Today we finally got a glimpse at the ongoing investigator sponsored study of Geron (GERN) imetelstat in myelofibrosis. We have previously discussed this program here. The abstract can be found here. An oral presentation is scheduled for Monday, December 9th at 4:45 PM. The study was carried out by Dr. Tefferi at the Mayo Clinic. A total of 33 patients were enrolled; these data are from the first cohort of 18 patients: 11 from cohort A, 7 from cohort B. Cohort A was treated by 2-hour infusion every 3 weeks while cohort B received drug weekly for three weeks, then once every three weeks. The median follow-up was 3.2 months. Not surprisingly, rates of adverse events were higher in cohort B. Safety

At a median f/u of 3.2 months, 16 (89%) patients remain on treatment; the two discontinuations were from unrelated death and disease progression. In cohort A, there were no grade-4 treatment-related adverse events; grade-3 events were limited to thrombocytopenia in 27% and anemia in 9%. In cohort B, two (29%) patients experienced grade-4 thrombocytopenia; grade-3 events were limited to thrombocytopenia, neutropenia and anemia in one patient each. Dose reduction was necessary in only two (11%) patients because of grade 3 or 4 myelosuppression.

The major toxicity is thrombocytopenia, with 27% grade 3 in cohort A and 29% grade 4 in cohort B. Interestingly, no rates of grade 3 thrombocytopenia were listed. By comparison, Jakafi is considered highly immunosuppressive, with thrombocytopenia as a dose limiting toxicity. It had a combined grade 3 and 4 rate of 13% in the pivotal COMFORT-1 study. Efficacy

Overall response rate was 44%. This included five (28%) patients who met the BM and peripheral blood morphologic criteria for CR (n=4) or PR (n=1) and 3 patients with clinical improvement, pending validation of response duration and resolution of drug-induced grade-1 thrombocytopenia. The four (22%) CR patients experienced reversal of BM fibrosis and recovery of normal megakaryocyte morphology. Two CR patients were transfusion-dependent at baseline and became transfusion-independent. Complete molecular responses were documented in 2 CR patients: one had U2AF1Q157P and 10% JAK2V617F and the other SF3B1K666E and 50% JAK2V617F. A third CR patient had a >50% reduction in U2AF1 469_insAGTATG mutation. Among 13 patients with leukocytosis, 10 (77%) normalized their count or had >50% reduction. Eleven (61%) patients had complete or partial resolution of leukoerythroblastosis.

The efficacy here was somewhat cherry picked. It is ironic because Tefferi wrote the paper defining response criteria for MF. Based strictly on the paper, there were no responses. This is because CRs, PRs, and CIs all require a spleen response, symptom relief, and no thrombocytopenia. These have obviously not been met despite a stacked patient pool with a relatively small spleen size (median 13 cm vs. 19 cm for Jakafi’s trial) and only 11 of 18 patients with constitutional symptoms. Instead, Tefferi turns the focus to bone marrow morphology. This is a legitimate endpoint as it may indicate a disease modifying effect. Imetelstat appears to affect the bone marrow, reducing blasts and normalizing cellularity. More details will be needed to determine its extent and relevance. The results must be taken with caution, particularly since the PI has taken liberties in defining these responses, to put it gently. Also, it would be nice to know which dose led to the best response. In summary, this does not appear to be the “cure” for MF, but it is a promising program. There will be plenty of work ahead for Geron. Manufacturing scale of imetelstat will be no easy task given the complexity of the drug and the process by which it is made. We expect Geron will seek to raise over $100 million in the near future. Disclosure: Author is Long INCY