Science & Medicine

Thinking imetelstat? Think again.


Imetelstat’s tortured path to approval

JJ old fashionedEffective, toxic, failed and successful in prior clinical trials, challenged by the FDA,  abandoned by its Nobel Prize-winning discoverers.  Now:  The Myelofibrosis Clinical Trials, under new management. Brought to you by Johnson & Johnson’s Janssen division and Geron. (Don’t rush.) 

We can expect good news about imetelstat coming out of Chicago next week.

In the morning of June 6,  Dr. Ayalew Tefferi will be presenting findings of the dosage and toxicity trial of imetelstat at the 2016 meeting of ASCO.  This is a Phase 2 study of the telomerase inhibitor and is open to myelofibrosis patients, intermediate risk and higher, who have relapsed after JAK inhibitor treatment, or simply don’t qualify for Jakafi.

The results have not yet been published but Dr. Tefferi is an enthusiastic and optimistic investigator.  There are high hopes and millions of milestone dollars hanging in the balance.NEJM Tefferi Sept 2015  A clue to anticipated findings can be found in two papers in the New England Journal of Medicine September, 2015.  One by Tefferi, on his own Investigator Sponsored Trial (NCT01731951.) involving 33 patients and one by Dr. G.M. Baerlocher, on the long-running imetelstat trial  of 18 patients (NCT01243073).

The general conclusion, supported by graphic evidence of reversal of bone marrow fibrosis, is:  “The current study suggests the potential value of telomerase-targeting treatment strategies in patients with myelofibrosis and identifies imetelstat as an active drug for this disease. Along with activity, Tefferi noted imetelstat “had the potential to cause clinically significant myelosuppression ” (See Toxicity, below.)

The FDA and safety issues

Tefferi had previously presented controversial findings from his imetelstat IST  at ASH   And he’s had to defend the drug when Geron’s Independent New Drug trial was suspended by the FDA for toxicity issues.Tefferi video The FDA placed imetelstat on full clinical hold due to “the occurrence of persistent low-grade liver function test (LFT) abnormalities observed in the Phase 2 study of imetelstat in ET/PV patients and the potential risk of chronic liver injury following long-term exposure to imetelstat.”  Tefferi’ own Investigator Sponsored Trial of imetelstat was placed on partial clinical hold  since “a safety signal of hepatotoxicity had been identified in clinical trials of imetelstat,  it is not known if this hepatotoxicity is reversible.”  The FDA said that patients currently enrolled in this trial at the Mayo Clinic Rochester, Minnesota, who are deriving clinical benefit may continue imetelstat treatment under a partial clinical hold placed by the FDA..

In order to resolve the partial clinical hold on the Myelofibrosis IST, Tefferi was called on to demonstrate the safety of imetelstat or the reversibility of  hepatotoxicity.   The FDA lifted its partial clinical hold on the Mayo Clinic trial in June and lifted the full clinical hold on Geron’s IND in November 2014, setting the stage for further testing

But would Geron, with only this single investigational drug in the pipeline, one that had already failed  breast cancer and small lung cancer clinical trials, have the resources?

The question was answered when Johnson & Johnson’s  Janssen R&D stepped to invest in Geron giving imetelstat a clear path  forward in clinical trial. As of June 18, 2015, the J&J division, Janssen R&D, became the official sponsor of the Geron trial NCT01731951 that started in November, 2012.

Telomerase inhibition — The hopes and fears behind blocking cellular repair.

It’s an appealing idea.telomeres new Telomeres, those sticky elongated ends of chromosomes, shrink with each cycle of reproduction. For cells to continue dividing, a certain telomere length is required. With significant shortening, apoptosis sets in and the cell dies.  An enzyme, telomerase, repairs damaged telomeres and maintains their length  The scientists who discovered this – Jack Szostak at Harvard, Carol Greider at Johns Hopkins and Elizabeth Blackburn, UC Berkeley – also found the process to repair and lengthen telomeres required an enzyme, telomerase.

 A biomarker for aging, a target for cancer treatment 

For their work on telomeres the three scientists shared the Nobel Prize in Medicine or Physiology in 2009 sparking intense activity among aging specialists as well as oncological researchers. Here’s the language of the Nobel award:

 “If the telomeres are shortened, cells age. Conversely, if telomerase activity is high, telomere length is maintained, and cellular senescence is delayed. This is the case in cancer cells, which can be considered to have eternal life.”

Together Greider, Blackburn and Szostak  split the associated $1.4 million award.

Menlo Park:  Telomere Country…briefly

Menlo Park might be the Northern stretch of Silicon Valley but for a brief time it was Telomere Country.

