MPNforum Magazine

It just might work.

by Zhenya Senyak

The reports from two women on the imetelstat clinical trial lay on my desk. They could have been reporting on different drugs.

 Within two months of starting the trial all my symptoms — fatigue, night sweats, itching and bone pain are gone. Dr. Tefferi told me there are no safety issues with long-term use of this drug…It’s  beyond wonderful. The infusion routine every three weeks itself was a little taxing, requiring a flight in to the center the night before, a full day of labs, the three hour infusion process itself and exams…it’s a miracle drug.

Going through the trial journal of a woman with ET, the story is different.

The day after infusion I was OK but on the third day the story changed. I lost all appetite and had painful intestinal problems that lasted a last a couple of days.  The good news is my hemoglobin remained above 8.5 and  only required one transfusion for the whole year on imetelstat.  Sleeplessness became a problem, mood changes, too. And then, after ten months on the trial, everything changed…15 minutes into the infusion “my pelvic area would be so painful I couldn’t stand it. … After the third time the doctor and I agreed I would not continue on the trial….There was another patient who also had to stop because she had severe liver problems.  Why Dr. Tefferi reported that imetelstat had little or no side effects only he can answer. There were patients 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.

Whether or not imetelstat can ultimately roll back the ravages of myelofibrosis will be decided not in the hype of publicity or cold statistical tables of clinical abstracts but in the blood,  bones and marrow of patients, perhaps hundreds of us worldwide as this highly preliminary study rolls out. That rollout in full blown multi-site clinical trial is expected to start in 2014

Imetelstat may turn out to be the next blockbuster myelofibrosis drug or a total bust. Either way it’s an historic MPN research and development effort that just might turn things around.  

The main MPN event in next month’s ASH meeting is the presentation of findings in a small, very  brief, single-site pilot study of this unlikely candidate. Imetelstat is a product of the labs of Geron Corporation, a Menlo Park-based company that has raised and dashed hopes for nearly two decades and recently reinvented itself. And imetelstat is  a drug that failed in two major attempts in the recent past before regaining its footing.

Now, with a realigned corporate vision and the help of an eminent and controversial hematologist, Geron and imetelstat may well be staging a successful comeback. 

What imetelstat does

Imetelstat targets the telomerase enzyme that stimulates growth of telomeres.
Every chromosome in every human cell comes with multiple copies of a repeated TTAGGG DNA code that essentially signals the chromosome’s boundary .  Telomeres are the repetitive code at the ends of chromosomes. The main function of telomeres is to preserve the integrity of the chromosome, avoid fusion, inappropriate combination.  They’re often compared to shoelace tips.  Telomeres are also, in a sense,  the ticking clock of most normal cells. They grow smaller — less code — each time most cells divide. until a certain minimum size is reached and the cell can no longer divide and dies.

Telomerase is an enzyme that supports the survival of the telomere.   In the presence of telomerase,  telomeres maintain or elongate their structure and protect the dividing cell.

No TERT, no telomerase.

Genes code for proteins, that is they contain the code that makes something that does something. In this case, the TERT  (human Telomerase Reverse Transcriptase [hTERT] ) gene encodes for the protein telomerase.  We’ll get back to TERT but for now, consider telomerase. It’s an enzyme that acts as a catalyst for a metabolic process.  And the process it helps move along is survival of the telomere.

So, in simplest terms, if there’s a cancer cell you want to destroy  you would deprive its telomeres of telomerase and eventually it would die as the telomeres used up their supply of code and were unable to replenish it. 

3-D telomere source: wikipedia

The ideal target for such an attack  would be leukemic cells functioning with relatively short telomeres, cells that depend on a telomerase rich environment.

Some cells, like stem cells in the bone marrow, continue to divide during our entire lives, a function made possible by the presence of telomerase.  But malignant cells can also flourish when supplied with telomerase. It’s estimated up to 80-90% of human cancer cells express the TERT gene  and associated proteins and the resulting telomerase storm  prevents the cell from dying.  Instead of the normal aging process these cells  just keep on proliferating  causing MPNs or, in other cancers, solid tumors.

In a sense, like blood to a vampire, the telomerase enzyme confers a kind of immortality on cancer cells.  Inhibiting its action would put a wooden stake in the heart of the cancer cell.  Theoretically.

A  trial that changed everything.

Imetelstat wasn’t effective when Geron tried it on breast cancer or another solid tumors, non-small cell lung cancer.  But blood, a liquid medium, appears to be a more likely environment. After getting reportedly promising initial results in a phase I  essential thrombocythemia/polycythemia vera trial that opened in November 2010,  the Menlo Park company began the process that would lead it to ASH next month.

