Understanding the role of telomeres and telomerase in human disease and cancer in the pursuit of innovative treatments for patients has been a vision since our founding in the 1990s.
Our name comes from the Greek word geron, which means “old man”, as a reference to the then newly discovered relationship between telomeres and cellular aging or senescence.
Our early research conducted together with many academic scientists led to foundational discoveries: showing that telomerase is active in many different types of cancers, but is not found in normal tissues, and demonstrating the association between telomerase activity and indefinite proliferation of human cells. With our academic collaborators, we also cloned the catalytic and RNA template components of human telomerase.
Our singular focus today is oncology, but our core expertise in telomerase and bold scientific vision gave rise to research that included a cell therapy platform and led to the first human clinical trial of cells derived from human embryonic stem cells.
Telomerase is now considered one of the key molecular targets in oncology. In the mid to late 1990s most pharmaceutical companies entered the search for small molecules that were potent inhibitors of telomerase. We signed collaborations with two pharma companies, Kyowa Hakko for Asia and Pharmacia & Upjohn for Europe, and screened millions of compounds. No company declared success, and telomerase was considered an undruggable target by most in the pharmaceutical industry.
Undeterred, our efforts continued as we investigated several novel ways to target telomerase, including oncolytic viral strategies and dendritic cell-based immunotherapy.
By the early 2000s we turned to an alternative approach: nucleic acid chemistry. Based on phosphoramidate chemistry acquired from Lynx Therapeutics, our scientists developed a novel and proprietary oligonucleotide with a lipid tail (GRN163L) that could penetrate the cell membrane and bind with high affinity to the RNA template component of telomerase and block telomere binding, resulting in direct, competitive inhibition of telomerase enzymatic activity.
In 2005, we initiated the first Phase 1 clinical trial of our first-in-class telomerase inhibitor, GRN163L, which later became known as imetelstat. Since telomerase is upregulated in most types of human cancers, we conducted a broad program of early phase clinical trials, including small single arm studies as well as larger multi-center randomized trials testing imetelstat as a single agent and as combination therapy with standard treatments both in solid tumors and hematologic malignancies. Over 500 patients have been enrolled and treated in Phase 1 and 2 clinical trials of imetelstat.
Data from these clinical trials led to the observation that imetelstat had potentially disease-modifying activity in hematologic myeloid malignancies, which has become our focus today.
We believe that data from two prior Phase 2 clinical trials provide strong evidence that imetelstat targets telomerase to inhibit the uncontrolled proliferation of malignant stem and progenitor cells in hematologic myeloid malignancies, potentially resulting in meaningful clinical benefits for patients. Data reported from our Phase 2 clinical trial in lower risk MDS provide evidence that imetelstat may achieve meaningful and durable transfusion independence and increase in hemoglobin levels, suggesting potential recovery of normal blood cells. Similarly, data reported from our Phase 2 clinical trial in myelofibrosis, or MF, suggest imetelstat potentially improves overall survival, or OS, for MF patients who have relapsed after or are refractory to prior treatment with a janus kinase, or JAK, inhibitor, or relapsed/refractory MF. Additionally, from these Phase 2 clinical trials, we have observed depletion of cytogenetic abnormalities and reductions in key driver mutations of the underlying diseases in both lower risk MDS and MF patients, as well as improvement in bone marrow fibrosis in MF patients, all of which we believe provides evidence of disease-modifying activity. Furthermore, these molecular and histology data have been correlated with the clinical benefits of transfusion independence in lower risk MDS and improved OS in relapsed/refractory MF. We believe the clinical benefits, molecular observations and correlations from these two Phase 2 trials highlight the magnitude of imetelstat’s unique mechanism of action of telomerase inhibition, and provide strong evidence that imetelstat may alter the course of MDS and MF. We believe this disease-modifying activity has the potential to differentiate imetelstat from other currently approved and investigational treatments for MDS and MF.
Clinical trials of imetelstat include a Phase 2/3 trial called IMerge in lower risk myelodysplastic syndromes (MDS) and a Phase 3 trial called IMpactMF in Intermediate-2 or High-risk myelofibrosis (MF). Imetelstat has been granted Fast Track designation by the United States Food and Drug Administration for both the treatment of patients with non-del(5q) lower risk MDS who are refractory or resistant to an erythropoiesis-stimulating agent and for patients with Intermediate-2 or High-risk MF whose disease has relapsed after or is refractory to janus kinase (JAK) inhibitor treatment.
Imetelstat is the only telomerase inhibitor in clinical development.
