Why Imbark gets approved

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phil
Posts: 16
Joined: Wed Dec 09, 2015 2:53 pm

Why Imbark gets approved

Post by phil » Wed Sep 19, 2018 3:24 pm

While we all wait for JNJ to $hit or get off the pot, thought I might take a stab at why it looks like even though the MDS data should be significant, MF data will be superior and MF approval will be first and could come sooner than expected. I think the results in Imbark could be very good.

As opposed to conspiracy theories - no the Russians didn’t recruit Trump as an agent 20 years ago, and No, the shorts didn’t hack into the LinkedIn website, I will do my best to just look at the facts. If there is indeed some “approval” lurking, just remember the Imbark trial has three times the patients (roughly 105 vs 35) and has had them fully enrolled for nearly four times as long (roughly 24 month vs 6 months) as compared to Imerge, and therefor much more significant data for the FDA or Eu to gain approval.

I think Median Overall Survival MOS could be 30-36 months for the Imbark 9.4 mg/kg patients, and if so, that could lead to a fairly quick approval as it would triple life expectancy for R/R patients. How do I get that number, it’s just an educated guess, but here goes…

Let’s assume that there are three cohorts in Inbark: 9.4mg/kg, 4.7mg/kg, and those that switched from 4.7 to 9.4. It is possible JNJ and the FDA considers there to be just two, but I think (thinking back to Tefferi and the Mayo multiple cohort data) it has to be considered three, so let’s try that. As we recall from two years ago at the “hold” there were 45 patients in 4.7, 45 patients in 9.4 and 15 new patients in the enrollment pipeline that were allowed to go into the 9.4 cohort. Of the 45 in 4.7, those that were still in the trial, and that wanted to, could move to the higher dose- the crossover group.

So, lets assume 60 patients in 9.4, but we have to make an educated guess in the 4.7 group. Based on the fact that the MDS trial saw many drop, and because the 4.7 patients were not responding, I’m going to guess that maybe only 25 were left, and lets say 15 of those transferred over to 9.4. You can alter the numbers, but I’m probably pretty close, I usually am. So, we have roughly 60 in 9.4, 15 in crossover, 30 in 4.7. Just go with it for now, please.

Now let’s step back and take a look at how long these patients have been treated. A year ago I estimated that the median start date for the 4.7 patients was April 2016 and the median start date for the 9.4 was July of 2016 (later median start for 9.4 because of the 15 late enrolled patients at end of Sept 2016 into 9.4). The average overall start was then June of ’16. Fast forward to Geron’s announcement 19 months later that in January of 2018, yes, NINETEEN MONTHS AFTER JuNE ’16, that Median Overall Survival in all cohorts was at 19 months! None had yet hit MOS.

The preceding info and exercise was done to somewhat prove my numbers are correct, well, because, they usually are :-) So, good job, our numbers match, what does it mean?

Let’s now look at the 4.7 cohort. Why? Because we can work off those numbers in order to estimate what MOS we might see for the 9.4 patients. So, if in January ‘18, the 4.7 patients were in the trial roughly 21 months and the 9.4 patients were in for 18 months, that’s a good thing, not a bad thing as AE so stupidly misunderstood when he thought the 9.4 cohort wasn’t living as long as the 4.7 patients, they simply had not been enrolled as long!

I am going to be conservative and suggest that the “predetermined number of deaths” that happened in April was hitting the middle (median) death in the 4.7 cohort, meaning that the MOS of the 4.7 patients is 24 months, but it certainly could be longer. This is very important. Let’s look at this cohort that hit a MOS of 24 months (it can’t be less than 23, but could certainly be longer).

According to Geron, these 4.7 patients were NOT responding to the drug and that is why the 4.7 group was discontinued in Summer of ’16. These patients got half the drug, they probably dropped out at an alarming rate, therefore getting even less drug because many stopped infusing two years ago. It is possible only 10 or so in the 4.7 group got the drug after the hold! And think of this, those in that group that did respond, those that should possibly live longer and might make the 4.7 MOS metric longer, might well have migrated to the different crossover cohort, thus making the 4.7 MOS numbers worse. What I am trying to say is that this 4.7 cohort should NOT get very good results: They got much less drug, they got far fewer infusions, many stopped taking the drug, those that did respond, probably left that cohort, and yet, AND YET, they STILL MANAGED TO SuRVIVE 24 months!

So, if a group that really had everything going against it, did well at 24 months MOS, what do you think of a cohort that got twice as much drug, more infusions, and was KNOWN to have been responding well would get??? Those results must be better. They must be SIGNIFICANTLY better. I am guessing 30 to 36 months, and possibly, just possibly, more.

