ImetelChat

MENLO PARK, Calif., Sept. 12, 2016 (GLOBE NEWSWIRE)
Geron Corporation (Nasdaq:GERN) today provided updates on the clinical trials being conducted by Janssen Research & Development, LLC, of the telomerase inhibitor imetelstat. Planned internal reviews of initial data from both trials have been completed by Janssen, and both trials are continuing in order to evaluate additional and more mature data.

IMbarkTM
IMbarkTM (NCT02426086) was originally designed as a Phase 2 clinical trial to evaluate two dose levels of imetelstat (either 4.7 mg/kg or 9.4 mg/kg administered every three weeks) in approximately 200 patients (approximately 100 patients per dosing arm) with Intermediate-2 or High risk myelofibrosis (MF) who have relapsed after or are refractory to prior treatment with a JAK inhibitor. The co-primary efficacy endpoints for the trial are spleen response rate and symptom response rate at 24 weeks. To date, over 90 patients have been enrolled in the trial across both dosing arms.

To inform an assessment of the appropriate dose and schedule for relapsed or refractory MF patients in IMbarkTM, Janssen conducted a planned internal interim review of safety, efficacy and pharmacokinetic data from 20 patients from each dosing arm who have been followed on the trial for at least 12 weeks. Based on this first internal review at the early 12-week time point, the following has been determined by Janssen:

The safety profile was consistent with previous imetelstat clinical trials in hematologic myeloid malignancies. No new safety signals were identified.

Activity in the 4.7 mg/kg dosing arm does not warrant further investigation of that dose and this arm will be closed to new patient enrollment. An amendment to the trial protocol is planned to allow eligible patients in this arm to increase their dose to 9.4 mg/kg per investigator discretion.

In the 9.4 mg/kg dosing arm, even though at the week 12 data assessment an insufficient number of patients met the protocol defined interim criteria, this arm warrants further investigation because encouraging trends in the efficacy data were observed. Patients already enrolled in this arm may continue to receive imetelstat. New enrollment in this arm will be suspended while the trial continues in order to obtain additional and more mature data that includes a longer follow-up of patients at 24 weeks, consistent with the co-primary efficacy endpoints. The number of patients enrolled to date is expected to be sufficient to inform potential future development of this dose.

Janssen plans to conduct an additional internal data review in the second quarter of 2017 to include a longer follow-up of patients at 24 weeks. Potential outcomes of the second internal review at the 24-week time point could include resuming enrollment in the 9.4 mg/kg dosing arm, with or without changes to the dosing regimen; adding a new dosing arm; or closing the trial.

Any protocol amendments will be subject to review by health authorities around the world.

IMergeTM
IMergeTM (NCT02598661) is a Phase 2/3 clinical trial evaluating imetelstat in transfusion dependent patients with Low or Intermediate-1 risk myelodysplastic syndromes (MDS) who have relapsed after or are refractory to prior treatment with an erythropoiesis stimulating agent (ESA). The clinical trial is in two parts: Part 1 is a Phase 2, open-label, single-arm design in approximately 30 patients and Part 2 is a Phase 3, randomized, double-blind, placebo-controlled design in approximately 170 patients. The primary efficacy endpoint is the rate of red blood cell transfusion-independence lasting at least 8 weeks. Part 1 of the trial is fully enrolled.

Janssen has conducted an initial internal review of efficacy, safety and pharmacokinetic data from a subset of patients from Part 1 of IMergeTM and this review indicated that emerging safety and efficacy in IMergeTM is consistent with data reported from the pilot study conducted at Mayo Clinic in MDS patients. IMergeTM will continue unmodified at this time.

Further assessment of data from IMergeTM is expected to occur in the second quarter of 2017 to include longer follow-up of all patients enrolled in Part 1. A decision on whether to move forward to Part 2 of IMergeTM will be based on an assessment of the benefit/risk profile of imetelstat in these patients. If Janssen decides to move forward with Part 2, the Phase 3 clinical trial is expected to be open for patient enrollment in mid-2017.

Janssen expects to submit data from Part 1 of IMergeTM to be considered for presentation at a medical conference in the future

IMERGE trial did fine why is GERON getting destroyed this bad?

