Thoughts on this week's presentation

[biopearl]

Thoughts on this week's presentation in no particular order or organization, in other words if you read this prepare yourself for some chaotic thinking, others are welcome to modify, criticize.

1. We can glean that the marker that allowed for the decision to drop the 4.7 arm was HI (hematologic improvement). This would have shown up early and would not require bone marrow studies or major spleen effect. We know that Dr. T has stated the effect in MF is deeper or more profound than in MDS and in MDS there was an impressive alteration in TI between 30 and 50%. HI should address the FDAs need for a surrogate marker for drug effect.

2. Even 10% improvement in spleen volume is associated with an improvement in survival. Its not about spleen effect for approval, that is a byproduct of targeting the malignant clone. Get over the pursuit of 35% spleen reduction in R/R population. But (implied) improvements in bone marrow in some patients has been seen (don't know if this applies also to R/R patients because we don't know if they have had BM bx). The marker however is HI and this is where the action is. If there is HI, one could assume symptom improvement and improvement in hematologic parameters and reduction in transfusion requirement. Scarlet said "it does happen" (re bone marrow clearing) not it "has happened"(which we know). Small tense issue but it suggests a more current view.

3. Lots of patients on Imetelstat for 3+ years. This can only apply to the pilot study (unless some patients from the old ET study are still on Rx and we don't know that.) If so more evidence for survival effect.

4. FDA has asked for MF info not because there is trouble but because they wish to consider BAT/accelerated approval.

5. If granted, drug approval in R/R could precede the anticipated "continuation agreement". In other words get over holding your breath for the Janssen agreement, this is likely to happen. Its really about FDA approval which may antedate action by Janssen.

6. All those disclaimer about how things can change are always (and usually are) thought about as negatives. In this case timing could change in favor of the drug and the timelines could be revised.

7.OS looks good and is the gold standard, especially in a population with a life expectancy so short. The antecedent bar for spleen reduction must be revised in light of new data in a heretofore unstudied population. FDA knows this.

8. Patients have remained in the 4.7 arm for reasons we don't know but presumably showed something, but not as profound as the 9.4 group which is the "right dose".

9. They are looking for survival effect in MDS as well and think they will find it.

10. Targeting the malignant clone is unique to Imetelstat and address a very primary etiology of the disease.

11. A disconnect between the "continuation" agreement which everyone is holding their breath for and FDA approval for R/R could be real in favor of an approval time line.

Best Regards, and good luck to all bp

[Dogonenuts]

Bio, thanks for the summary and thoughts. I listened to the webcast, and my impression was that Scarlet seemed a lot more confident when referring to JnJ than he has in a long time. I think he knows we have a winner on our hands. It is just going to be a matter of how big a winner. I am an MD, but it has been a long time since I studied hematology. I appreciate all those that have more knowledgable input here.

By the way, I have never been accused of being a pessimist. Dr. T's news at ASH back a few years got me invested heavily here. I never dreamed it would be this long a wait with so many disappointments. It does feel like we may be on the cusp of a break in our favor, finally.

[biopearl]

Dogonenuts, Disclaimer: I am not even close to being a hematologist or oncologist just a humble student of this very interesting space. bp

[biopearl]

As we come into ASH, it is worthwhile to listen for the words the FDA loves. One couplet is "disease modification". While we have seen this suggested for MF, other than the emphasis on TI, we have not heard too much about it in MDS. Disease modification via direct proof or via surrogates is woven into the FDA approval regs as something highly valued especially with regard to BAT. Since the overall mechanism of action for Imetelstat is to target the malignant clone and since the mechanism of action for Jakafi is to not, this will very likely be a place Janssen will highlight, its just a question of when they choose to do so. The mystery as to why the continuation agreement is coupled to life expectancy in MF is that the this selfsame invisible thread is connected to MDS with a tacit expectation of improvement in life expectancy as well, they just haven't said it. The same could be applied to AML. Jakafi may show some modest improvement in LE and certainly can improve symptoms and spleen volume in some but it does not target the malignant clone, the grinding driver of this genre of diseases. Imetelstat is truly transformative for this reason and with combination therapy may be one step closer to cure or at least control. Am still holding out irrational hope for a late breaker re R/R study. bp

[biopearl]

My apologies for getting anyones hopes up unnecessarily. There is no late breaker I can find. Since FDA did ask for information I hope the conclusion that it was to evaluate for accelerated status is correct. Best wishes, bp

[Fishermangents]

Thanks for sharing your thoughts, bio. Always appreciated.

[biopearl]

Reference courtesy of Sargasso:
http://bit.ly/2jP8aPy

[Fishermangents]

Interesting article. It says in the conclusions:
'In conclusion, drugs in oncology achieving BTD are those in which an approximate doubling of OR or PFS rates compared with control arms and a reduction of HR by approximately half are achieved in either the single-arm or double-arm setting. The setting for these clinical trials can be early (phase I or II), and these trials may incorporate large safety and efficacy components that may serve as the basis for pivotal trial registration. A BTD drug must be both safe and tolerable according to standard FDA criteria.'

OR = Objective Response (= proportion of patients with reduction in tumor burden of a predefined amount)
PFS = Progression Free Survival (= time from randomization until disease progression or death)
HR = Hazard Ratio (= the relative risk of a complication based on comparison of event rates, typically used in the context of survival over time: if the HR is 0.5 then the relative risk of dying in one group is half the risk of dying in the other group.)

So this roughly outlines the requirements for a drug to achieve BTD.

More info about end-points:
https://www.biooncology.com/clinical-tr ... oints.html