’s efruxifermin is the more attractive asset given the robust and unambiguous Phase II studies that were conducted and its more expansive Phase III program, which includes what we believe is important and what 89bio’s Phase III program lacks, a noninvasive testing trial for real-world use,” Nash added.
Leaders and laggards
aTyr Pharma (NASDAQ: ATYR) shares cratered 83% from $6.03 to $1.02 on September 15 after the company acknowledged that its sole clinical-stage program assessing efzofitimod in pulmonary sarcoidosis failed the 268-patient Phase III EFZO-FIT trial (NCT05415137) by not meeting its primary endpoint of change from baseline in mean daily oral corticosteroid (OCS) dose at week 48. Efzofitimod showed a change from baseline, averaging 2.79 mg for the 5.0 mg/kg dose, vs. 3.52 mg for placebo. aTyr said it planned to engage with the FDA to determine the path forward for efzofitimod in pulmonary sarcoidosis. aTyr said the trial also showed clinical improvement in patients’ King’s Sarcoidosis Questionnaire (KSQ)-Lung score at week 48 for 5.0 mg/kg efzofitimod vs. placebo. Improvement vs. placebo was also seen in a responder analysis of patients who achieved complete steroid withdrawal at week 48 with an improved KSQ-Lung score.
Reviva Pharmaceuticals (NASDAQ: RVPH) shares tumbled 36% from 42 cents to 27 cents on Friday, the day after the developer of drugs for central nervous system (CNS), inflammatory, and cardiometabolic diseases announced after the close of markets that it priced its public offering at a combined $0.335 per share. The offering consisted of 27 million shares of its common stock with Series E warrants to purchase up to 27 million shares of common stock, and Series F warrants to purchase up to 27 million shares of common stock. Reviva said its offering would generate $9 million in gross proceeds. “The company currently intends to use the net proceeds from the offering to fund research and development activities and for working capital and other general corporate purposes,” Reviva stated.
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