Rob, I am not sure. Geron goes well as from second half 2014. Consistant positive news, or news that confirm that imetelstat is going according to plan. Maybe people are losing their patience. Or shorts are using this news to play their games. They need to cover at these low levels.

The call was in fact confirming all earlier data. Imetelstat is effecitve and safe enough to move the 4.7 arm patients to the 9.4 arm. Dr. Scarlet also stated various times that there is confidence in the data and that the 9.4 data show 'encouraging trends' with regard to the co-primary end-points. That means that today he has the expectation that approval is realistic.

The 12 weeks and 4.7 dose were both expected as being the absolute minimum. So now they know the bottom line of response time and dosing, which are important findings on the road towards Phase III.

IMerge clearly replicates earlier findings. There are no safety concerns, also not for the 9.4 dosing.

In all it seems pretty positive, although it is also clear that things take time. Next stop: presentation at a medical conference and 2nd interim review in Q2 2017.

Still have Dr.T speaking maybe something from that will be encouraging.

What Scarlett said, or didn't:

1. Enrolled folks have about six months to live on average. We'll take another look in about six more months. Shouldn't most of them be dead? We only looked at twenty patients in each arm anyway.

2. Nope, not enough spleen effect or symptom control to call it (but we thought we'd look anyway to see if study could be stopped early--that would have been a wow). But there is a trend. Remember why spleens are big. There is extra medullary hamatapoesis--the spleen is trying to make enough blood to make up for the fibrosed bone marrow. The spleen is keeping the patient alive trying to make blood. Its not big just because its full of abnormal cells. For it to shrink, the bone marrow has to get better. Tall order to happen in three months. Be patient. Patient won't feel too much better til that spleen gets smaller anyway.

3. MDS results mirror NEJM report. Be patient this is a big market with no good drugs. We will submit part one data eventually so there must be something there. Maybe we will even go for approval before MF!

4. The low dose doesn't work in MF--no surprise, thought we'd look anyway knowing we could always roll these guys over to the other arm since were already enrolled anyway, saves paperwork.

5. We don't need 200 patients to have a meaningful study, just need to roll the low dose into the high and there will be over 90 evaluable patients. We expect to have enough living patients to say something relevant by next June.

See you then. Love, John Oh, and Regards to all, bp

I have read the comments here and some SA comments about the update today. I will add mine in 3 posts. First: what we know.

1. MDS results consistent with Mayo results. MF not there yet.

2. The study is not "suspended". Geron: why did you even use that language in a press release? I again volunteer to write your PR statements.

3. The study rolled over the 4.7 arm into the 9.5 arm so study is not "suspended" - just closed to new patient enrollment. Study just not accepting any new enrollment because with 4.7 arm rolled over there is a sufficient number now in study. And, JJ does not want to pay for 'unnecessary' study participants.

4. 12 weeks might get response but likely not statistically significant that quickly especially with small number assessed at that mark.

5. If you expected 4.7 dose to be effective, you have not been paying attention. I think placebo dosage used to claim "randomized" and "randomly assigned" trial. Throwaway dose that just wasted time I think but no one asked me. I think Mayo knew 9.4 every 3 weeks is what works based on initial ET and MF studies.

I will clarify John's dosage and dosing schedule and response time in another post (there are some misunderstandings) as well as Jakafi free versus Jakafi refractory patients in the Mayo pilot that was point of discussion on SA.

To keep things in perspective: Anna has been kind enough to confirm that the twelve week mark is for each patient. That means that no patient was analyzed in a way that reflected more than 12 weeks of therapy each. In other words its not an analysis that included every patient that was initiated twelve weeks after the last patient was enrolled (meaning some would have been on drug longer then 12 weeks at the time of analysis--they weren't). It is a lot to ask to have someone with a six month life expectancy, a huge spleen who feels terrible; to have their spleens shrink by nearly half and feel much better after three months. What happened today was what Scarlett told us would happen. They settled on the best dose and as a bonus reduced the total number of patients that will need to be enrolled in the study. bp

