ImetelChat

I have never understood the rationale of a 35% reduction in spleen size in the Geron MF R/R CT as one of the two primary outcome measures (POM). For completeness on this post I’m adding background regarding association with a relative with MF. I apologize for the length of this.

He became R/R to available treatments 4Q2018 and had his spleen removed in February 2015. While he was just hoping to live long enough to be included in the JNJ/Geron MF CT, having his spleen removed limited and probably eliminated that possibility but became a very painful problem for him as it continued to increase in size. He died in June of 2015 so it was never an available option anyway with the first Imetelstat CT infusion given in September. Essentially he died less than 4 months after his spleen operation, partly due to complications arising from the spleen surgery adding to his overall struggle with the disease.

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Wikipedia quote re spleen structure as of 02-28-2018:
Structure
The spleen, in healthy adult humans, is approximately 7 centimetres (2.8 in) to 14 centimetres (5.5 in) in length. It usually weighs between 150 grams (5.3 oz)[9] and 200 grams (7.1 oz).[10] An easy way to remember the anatomy of the spleen is the 1×3×5×7×9×11 rule. The spleen is 1" by 3" by 5", weighs approximately 7 oz, and lies between the 9th and 11th ribs on the left hand side.
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Prior to his spleen operation, it could be roughly observed from the protruding outline on his left side, taking up much of his entire left size. It had continued to expand to a point where it crowded his left lung and actually during the operation was found to have attached to his diaphragm, all adding to congestion and making breathing more difficult and was extremely uncomfortable at all times. Following the operation we were told the spleen weighed 10+ pounds not including various amounts of other fluids that were removed in conjunction and from the picture we saw with a small ruler beside it appeared to be 10+ inches long and probably 6+ inches wide, not sure what the depth would be in that case but suffice to say it was huge.
So then compared to a normal spleen (see Wikipedia info above), to one example of a man normally weighing 160 pounds with R/R MF, and just looking at spleen weight size we are talking an increase of approximately 20+ to 1. What I’m wondering is, given a frontline MF patient with a much smaller spleen (not sure what average would be in this type of patient but much, much smaller), reducing it’s size by 35% is possibly orders of magnitude less that 35% of a 10 pound spleen that has been stretched to the max.
Why I provided all the background and what I have trouble understanding is that we have a MF R/R CT with a primary end point that appears to likely be comparing spleen reductions apparently to the MF Comfort frontline study. Hopefully this focus point can be minimized from here but why would the same percentage (35%) reduction be used as POM for both frontline and R/R patients in the first place? How could that have ever been an apples to apples comparison given differences in spleen size of the two types of patients and the physical difficulty of reducing the size of the spleen let alone the spleen contents? Certainly, one MF R/R patient is not a valid comparison to a study, but still, is this just an outlandish outlier? I personally don’t think so. From my perspective, this appears to be careless planning on a major point, but the other POM on total symptom score makes sense, as well as the secondary outcome measures. Is it possible that careless cut and paste / oversight left spleen size as a POM or just a requirement of the FDA, or some other entity?

Hi Hunt, thanks for this personal story. It tells a lot.... Within the MF patients population there is large heterogeneity. I have a friend with post ET MF. She has suffered from an enlarged spleen for many years, even far before it turned into MF. Now her spleen can't be removed anymore, because then she will not have any blood production anymore and no immune system. It is also a risky procedure, because a spleen that has been strongly enlarged is grown into complex shapes and contains labyrinths of large blood veins. There can be two reasons for splenectomy: palliation or preparation for a transplant. If the patients are low on thrombocites and/or have a weak immune system, such an operation will not be risked.

On the other hand, MF can be at very high risk with just a small spleen, but with 15% blasts e.g. In such case an AML is imminent. Only a transplant, pre-ceeded by an induction therapy (= heavy chemo to get rid of the blasts) gives a curative option.

From palliation point of view I understand that spleen size reduction makes sense. However, your story shows that spleen reduction is not the only valid end point. If a spleen size reduction is observed, but no improvements at the molecular level (fibrosis, hyper cellularity, marrow morphology clone burden etc.), it doesn't indicate that this patients health has genuinely been improved. Words like 'disease modification' , 'targeting the malignant clone' and 'survival benefit' are therefor the key words. So it is not about spleen reduction only. Geron's reporting always suggested there was more behind the data than just spleen size. Any spleen reduction (large or small) will need to be assessed together with the underlying molecular data.