In Menlo Park, Blackburn took some of that prize money to found Telome Health in 2010, a company providing analyses of telomere length from saliva samples. According to Science “she recently distanced herself from the company…and donated all her shares to a nonprofit organization.”

Elizabeth Blackburn. Photo: Sam Mooy Source: The Australian

Elizabeth Blackburn. Photo: Sam Mooy Source: The Australian

Carol Grieder, UPI/Lndov

Carol Grieder,

Greider for a time served as an advisor to another Menlo Park firm, Geron, the sponsor of imetelstat, but, as reported in Science, she left “because she felt the company was overstating the tests’ clinical benefits.”

She believes the diversity of telomere length among people of the same age disqualifies telomeres as an aging biomarker.  And as to cancer, “Scientists have discovered an apparent tradeoff between the age-buffering effects of long telomeres and a greater risk of some cancers.” (Emily Underwood, “The Final Coutdown” Science 4 Dec. 2015)

Off target treatment

Greider notes, in a Letter to the NEJM responding to the Tefferi  and Baerlocher et al. presentations, “In the studies reported here, the initial telomere length did not predict the clinical responses, and there was no change in telomere length over the course of treatment in the myelofibrosis cohort.”  In somewhat less direct language, Tefferi concurred: “Our preliminary correlative studies did not elucidate the precise mechanism by which imetelstat induces clinical responses in some patients but not others.”


Daniel El Fassi, MD, PhD of Herlev ad Gentofte Hospital, Denmark, commenting on the ET trial wrote, “The drug was effective in controlling platelet levels ….often at the expense of hemoglobin and neutrophil levels. However the other main treatment goals in essential thrombocythemia — controlling symptoms and preventing both disease and progression and thromboembolic complications — were definitely not achieved. Fatigue, diarrhea, and nausea were all reported by more than 70% of the patient A total of 3 patients had progression to myelofibroiss and 2 patient had a thromboembolic event Thus, treatment with imetelstat does not seem to be promising in this relatively benign disease.

On the small MF trial, toxicity of imetelstat was clearly evident:

At the data-cutoff date of December 5, 2014, treatment had been discontinued in 25 patients (76%); the median duration of treatment for all study patients was 8.6 months (range, 1.4 to 21.7). Causes of treatment discontinuation included insufficient response (16 patients); disease progression or relapse after an initial response (3 patients); death during the treatment period (2 patients), including 1 death due to intracranial hemorrhage that was attributed by the treating physician to drug-induced grade 4 thrombocytopenia after weekly dosing and 1 due to an upper gastrointestinal hemorrhage that was not considered to be drug-related; adverse events (2 patients) in the form of persistent thrombocytopenia; and other reasons (2 patients), including financial constraints in 1 patient and a preexisting condition (atrial fibrillation) in 1 patient.

Here’s a patient’s perspective on the imetelstat ET trial (extracts for brevity):

“I had to look into the journal I kept to make sure what I tell you was some of the effects of the imetelstat.

(1) Before the infusion I was given Benadryl; Decadron and Dipenhydramine. After 30 minutes the infusion was started.

(2) The day after I was usually all right and able to do necessary chores.

(3) On the third day the story changed. I was extremeely tired, lost all appetite …and had intestinal problems. .That area hurt. ..This lasted until the 5th day.

(4) The positive side is my hemoglobin stayed above the 8.5 range and at times even going as high as 9.2. I only had to have one blood transfuion during the entire year that I was on Imetelstat.

(5) The other problem that I had was sleeplessness. According to the journal I spent many a night from 03:00 to 05:30 reading…what woke me up was stomach aches.

(6) I’m usually an even-tempered person but during the latter part of the week  I would become very grumpy and had to be careful…

(7) Everything changed 10 months into the trial… Fifteen minutes into the infusion my pelvic area would be so painful that I could hardly stand it. The nurse would stop the infusion and eventually give me medicine to ease the pain.  The infusion would usually begin again after 30 to 45 minutes depending on te effect of the medicine for pain. This was the same for the next two times.

(8) There was another patient who also had to stop because of severe liver problems… There were pts. with serious side effects and that cannot be ignored or suppressed. Patients have to be aware that this medicine is not perfect. It can help many but it is not perfect. “

The last word may well come from Professor Goran Hansson, Karolinska Institute and member of the Nobel Prize Committee:  “Now it wil be very important to figure out what is real, what is mechanism and what is statistical noise.”

The question is squarely before high risk myelofibrosis patients.  Is the imetelstat trial now recruiting more likely to help or harm?