John was diagnosed with intermediate high risk - although borderline high risk - with complex karotype. He was previously misdiagnosed and so hard to say exact MF diagnosis date, but at least a year prior to Mayo treatment with imetelstat. He was deteriorating on hydroxyurea and was refractory to it with a 1-3 year prognosis at that point. He entered the Mayo pilot study in April 2013 Arm B with 9.4 dosage and weekly dosing for four weeks and then every three weeks. By mid-summer, he developed severe neutropenia with some advice to suspend treatment. As long as neutrophils stayed at minimum 1 (ranged from .7-1.), however, we could opt/insist to continue treatment. We did so and dosage was decreased to 7.5 shortly after and neutropenia stabilized about 4 weeks later. John was in partial remission by August and complete remission by September 2013 (~20 weeks) - and in and out of partial/complete remission thereafter as hemoglobin ranged from 9-10 (10 needed for complete remission) but meeting all other endpoints. His bone marrow fibrosis cleared and circulating cancer blast cells eliminated. After remission in September, at our request, John dosing schedule extended to 6 weeks continuing at 7.5 and his disease was stable until he voluntarily suspended treatment in July 2014 after 15 months for financial reasons and no medical reason. During this interim, he took no medication or received any other treatment and benefited from imet's lingering good effect. He sent monthly blood work to Mayo over the next 12 months. He started deteriorating slowly after treatment stopped (but much more slowly than pre-imet). About 12 months later, after blood clotting episode, he clearly needed imetelstat again and started treatment again about 15 months after he initially stopped imet treatment at Mayo and at same 7.5 dosage every 3 weeks (we would like 9.4 again) but he must stay on dosage last on and at Mayo for reasons inexplicable to us. Took a couple of months to get him back on for bureacratic and not medical reasons (another story). He has been on treatment again since last July 2015 with same good results on/going. The standard dosage in the Mayo pilot study was 9.4 every 3 weeks. That dosage was not problematic and was effective. The weekly dosing for first 4 weeks at 9.4 in Arm B was problematic. 9.4 dosing every weeks seemed to be sweet spot in Mayo study.

Irish, can't tell you how glad I am to have you here to help sort through this stuff and to provide guidance. Two small issues though, one is that I think Dr. S comments re consistency with Mayo data only applied to MDS not MF. Also this failure to reach some prespecified 12 week goal was a little concerning. Clearly we don't know what that goal was and the inability to reach it did not derail the study but it is a little unsettling to me what ever it was. That we need more time to assess is clear and thank you again for sharing your and John's experiences. bp

Thanks bio. Edited my error. You are, of course, correct. Love the editing function here. I am personally not too worried at the MF 12 weeek results or lack therof in that timeframe. I think in Mayo pilot MDS + effect may have been quicker overall than MF + effect. That leads me to a post I noticed on the SA board. Could it be because MDS patients never take Jakafi?

SA Post: Does anyone know how many of the first 33 patients at Mayo were refractory to Jakafi? We're all or most? If they got 21% remissions with that group, maybe a trial for first time MF patients would be easier and quicker? I understand the need for the refractory group to get results but maybe they are sicker because of their long-term exposure to Jakafi? Did every single one of the initial group take Jakafi first? I kind of don't think so.

About 1/2 of original Mayo MF patients had taken Jakafi prior. I am quite sure this number is published in some report. John was one of the group who had never taken Jakafi - only hydroxyurea and was refractory to it (it was no longer working and he was deteriorating rapidly and very sick). I wonder if there is any predictive correlational data/comparative data regarding prior Jakafi and non Jakafi MF patients with regard to imet effect?

John is headed to Mayo tomorrow. We look forward to his last trip to RST one sunny day.

Update: After more reading and thinking more, and based on the way imet seems to work, I doubt any difference between patients who took Jakafi prior and those who did not in terms of outcomes. I am sure Dr. T and JJ figuring out who, how, why it works. Complex with many genetic and chromosomal variations.

Hi Irish, thanks for your highly informative posts! I am not aware of any existing and publicly available comparative data. But JnJ should have some idea by now, so does Dr.T. For patients this is very important information. It could mean a high risk patient may be better to take interferon (e.g. the new P1101) or Hydrea instead of taking Jakafi (if imetelstat is still an option for him/her). Off course better to go to imetelstat immediately, but that is not always an option. It would be a great question for Dr.T. on the 17th.