I don't believe there has been some careless cut and pasting. They have been collecting all these molecular data for many years now and they have reported about those data at regular basis (all be it often in minimalistic and indirect ways). I don't think your friend was an outlier as an enlarged spleen is a major hallmark of the disease. Nor do I think that spleen size is the only metric to demonstrate how advanced the disease is and how well the drug works.

Thanks, Fishermanagents for your detailed thoughts and personal experiences adding balance, intelligence and sanity to my limited views and thoughts as usual. I always learn from your posts and responses.

I’m not trying to be negative here as I am mostly frustrated. I believe most people are doing the best they can and are well intended. What troubles me most about this is not even if major errors in planning and decision-making (in my opinion) were likely made in establishing the POM’s by including spleen size reductions as one of two POMs, as even I think, with very limited experience, could have used simple logic a few years ago to see the flaw in the plan; it is rather that several years have gone by in delaying general availability of this drug out to thousands who can use it to save / extend their lives. Unfortunately many of whom have already passed and the opportunity is gone. Yes, I think minimally, the bureaucracy kept this drug from reasonable access from my relative, Irish Trader’s John and thousands of others who have tried unsuccessfully to navigate the morass. Also, much time has been lost in getting to the all-important combination trials; hopefully pre-CTs are in progress for this purpose.

Looking at the future, nothing seems to have really changed with the drug, it’s effect or the CT results, just the focus being shuffled around on the board causing more delay. Now, I realize understanding of the MOA, etc. has likely been advanced considerably. However, while I am much less than a knowledgeable person of the science and have no idea of what is going forward behind the curtain, but I hope no time is being spent (wasted really) in trying to cover up mistakes, judgements, downplay previous decisions, etc . This drug has been on the launch pad far, far too long, when will the countdown begin? Unfortunately for many it should have been yesteryear.

I also wonder how much time has and should / could have been spent on developing the delivery of this drug to those who could administer it broadly vs CTs and focusing on how to administer it in a controlled, effective manner. Dr. T, to my knowledge, is still the only one to bring forward a patent administering Imetelstat and likely has many more ideas on accelerating the entire plan. It would do my heart good to see key people in this process wearing passion on their sleeves, not just the good doctors. While the process could be dragged out for frontline patients, R/R MF patients are out of runway and taking a little risk is not a concern.

Thanks again for your feedback!

Things change if you have relatives/close friends who actually suffer from this diseases. I have personal experience with that and feel very much with you. My father died in 2016 from complications of PV and I have a good friend suffering from Post PV MF. Another friend just had stem cell transplant after diagnosis of high risk MF and MML. For such patients things can't go fast enough, even when the drug may not have sufficiently been tested on the long term. This certainly counts for those patients who have a short survival prognoses without alternatives (like the MF R/R group). But as an investor I feel more comfortable if a totally new drug is being tested as thoroughly as possible in order to prevent nasty experiences in a later stage. With imetelstat it adds that the more they know about which patients may benefit most (e.g. genetic profile, disease stage), the more targeted will be their story towards the FDA and investors. This has all to do with feeling comfortable with a certain risk/benefit profile, which counts for patients, doctors, manufacturers and investors alike. Although they all have a different position in the same story. If (median) OS in IMbark is significantly better then the alternative (= no treatment, as IMbark patients are R/R), then approval can't be far away.

Thanks Fishermanagents for your balanced thoughts on moving Imetelstat through the processes to those in need. Also, I am sorry for your loss and first hand experiences with these diseases. Your passion regarding Imetelstat has always reflected personal experience with these diseases, thanks again for sharing.

As you noted, genetic profiles, disease stage, patient targeting, MOA, drug delivery, dosing, limited options, and more all go into the equation and let’s hope much progress is being made in this arena behind the curtains. But, as a layman in all of this, for R/R MF patients, continuing to boil the ocean first doesn’t make too much sense to me as I doubt we are looking at something like a thalidomide debacle for these patients. After all this time in trials, the risks versus extending their life is acceptable to most.

I guess so. That's maybe why we won't see a P3 in IMbark. That saves a lot of time...

If reversal of bonemarrow fibrosis is the result of imet tx, it would seem that splenectomy for sumptomatic relief could then be a viable option should this not occur with drug tx. I can’t beleive the drs did a splenectomy in the pt referred to in the op as this was taking away their only functioning source of blood cells!

It seems obvious that the future will see combination tx of Jakk inhibitors and imet in this dz to give both symptomatic and a slowing if not curative result. Approval for tx of the subset of responsive patients will be the first step in the right direction.