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Geron's Imetelstat Data in Myelofibrosis: 4 CRs, 1 PR. But Are These Responses Real? (Update)

We just got a first look at results from a Mayo Clinic study of Geron's (GERN - Get Report) imetelstat in myelofibrosis. The stock doubled at Thursday's open but has since sold off some, now up 61% to $5.80. 

The headline: 4 patients had complete remission (CR), 1 patient had a partial remission (PR) and 3 patients showed clinical improvement (CI). This is out of 18 patients evaluable for response -- 11 from the first Cohort A and 7 from Cohort B. 

But (uh oh) are these imetelstat CRs and PRs real? Maybe not so much. Maybe an exaggeration. I'll explain below, but first here's the text of the research abstract just released:

Background: JAK inhibitors, including ruxolitinib, are to date incapable of inducing complete (CR) or partial (PR) remissions, reversal of bone marrow (BM) fibrosis or molecular responses in myelofibrosis (MF). This is consistent with the fact that JAK2 mutations are neither specific nor pathogenetically essential for the disease. Other currently available drugs in MF are equally ineffective in terms of disease-modifying activity.

Methods: In an investigator-sponsored single-center study ( Identifier: NCT01731951), imetelstat, a lipid-conjugated oligonucleotide inhibitor of human telomerase, was administered to patients with high or intermediate-2 risk MF (JCO 2011). Adverse events were monitored by common terminology criteria (Version 4.03) and responses by the International Working Group criteria (Blood 2013). Eligibility criteria included platelets ≥50 x 10(9)/L. Study drug and funding were provided by Geron Corporation (Menlo Park, CA, USA).

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Imetelstat was administered by a 2-hour intravenous infusion (9.4 mg/kg) every three weeks (cohort A) or weekly x 3 followed by every three weeks (cohort B). Mutations with prognostic (ASXL1 and SRSF2) or phenotypic (SF3B1 and U2AF1) relevance were screened by DNA sequencing. Quantitative PCR was used to measure JAK2V617F burden (assay sensitivity 0.01%). Laboratory correlative studies included analyses of granulocyte telomere length, mononuclear cell telomerase activity and human telomerase reverse transcriptase (hTERT) isoforms.

Results: Thirty-three patients were accrued; the first 18 patients enrolled and followed for a minimum of 3 months or discontinued are presented in this abstract: 11 cohort A and 7 cohort B; 44% PMF, 33% post-PV MF and 22% post-ET MF. Median age was 68 years and baseline risk was high in 56% and intermediate-2 in 44%. Seven patients were transfusion-dependent. Median spleen size was 13 cm and 11 patients had constitutional symptoms. Karyotype was abnormal in 7 patients and 89% were JAK2-mutated. Fifteen (83%) patients were previously treated including 7 with a JAK inhibitor and 3 with pomalidomide.

i)                    Toxicity

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.

ii)                  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.

iii)                Laboratory correlative studies

Three (50%) of 6 spliceosome-mutated vs. 1 (8%) of 12 unmutated (p=0.045) achieved CR. Spliceosome-mutated patients were also more likely to experience grade-3/4 myelosuppression (67% vs. 25% ; p=0.09). Treatment was associated with suppression of telomerase activity, shortening of telomere length and alteration of hTERT isoform pattern.

Conclusions: The current study signifies the potential value of telomerase-based treatment strategies in MF and identifies imetelstat as an active drug in that regard. The observed morphologic and molecular remissions confirm selective anti-clonal activity, which has thus far eluded other drugs in MF, including JAK inhibitors. The association between response and spliceosome mutations suggests a broader application for the drug in myeloid malignancies.

There was buzz surrounding imetelstat going into Thursday's abstract release because the drug may have legitimate disease-modifying potential in bone marrow cancers like myelofibrosis. 

Incyte's (INCY - Get Report) Jakafi is approved to treat myelofibrosis but only provides symptomatic relief -- mainly by reducing the size of a patient's enlarged spleen, a hallmark of the disease.

Imetelstat, on the other hand, appears to be effective in the bone marrow, meaning the drug could to slow or even stop the malignancies which cause diseases like myelofibrosis. 

Here's a simple way to think about imetelstat's potential: Neither Jakafi nor any other similar (JAK inhibitor) drugs being studied in myelofibrosis today are capable of producing a complete remission (CR) or partial remission (PR). At best, these drugs only provide clinical improvement (CI) in myelofibrosis patients. 

But here's the hiccup on the imetelstat data revealed this morning, which I alluded to above: No clinical or symptomatic responses were reported, only bone marrow and blood response. The International Working Group (IWG) response criteria for myelofibrosis says a CR and a PR need to have bone marrow/blood response and clinical response, which usually means reduction in the size of the spleen.

Maybe doctors will treat myelofibrosis patients with a combination of imetelstat and Jakafi? Perhaps, but thrombocytopenia (low platelet counts) is a significant overlapping toxicity of both drugs. That might cause some problems.

Let the debate over Geron's myelofibrosis drug imetelstat rage on! We'll see updated results next month at the American Society of Hematology (AS) annual meeting.


Adam Feuerstein writes regularly for TheStreet. In keeping with company editorial policy, he doesn't own or short individual stocks, although he owns stock in TheStreet. He also doesn't invest in hedge funds or other private investment partnerships. Feuerstein appreciates your feedback; click here to send him an email.

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