Great post from Magictuzi on SA 13 September 2016), which to my opinion nails down the essence of the CC:

I agree that Scarlet should have said it differently but it's easier said than done. What's the reality now?

My previous posts stated that they would probably ditched the 4.7 dosage and move to the 7.4 (wasn't expecting the 9.4) and not enough data for MDS to divulge much about. I think I was closer to the reality than those predicting a Buyout scenario. I have to give credit to Phil though because he was the first one to implement that idea in my head a long time ago.

To summarise, Scarlett clearly said that the 4.7 dose to be quite a low dose and that he was NOT sorry to see inadequate efficacy. He added "It's NOT a failure in ANY means." The guy knew it that there would not be adequate activity. Maybe it's to calm down the FDA dogs by showing them that the very low dosage is not good enough. It probably was a prerequisite.

The Imbark trial is to NAIL THE DOSING. How many time will we have to say it? In the 2e quarter of 2017, at the 24weeks interim Janssen will still have the choice to either: dose adjustment, protocol adjustment or stopping the trial. They are very flexible, and it's a good thing. They are looking for the adequate dosage. And now they are going full steam with the 9.4 because they are seeing "encouraging trend efficacy" after 12weeks.

* 12weeks *

"We did not know how patients would response (because they are R/R) but we looked at this quite early". Scarlett words, not mine.

As per the NEJM the median timeframe to see activity in MF is more than 12weeks (3.5months). They know it was way too early to look at it but they did not want to hold patients with the low dosage for too long if it didn't help them much. That's exactly what's happening. Analyst Ling Wang asked a good question: "Euh.. what are we waiting for?" It just proves that everybody was off the hook after the announcement.

The most important factor when it comes to Imetelstat is the Time factor. We know that by adding time, the "encouraging trend efficacy" will improve. Scarlett words, not mine: "We feel quite confident that with more time on drug and more patients we will have sufficient information to make dosing decision." Here again, talking about dosing decision. They want to nail the dosing. And that's exactly what they are doing. Give them some TIME.

"We are expecting that the principal difference will be the TIME course".

And by encouraging trend efficacy he said "encouraging trend progressions towards the assessment of the co primary endpoints." If it's a trend, it means it's moving into the right direction but need more TIME. From now on the 90 patients will be full steam on the 9.4 for 24weeks. Which brings us in the 2 quarter of 2017 sometime near April or Mai. But even then, they still can make changes. They really want to find the optimal dosing. Once found, they will recrute more patients.

Regarding Emerge: All patients are already enrolled and are now being monitored. They already now the dosing for Emerge and are going full steam with confirmation of SAFETY & EFFICACY. Obviously is not a slam dunk scenario but I'm not sure it deserves a -30%. Once again, biotech stocks are very volatile and you definitely need nerves of steel. Time will tell if we are on the right course, see you all in the 2e quarter of 2017 but until then... please, no more pumping. It brings more harm than good.

Thanks fish - Just needed a break from posting. Will try to post when there are developments and add my perspective (or interesting speculation that pops into my mind) but living a healthy happy life now (and work) does get in the way of my MF hobby. John's only option prior to imet - post hydrea - was interferon but it is another brutal drug with tough side effects and he was trying to avoid if possible for as long as possible. Hydrea had already helped plummet his RBC'S. Not easy - a matter of picking how you will suffer. Basically, he was taking liposomal Vitamin C (can't hurt and some anecdotal evidence), holding on, and waiting for miracle - and in Dr. T's words trying to avoid drugs 'that can kill you faster' as much as possible. Actually, he would probably have moved to Bulsafan if imet had not come along (as treatment off label and not in prep for SCT). As we all know, MF and all myeloid leukemias have no particularly good options - yet. I wish I could be in SF with Dr. Tefferi at patient conference this week like I was in Miami - but will be there in spirit with that great man and brave patients. It is hard to be on the right side of a 'transformational' drug and have to keep waiting...we know. I agree that magictuzi commentary on update is outstanding so I will end this chapter there.