100% response as in everyone.

While “efficacy data” for the two PV patients participating in the early trial was not reported, data from the initial 14 continuing ET patients was presented at ASH in Dec. 2012.  Those results were updated in June. 2013 by principal investigator Dr. Gabriela M. Baerlocher of the University of Bern, Switzerland at the European Hematology Association conference with data from an additional six months of treatment for the original group of 14 plus four additional patients.

Baerlocher reported 100% hematologic response rate – platelet counts reduced in all patients – and normalized in 16 of the18 patients.   Seven of the eight patients with the JAK2 mutation saw reductions pf the allele burden in excess of 75%

All patients, however, demonstrated some liver function test abnormalities.The  majority were mild with occasional grade 2-3 elevations in ALT or AST. These were reversible by decreasing dose.

Enter Dr. Ayalew Tefferi.

Based on early returns from these trials, the Mayo Clinic’s Dr. Ayalew Tefferi initiated a myelofibrosis pilot study in November, 2012  and completed recruiting his first cohort of 11 patients in March, 2013

…and Geron changes course.

With Tefferi’s MF research cohort barely accrued,  Geron scheduled an 8:30 AM conference call in April of this year to announce first quarter 2013 results… and a radical change in the corporation’s development strategy.

Staff was stripped down from 64 to 44 positions and the internal discovery research program and research lab facility were terminated. Geron, announced Dr. John Scarlett, president and CEO, planned “to focus resources on hematologic malignancies.”  Essential thrombocythemia, however, was not to be included in that focus. Geron ended clinical development of imetelstat in ET to focus its resources on the MF market.

In the crosshairs of Geron’s development plan was the myelofibrosis market dominated by Incyte’s JAK-2 inhibitor, Jakafi.  Geron was betting the farm on imetelstat’s successful challenge to JAK2 inhibitors in the myelofibrosis space. It was a bold strategic move and, given the unproven efficacy of imetelstat, the long testing and approval process ahead and the deeply entrenched position of competition, a long shot.

Quick steps on the way to ASH.

Shortly before Baerlocher at the EHA meeting in June announced strong results in the now discontinued imetelstat ET trials, Geron initiated  an April 26 Conference Call with investors and media. CEO Scarlett indicated promising findings in the MF study from comments he got from Tefferi.  November 7, after a massive swelling of interest (and stock-price), Tefferi’s formal ASH abstract was published on-line.  

The Tefferi Pilot Study in one sentence.

The official purpose of the Tefferi pilot study was to “See how well Imetelstat sodium (GRN163L) works to relieve primary or secondary myelofibrosis symptoms.

Before publication of the preliminary results, fueled by controlled information leaks and overheated media responses to reports of Complete Response and recovery of the bone marrow, the Geron stock more than doubled in price and MPN social media buzzed with talk of remission and cure.

The results, in brief.
The actual reported results are somewhat less dramatic.    There were a total of 33 patients enrolled in the study.  Results from the first 18 patients – followed for a minimum of 3 months — are the subject of the published abstract.

Two patients were discontinued, one because of “unrelated death” and the other because of disease progression. Four patients were reported to have demonstrated Complete Response (bone marrow and peripheral blood), two Partial Response and three patients showed Clinical Improvement.

 The problem with the data.

The biggest issue of course is the research question hasn’t yet been answered. Prominent in both the abstract and in media reports are the claims of Complete Response and Partial Response.  A few reporters protested that characterization of response as Complete or Partial  required clinical or symptomatic responses according to the often disputed and contentious International Working Group criteria. But so far as the stock market and MF patients were concerned this was an unimportant technicality. 

The abstract report narrowly confined its target results to bone marrow and blood, presumably because hard data supported those claims. An argument could be made that resolution of fibrosis in the marrow and return to normal cellularity would be reflected in resolution of spleen and liver swelling and other MF symptoms. Maybe.  We should know more during the oral presentation of findings at ASH, December 9, at 4:45 PM in the Convention Center’s  New Orleans Theatre.

 In any case it’s unlikely that Tefferi, the author of the Revised response criteria for MF from the International Working Group and European Leuikemia Net would have been unaware of the criteria.

However the trial’s purpose was not to measure improvement in marrow architecture or peripheral blood values. The purpose was to see how well Imetelstat sodium (GRN163L) works to relieve primary or secondary myelofibrosis symptoms.  And so far, we have no data on that

Adverse events

More significantly, two adverse events that occurred in the earlier imetelstat ET trial were thrombocytopenia (low platelets) and elevated liver enzymes.  Imetelstat’s successful lowering of platelet levels in ET may well be a formidable obstacle to its use in myelofibrosis where thrombocytopenia is often a dose-limiting issue. The data on adverse events in the abstract is sparse.  33 patients were in the trial. The abstract reported on treatment results of the first 18 .Two  discontinued, one from unrelated death, the other because of disease progression. Thrombocytopenia (low platelets) was a problem in over 25%. 

