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John A. Scarlett, CEO of Geron, sat down with Onyx for a feature-length interview.
Could we start with a bit of your background before you arrived at Geron?
I started at the University of Chicago, where I spent four years in Arthur Rubensteinʻs lab studying insulin and C-peptide secretion while obtaining my MD degree. I then completed my internship and residency in internal medicine at the Hospital of the University of Pennsylvania, and, after that, I completed a fellowship in endocrinology and metabolism at University of Colorado while continuing to work actively in both clinical research and the lab.
I joined Johnson & Johnson in 1982 and spent several years there learning the pharmaceutical industry from a physician's perspective. Later, I worked for Novo Nordisk as the head of North American Clinical Development organization. After that, I co-founded several companies, two of which were in the endocrine space—one focused on acromegaly and the other on short stature, and subsequently became CEO at Proteolix, which was developing a second generation proteosome inhibitor for multiple myeloma. That product is now sold as Kyprolis (carfilzomib). Thirteen years ago, I was asked to take the reins at Geron.
Geron spent more than 30 years working to bring the potential of the Nobel-prize winning discovery of telomeres to patients. Telomeres are specialized DNA sequences linked to cell immortality.
Our big idea was that you can kill cancer cells by targeting and inhibiting an enzyme that maintains telomeres, called telomerase, to prevent the uncontrolled growth of blood cancer cells. We developed a medicine around this big idea called imetelstat.
Why is telomerase activity a good target for cancer treatment?
Telomerase is an enzyme that supports rapid cell proliferation by maintaining telomere length, allowing cells to bypass the Hayflick limit—the point at which cells can no longer divide. Dr. Leonard Hayflick discovered that cells have a finite number of divisions before they become senescent or undergo apoptosis.
In normal biology, telomerase is upregulated in cells that need to proliferate rapidly, like stem cells and progenitor cells. In cancer, telomerase is constitutively upregulated, meaning it stays active, allowing malignant cells to become immortal.
This is particularly relevant in hematologic malignancies because the bone marrow is one of the most rapidly proliferating tissues—we produce about 4 billion cells a day there. Malignant clones in the bone marrow become "addicted" to telomerase to maintain their rapid division.
With the approval of RYTELO (imetelstat) in June 2024, Geron is the first and only company to bring a medicine based on telomerase inhibition to treat hematologic malignancies.
You had your first approval earlier this year. Could you comment on the timeline for your other trials and potential readouts?
Our first FDA approval is for the treatment of certain patients with lower-risk myelodysplastic syndromes (MDS). This is a serious cancer of the blood where many patients become anemic and become dependent on blood transfusions to survive.
In lower-risk MDS, we observed that imetelstat significantly reduced blood transfusion requirements and achieved transfusion independence for many patients, addressing a primary clinical problem in this disorder.
Imetelstat is being studied in the first and only Phase 3 trial in myelofibrosis (MF), in patients who are relapsed/refractory to JAK inhibitors, with overall survival as a primary endpoint. Interim analysis is expected early 2026 with a final analysis expected early 2027. We and the trial investigators remain excited about this study and the potential of a treatment that could improve survival for these patients who currently have few treatment options and dismal survival rates.
Could you elaborate on the commercial strategy for expanding these treatments to the market?
We spent several years preparing the marketing and building an internal commercial leadership team in the US which includes ~50 sales representatives. Our goal is to reach approximately 8,000 key accounts across the United States, comprising of hematologists in both community and academic settings. Our focus in preparing for the launch was to ensure patient access and smooth adoption among prescribers.
In terms of competition, we believe imetelstat has significant differentiation due to its MOA as a first in class telemorase inhibitor. Our drug demonstrates efficacy across a broader patient population, including both ring sideroblast (RS)-positive and RS-negative patients. Approximately 75% of lower-risk MDS patients are RS-negative—a group where our main competitors have limitations in their labeling.
Moreover, we see higher durability in transfusion independence and the ability to treat patients with higher transfusion burdens. Our approval comes with a broad label without the restrictions seen in some competitors' products.
How are you going to compete with BMS? It's not something many would wish to do.
Bristol Myers Squibb (BMS) is indeed a large and sophisticated company—a very worthy competitor. The only way to compete with a larger, more entrenched company is to be differentiated. In some major segments, we demonstrably have that. For example, in the second-line setting, where most patients end up after failing frontline treatments, their product doesn't have approval for the largest segment of patients—the RS-negative population. We can and do address this segment effectively.
It's about product differentiation, and it's our job to communicate these qualities to the marketplace to reach the patients that can benefit.
Can you discuss any challenges you've faced, particularly regarding side effects like cytopenias?
As with any drug, there may be side effects. Imetelstat has well-defined safety profile; the most common adverse events, thrombocytopenia and neutropenia, were generally manageable and of short duration.
Cytopenias occur because the drug targets malignant clones in the bone marrow. We believe that when these malignant cells are eliminated, there's a temporary period where the normal bone marrow needs to repopulate, leading to lower blood counts. We believe it's a consequence of the drug's mechanism of action and reflects its effectiveness in targeting the disease. There are protocols to manage these cytopenias based on years of clinical trials and included in RYTELO’s prescribing information, such as holding or adjusting the dose, and most patients can continue therapy. Hematologists are accustomed to managing cytopenias, which are a common side effect of many hematology drugs, and it is a priority of our field team to make sure hematologists understand the kinetics of these cytopenias and how to manage them.