Take me back to the contents

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Comments on: "Thinking imetelstat? Think again." (3)

  1. Loved reading thiis thank you

  2. Taylor Anderson said:

    Zhen two replies that should be included in the article also you are quoting Dr Elfassi and not pointing out he was not an investigator in the trial. This trial was not designed to study its effects on progression but on proof of concept. All of the ET trial patients had failed other therapies and were considered high risk for transformation into MF.

    Dr. Baerlocher and colleagues reply: Our phase 2 study of imetelstat enrolled 18 patients with essential thrombocythemia with a median interval of 7 years since initial diagnosis. All the patients had received a median of two previous therapies, including hydroxyurea, anagrelide, and interferon. Although interferon is used in patients with essential thrombocythemia, this disorder is not an approved indication. A total of 4 patients in our study were previously treated with interferon; 1 had resistance, and 3 had unacceptable side effects. All 4 of these patients had a hematologic response to imetelstat, and 2 of the 3 patients with mutations had a molecular response.

    Rapid, substantial hematologic and molecular responses that were observed in such patients provided evidence of anticlonal activity and proof-of-concept data for further investigation of imetelstat in patients with advanced myeloid cancers. The interpretation of data with respect to progression to myelofibrosis and thromboembolic events in patients with long treatment histories is difficult from this single-group study. Randomized clinical studies are required to compare such end points. Furthermore, complete and partial remissions, including reversal of bone marrow fibrosis and molecular responses, were recently reported in the study by Tefferi et al.

    Gabriela M. Baerlocher, M.D.
    University Hospital of Bern, Bern, Switzerland

    Bart Burington, Ph.D.
    Geron, Menlo Park, CA

    David S. Snyder, M.D.
    City of Hope, Duarte, CA

    Dr. Tefferi replies: It is true that imetelstat may not have the side-effect profile that justifies its further consideration for the treatment of essential thrombocythemia, as reported by Baerlocher et al. However, drug benefit–risk assessment is best accomplished in the context of randomized studies and should not be surmised from the results of a small proof-of-concept study. The same holds true for other drugs for the treatment of essential thrombocythemia, including interferon alfa. Treatment-induced reduction in the JAK2 or CALR mutant allele burden in patients with essential thrombocythemia has been observed with imetelstat, interferon alfa,1 and busulfan.2 Such observations do not necessarily imply that each of these drugs has the same effect on coexistent disease clones with different mutations3 or an advantage in terms of meaningful health outcome; the latter requires evidence from controlled studies and not conjecture based on local treatment practices. The observations from our pilot study of imetelstat support a unique mechanism of action that deserves further laboratory-based investigation.

    Ayalew Tefferi, M.D.
    Mayo Clinic, Rochester, MN

    • Thank you for providing the responses from Drs. Tefferi and Baerlocher, et al. I’m not sure there’s much reassuring to patients in those comments or the studies published in the (N Engl J Med 2015; 373:920-928 September 3, 2015)

      it’s hard to understand your challenge of Dr.Fassi We identified Daniel El Fassi, MD, PhD, whose letter the NEJM published. That he was not an investigator in the imetelstat ET trial enhances his standing as an independent, disinterested and qualified observer. His comment on the published results are compelling:

      “However the other main treatment goals in essential thrombocythemia — controlling symptoms and preventing both disease and progression and thromboembolic complications — were definitely not achieved. Fatigue, diarrhea, and nausea were all reported by more than 70% of the patient A total of 3 patients had progression to myelofibrosis and 2 patients had a thromboembolic event Thus, treatment with imetelstat does not seem to be promising in this relatively benign disease.”

      I’m afraid you’re simply wrong about the design and endpoint of this trial. This was a Phase 2 toxicity and dosage trial in which two cohorts of patients were given two different doses of imetelstat “until a platelet count of approximately 250,000 to 300,000 per cubic millimeter was achieved or toxic effects occurred.”

      According to Baerlochcer: “The primary end point of the study was the best overall hematologic response.. “Secondary end points included the frequency and severity of adverse events….” exactly the issues raised by Dr. Fassi.

      Finally, we focused on the patient’s journal report of pain, on toxicity, lack of effect and side effects as reasons to avoid participation in imetelstat trials as this time. Dr. Baerlocher presented an even more pressing reason. The rate of progression from ET to MF is fairly rare, estimated at < 9% after 15 years. The rate of progression to myelofibrosis in the Baerlocher study was nearly twice that. (17%), not a promising outcome, as Dr. Fassi points out, in this "relatively benign disease."

      Please don't contribute to muddying the waters. Presenting the simple facts to patients gives us the opportunity to make an informed decision. As you know, I have long felt there was far too much hype attached to imetelstat so it is good to see these reports and comments. For some of us, with MF refractory to any drug and unqualified for SCT, even though imetelstat appears likely to have adverse health impacts, this trial might have some appeal.

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