Geron has seen more than its share of setbacks during its 33 years in business. But investors love a comeback story as much as anyone else, which explains why the company’s shares soared by more than one-third on Wednesday after it announced positive Phase III results for its lead candidate imetelstat in low- and intermediate-risk myelodysplastic syndrome (MDS).

Data from the Phase III IMerge trial (NCT02598661) showed imetelstat more than met its primary efficacy endpoint of statistically significant eight-week transfusion independence (TI), as well as a key secondary endpoint of 24-week TI. Roughly 40% (39.8%) or 47 of 118 patients randomized to imetelstat showed no need for a transfusion eight weeks following treatment, compared with 15% or 9 of 60 placebo patients.

Also, 28% or 33 of 118 imetelstat patients needed no transfusion after 24 weeks, versus only two of the 60 randomized to placebo. Based on that data, plus data from earlier studies, Geron said it will file for FDA and European approvals of imetelstat in the United States in mid-2023, and in Europe in the second half of this year.

“We’re just totally delighted,” Geron CEO John A. “Chip” Scarlett, MD, told GEN Edge.

So too were Geron investors, who sent the company’s shares leaping 58% at the start of trading, to $3.8075 as of 9:48 a.m., before the stock settled for a 33% gain, closing at $3.19.

“We view today as a great day for patients with low-risk MDS,” Scarlett said. “Assuming the drug gets approved, imetelstat will be the first of its kind treatment that can help a broad set of patients stay off of blood transfusions for an extended period of time.”

“At the end of the day, both the clinical and molecular evidence support the potential for disease modification. So I think it is practice changing, and I think it’s very, very exciting for these patients. This will be a major new alternative for them,” Scarlett added. “For our shareholders, we expect these data to translate to a very meaningful potential commercial opportunity in lower-risk MDS.”

$1.2B opportunity

Geron has pegged that opportunity at about $1.2 billion in the peak sales year of 2030 for the United States and Europe’s five largest countries.

To realize that opportunity, Geron will need to attract lower-risk MDS patients who now would likely be treated with Bristol Myers Squibb’s (BMS) Reblozyl® (luspatercept-aamt), indicated for low- to intermediate-risk MDS patients who have failed treatment with Erythropoiesis Stimulating Agents (ESAs). Reblozyl’s label discloses that the drug has generated eight-week TI of 38%, just under the percentage achieved by Geron in IMerge.

During the first nine months of 2022, Reblozyl generated $518 million in product revenue for BMS, up 30% from $400 million a year earlier.

Imetelstat is less of a threat to BMS’ other MDS-related drug Revlimid® (lenalidomide), which is indicated for transfusion-dependent anemia due to low- or intermediate-1-risk MDS—but only lower-risk MDS associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.

Geron is well along in work toward exploring two additional indications for imetelstat, both as monotherapy and in combination with other drugs—myelofibrosis and acute myeloid leukemia (AML).

The top-selling myelofibrosis drug is ruxolitinib, marketed as Jakafi® by Incyte in the United States and by Novartis as Jakavi® in Europe. Jakafi and imetelstat will soon be studied by Geron as a potential combination treatment for front-line MF in a trial set to start soon, Scarlett said.

Geron’s success with imetelstat was more than three decades in the making. Based in Foster City, CA, the company was established in 1990 to commercialize a treatment for inhibiting telomerase, the enzyme producing the DNA of telomeres. Early on, Geron collaborated on research with Elizabeth H. Blackburn, PhD, of the Salk Institute for Biological Studies, Carol W Greider, PhD, of Johns Hopkins School of Medicine, and Jack W. Szostak, PhD, of the University of Chicago. The three share the 2009 Nobel Prize in physiology or medicine for the discovery of telomerase as well as how chromosomes are protected by telomeres.

Scarlett, who took over as CEO in 2011, addressed financial pressures on Geron by repositioning the company as a developer of first-in-class oncology drugs, and eliminated 66 full-time positions, representing 38% of its workforce at the time, after dropping its embryonic stem cell (ES) program and selling it to BioTime in 2013, despite being first to go into clinical trials with an ES cell product.

Early efforts to develop imetelstat in cancer yielded disappointing results in 2012 and a full FDA clinical hold imposed in 2014 and lasting eight months. The hold resulted from Phase II studies that linked the blood cancer treatment to persistent low-grade liver function test abnormalities, raising FDA concerns about the potential risk of chronic liver injury following long-term exposure to the first-in-class telomerase inhibitor.

Leaders and laggards

  • Fate Therapeutics (FATE) plunged 61% on Friday, from $11 to $4.24, after the company announced plans to eliminate more than half its workforce, shrinking from the 449 employees disclosed as of December 31, 2021, though Pitchbook recorded 545 last year. Fate also terminated its nearly three-year-old collaboration with Johnson & Johnson’s Janssen Biotech to develop induced pluripotent stem cell (iPSC)-derived chimeric antigen receptor (CAR) natural killer (NK) and CAR T-cell product candidates for cancer, which could have generated up to $3 billion in milestones, after declining to continue on undisclosed revised terms.
  • Graphite Bio (GRPH) shares tumbled 40% on Friday, from $3.06 to 1.85, after the company said it was voluntarily pausing the Phase I/II CEDAR trial (NCT04819841) of nulabeglogene autogedtemcel (nula-cel) for sickle cell disease after the first patient dosed with the gene editing autologous hematopoietic stem cell therapy showed prolonged pancytopenia requiring ongoing transfusion and growth factor support, and the company’s conclusion that the event is likely related to study treatment. Graphite said it no longer expected to file an IND application for GPH102 in beta-thalassemia by mid-2024, and was working to identify “operational efficiencies” to extend its cash position to at least 2026.
  • Phathom Pharma (PHAT) shares sank 31% on Wednesday, from $11.99 to $8.26, a day after the company acknowledged that the FDA will not decide on its NDA for its erosive esophagitis treatment candidate vonoprazan on or before January 11, the Prescription Drug User Fee Act (PDUFA) target action date previously set by the agency. The FDA has requested additional stability data demonstrating that levels of N-nitroso-vonoprazan (NVP) remain below 96 ng/day throughout the proposed shelf life of the product, Phathom said—five months after the company detected trace levels of NVP in commercial batches.
  • Vera Therapeutics (VERA) shares plunged 60% on Tuesday, from $18.30 to $6.46, as investors expected better data than the topline results announced by the company for its Phase IIb ORIGIN trial (NCT04716231) assessing atacicept in patients with immunoglobulin A nephropathy (IgAN). Atacicept met its primary endpoint of statistically significant change in proteinuria from baseline at week 24 in the 150 mg dose group with a 33% mean reduction. The pooled 75/150 mg dose groups showed a 31% mean reduction vs. baseline. However, results for the 25 mg and 75 mg dose groups alone failed to achieve statistical significance.
  • Vyant Bio (VYNT) shares jumped 57% on Thursday, from $0.7698 to $1.21, a day after the company said it engaged LifeSci Capital as its financial advisor to assist in exploring “a range of strategic alternatives focused on enhancing shareholder value.” Vyant develops treatments for complex neurodevelopmental and neurodegenerative disorders through a proprietary central nervous system drug discovery platform that combines human-derived organoid models of brain disease, scaled biology, and machine learning.
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