Geron's (NASDAQ:GERN) Imetelstat hit a road block this past week when the FDA placed a clinical hold on two company sponsored clinical trials due to persistent low grade liver functionality test (LFT) abnormalities in patients remaining on drug in the Essential Thrombocythemia (ET) or Polycythemia Vera (PV) and Multiple Myeloma trials. The report of low grade LFT abnormalities in these patients is not new. As stated in the June 2013 press release:
At least one abnormal liver function test was observed in laboratory findings in all patients. The majority were Grade 1 elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST); two Grade 3 increases in ALT/AST were reversible on dose reduction. With longer dosing, Grade 1 increases in alkaline phosphatase were observed, associated with mostly Grade 1 to some Grade 2 unconjugated hyperbilirubinemia. LFT abnormalities do not appear to progressively worsen over time. No liver injury symptoms were reported and no patients discontinued study treatment due to enzyme elevations.
Importantly, as presented at the European Hematology Association Congress, these ET patients had been on treatment for an average of 14 months, with the longest being 2.5 years without any progression of LFT abnormalities. This is a very good sign. If chronic exposure to the drug resulted in severe liver cirrhosis, you would expect complications to progress over time. I expect we will see LFT levels be reduced to baseline after complete drug removal, just as the rare Grade 3 increases were decreased with dose reduction.
In the written notice received by Geron, the FDA detailed that there was a clinical hold due to lack of liver toxicity reversibility data and lack of adequate follow-up in patients who experienced hepatotoxicity. To remove the clinical hold, the FDA wants Geron to:
- provide clinical follow-up information in patients who experienced liver function test, or LFT, abnormalities until LFT abnormalities have resolved to normal or baseline.
- provide information regarding the reversibility of the liver toxicity after chronic drug administration in animals.
Geron stated that they will be supplying the FDA with preclinical and clinical data from their own studies as well as the data obtained in the Myelofibrosis Mayo Clinic study regarding LFT abnormalities and the incidence and reversibility of hepatotoxicity.
The FDA understands that Imetelstat is a drug that will need to be continuously administered and therefore any detrimental side effects will be chronic. Since, there are only 10 patients left in the trials and Geron has recently submitted an application to begin a large, multi-site Phase II Myelofibrosis trial, it is not surprising that the FDA wants more clarification regarding elevated liver enzymes and if these can be reversed upon drug removal. Without getting into too much detail, a lot of FDA approved drugs cause asymptomatic elevation of liver biomarkers ALT, AST, and alkaline phosphatase. The FDA inquiry requesting more data on Imetelstat effects on LFTs is warranted and presents a big opportunity for risk tolerant biotech investors like myself. The stock has been brutally punished on the news, down over 60%. Although responding to the FDA's concerns will likely delay the start of Phase II trials, the delay will be temporary for the important Myelofibrosis company sponsored trials.
Mayo Clinic Myelofibrosis Trial is Ongoing
The current clinical hold only applies to the ET, PV trials and MM trials where 10 patients continue to receive the drug. It is also my understanding that the clinical hold does not currently affect the Mayo sponsored clinical trial for Myelofibrosis and those patients are still receiving Imetelstat treatments. As there are several patients in that trial that have experienced never before seen complete or partial remission, it would be seemingly unethical to withhold the drug as a result of low grade LFT abnormalities in these patients. From the last data set it appeared that only ~6% of patients in this trial had elevated hyperbilirubinemia. This doesn't seem too alarming to me. The head investigator of the study and world-renowned Myelofibrosis expert Dr. Ayalew Tefferi of the Mayo Clinic has not acknowledged or revealed any concern over LFT abnormalities in his treated Myelofibrosis patients.
Myelofibrosis is not curable and there are no drugs on the market or in development, besides Imetelstat, that have been shown to have any disease modifying activity. Only Imetelstat treatment has ever resulted in complete or partial remission of Myelofibrosis. It is also important to remember that the average life span of individuals with intermediate-2 and severe Myelofibrosis is 1-3 years. At a recent (reported on by Jeremy Smith) MPN support meeting on February 23, 2014, Dr. Tefferi was speaking on the significant clinical responses seen to date with Imetelstat treatment. To illustrate how powerful the drug is, a current Myelofibrosis patient who is part of the Imetelstat clinical trial was in attendance to give her story. Here is the description of the patient from an attendee:
She has been part of a clinical trial of Imetelstat and has had amazing results. She was looking at a Stem Cell Transplant. Today her JAK2 is no longer positive her fibrosis appears normal and she looks very healthy and full of energy. This is amazing when you consider how far she has come in her journey. Seeing similar results to an SCT transplant with her bone marrow biopsy and blood work without the risks of an SCT blew everyone away. As she shared her story you could feel the electricity in the room as she stood before us presenting her story with bold smiles. This was the most inspirational story I have witnessed at an MPN event
Will the FDA pull this patient off the drug? One needs to consider the risk benefit analysis if the liver enzyme elevations are not reversible. The existence of mild LFT abnormalities should not derail the Myelofibrosis study as very few options currently exist for these patients. We are not talking about a drug to treat high cholesterol or depression. This is a drug to treat a very severe myeloproliferative disorder in which there are currently no available drugs that offer a substantial benefit. It should be noted that Jakafi, which is FDA approved and has no disease modifying activity in Myelofibrosis, has abnormal liver function tests as one of the common side effects of the drug (occurs in ~23% of patients). A similar warning would be included for Imetelstat. In concordance, Geron has had outside liver specialists review the data and they believe the benefits greatly outweigh the risks. However, before Geron can begin a company sponsored Myelofibrosis study it will need to provide more data and guidance to the FDA regarding these LFTs and how they will go about monitoring them in the future. A risk is the FDA may restrict the Phase II trial to only severe Myelofibrosis patients if the LFTs are not reversible upon drug removal.
The release of the clinical hold on the Geron sponsored Myelofibrosis trial seems to be common sense. The median survival of patients with intermediate 2 or high risk Myelofibrosis is ~1-3 years. The ET trial already illustrated that patients can take Imetelstat for over 2 years and not experience progression of LFT abnormalities. Seems like an easy decision to me.
There have been several articles lately stating that Geron is a risky buy. In my opinion, at these levels there is risk but the bet now is different. To get a doubling in stock value, when the stock was trading at $5/share the larger Phase II trial data would have had to mimic the small Mayo trial results. Now, at $1.8/share investors are betting that the clinical hold will be released. To me, at these levels a doubling in value will be much easier than before and I'm taking my chances that it will happen. There is absolutely no way the FDA will completely kill Imetelstat in Myelofibrosis treatment due to low level LFT abnormalities as it is the only drug ever to result in complete or partial remission of the incurable disease. Currently, Geron sits on ~$150M in cash, having luckily raised ~$100M in a recent offering at $4/share. The price today, provides risk tolerant investors a significant opportunity to double their investment in a short period of time.
Disclosure: I am long GERN. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.
Additional disclosure: I will be adding to my position