Jason Chew of Chimera Research considers the efficacy reported in the trial to be somewhat “cherry picked” not only referring to the International Working Group criteria but “a stacked patient pool with relatively small spleen size…and only 11 of 18 patients with constitutional symptoms.”

Those issues, as well as questions of durability of response and the willingness of patients to maintain the very long clinic-based infusion process every three weeks will be resolved over time

We can’t know with so small a cohort treated over so brief a time what the long-term effects of telomerase inhibition will be, whether in fact the effect can be limited to the hematopoietic system or might impact other systems.  Only multi-site formal clinical trial can give us the answers now. 

Let science work

A courageous — or desperate — corporate commitment has been made and solid clinical investigation work has done to get imetelstat to this point.  Clearly the next steps require money – one estimate is $100 million for openers – and the steady application of solid testing and development.  The need for capital can sink imetelstat if it leads to hyping of product to boost share prices and anything less than rigorous clinical trial design.

Biggest question is will science trump marketing or is imetelstat to go down as another oversold boondoggle. What happens next, whether focus on celebrity or science, will come from the playbook of P.T. Barnum or Sir Isaac Newton.

First indications are the circus has come to town.   Clinical trial indications were presented to media before publication of data. Biotech trade media headlined stories promising important developments and highlighting “Complete Response,”and the stock market, ever eager to pounce on emerging opportunities, bid up Geron’s price over 150% in just a day or two on these advance rumors from a small and promising but inconclusive pilot study.

Another ominous indication is in the first sentence of Tefferi’s ASH abstract in which he refers to the ineffectiveness of ruxolitinib (Jakafi) to modify MF disease activity. Since nothing in the clinical trial protocol proposed any comparison with Jakafi or any assessment of its effectiveness, this opening with blazing guns suggests there are still scores to be settled. Adam Feurstein from The Street refers to “…Tefferi …as a bit controversial for publicly disdaining Jakafi. (The attack on Jakafi and several colleagues was reported in MPNforum.)

The most important takeaway however is this:  Imetelstat might actually work and based on preliminary findings deserves a clean shot. Before massive investment pours in and further buries the science in a mountain of money, marketing and media hype, we can only hope a solid strategic plan guides the next steps.  As MPN patients and caregivers all we can do is take a deep breath and wait with cautious optimism. 

A page from the Incyte playbook

Incyte — for all our complaints over its aggressive marketing and unconscionable product pricing — did the clinical development work right. Slowly, over more than three years, its carefully designed clinical studies, climaxing in the broad based double blind Comfort I and COMFORT II  Phase III trials,  conclusively proved Jakafi, in most cases, will reduce splenomegaly for a time.  (Since virtually all Jakafi’s benefits can be traced to this one aspect of the drug’s effect we would have been better served if it were honestly promoted as an MF spleen reduction drug   — alleviating some of the worst effects of the disease —  and not a $120,000/year wonder drug for advanced MF.  Still, that part is the marketing/money complex not science.)

Remember TERT?  Interferon does!

While looking ahead at Jakafi charging through the MF patient population, Geron product managers should also look over their shoulders at a well-established drug that has a legitimate claim on its telomerase turf:  the interferons.

Last year, the personal genomics company 23andMe issued a bulletin to subscribers about a discovery:  “Within  rs285367,  a SNP, [a small section of DNA] on Chromosome 5, a variant of a TERT gene has been found to be significantly associated with classical MPNs…as well as other cancers!  TERT catalyzes the enzyme telomerase that extends strands of telomere in at the end of DNA chains .”

Way back at the turn of the century, a Swedish group established interferon’s ability to inhibit the TERT gene and cut off the flow of telomerase to malignant and non-malignant hematopoietic cells. In August of this year an Italian group delineated how naturally occurring interferon alpha inhibited telomerase during viral infections contributing to the literature supporting interferon’s multiple effects in reducing MF symptoms and restructuring the marrow architecture.  (Note: Thanks to Ferdinand M. for help in reporting the interferon/telomerase link.)

Conclusion

In the case of imetelstat, we can only hope there will be a cooling off period after this over-heated run up to ASH. The Big Top carnival atmosphere, with trombones, marching band, and somersaulting clowns juggling premature conclusions before the amazed eyes of spectators is counterproductive.

We just don’t know how good this drug is but the data presented so far gives us cause to hope it will prove effective. Which, for myelofibrosis, is a lot more than anything else on the table this season.

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