That’s my take,

phil

jpheis
Posts: 24
Joined: Thu Jul 27, 2017 2:55 pm

Re: Why Imbark gets approved

Post by jpheis » Wed Sep 19, 2018 5:10 pm

Phil- nice post. Thank you. I fully agree that MF gets approval first. The recent MF update on clinical trials.org indicates to me that significant impact was realized with 4.7, and perhaps there is a benefit for some/more compromised patients to start at 4.7 then escalating to the higher dose. Add to this the J&J slides on 9/13 where MF is listed at the New Molecular Entity while MDS is listed as a line extension(I posted this somewhere last week but it may have been on SA). All points to strong MF results and MF approval first.

biopearl123
Posts: 353
Joined: Fri Jul 20, 2018 5:13 pm

Re: Why Imbark gets approved

Post by biopearl123 » Wed Sep 19, 2018 5:51 pm

Hi Phil, very nice synthesis and summary. Agree that all signs point to imminent MF approval. No plans for a phase III R/R study says a lot in a study that had to be extended because of the surprising extension of MOS. I imagine a front line study will follow but at least the drug would be on the market for MF. bp

j6proulx
Posts: 23
Joined: Mon Jun 25, 2018 10:20 pm

Re: Why Imbark gets approved

Post by j6proulx » Wed Sep 19, 2018 6:26 pm

Regarding the effectiveness of various doses of imetelstat, I have been impressed with the responses of the MDS patients, for example, as shown on Slide 11 of the EAH presentation from June (https://www.geron.com/file.cfm/53/docs/Imetelstat-IMergePart1-EHA-2018.pdf). The dot represents a dose of 7.5 mg/kg, the triangle identifies 6.0 mg/kg, and the star shows the 4.7 kg/mg dose. Two of the four patients shown on this slide are on the 4.7 mg/kg dose for extended periods with the transfusion independence maintained (12 weeks for one patient and 22 weeks for the other). This slide demonstrates to me that they have a handle on how to adjust dosing and administration to manage adverse events, which will only make future trials more successful (assuming earlier trials may have suffered from patient withdrawl due to adverse events, which are now being effectively managed through dose adjustment).

huntingonthebluffs
Posts: 152
Joined: Wed Feb 24, 2016 12:00 am

Re: Why Imbark gets approved

Post by huntingonthebluffs » Wed Sep 19, 2018 9:14 pm

Phil, thanks for putting music to the numbers in detail. You have further opened the window into how JNJ/Janssen have managed to turn what appeared to become a lemon of a CT into lemonade. They have likely confirmed the powerful capabilities of Imetelstat and finally paved the way to commercial use for the thousands of patients in need. Your thoughts (and j6proulx) on dosing also help to continue opening up many ideas regarding how to treat patients depending on their condition and hopefully types of mutations. Except in cases of fraud, companies usually don’t keep secrets unless the news is good, so I suspect we are on the verge of breath taking news regarding the many finding coming out of the trials.

Saltrock
Posts: 1
Joined: Tue Sep 18, 2018 3:18 am

Re: A question

Post by Saltrock » Thu Sep 20, 2018 12:56 am

I'm hoping one of you may be able to answer me. First of all has JnJ filed an NDA based on either of these 2 clinical trials Imerge or Imbark? I know there has been speculation about this happening. And I have looked for past CTs especially in cancer therapies where an NDA has been filed based on phase 2 success. I haven't been able to find one. Is it a possibility that we could get an FDA approval without a phase 3 CT?

And finally just a comment, I am grateful to have found this forum where emotions are contained and insightful wisdom is shared. I want to believe we are all hoping for the success of imetelstat but name calling and pie in the sky dreamers do not provide anything more than noise.
Thanx
Saltrock

biopearl123
Posts: 353
Joined: Fri Jul 20, 2018 5:13 pm

Re: Why Imbark gets approved

Post by biopearl123 » Thu Sep 20, 2018 3:09 am

Salt rock, thank you for your kind words regarding this forum. Fortunately I have only rarely had to exercise my privilege as moderator regarding content and then only with warnings. I have thus far have not had to ever exercise censorship. (But I will if anyone tries to post irrelevancies or ad hominem attacks). To your questions. As far as I know an IND was filed and accompanied the Geron transfer of study stewardship to J and J. As far as NDAs, well, these have been shrouded in secrecy and many have asked whether a company is obligated to make this filing public. Near as I can tell they don't (presumably for competitive reasons) and Geron/Janssen certainly have been secretive about this which to me is a case of deafening silence suggesting, especially in light of what appears to be a clear path to approval, that they have or at least will shortly. Regarding approval after P II studies. Yes, it has happened. I called this to the attention of Lsv. on the SA boards within the last year but it is rare. In the case of end stage MF patients the ethical considerations of trying to have a double blind placebo controlled study are pretty clear and have also been addressed in previous articles again suggesting that the current study structure should be adequate for the FDA. Hope this helps. While the R/R study "failed" to achieve its primary end point of SVR (spleen volume reduction), as MTB and others have pointed out on SA this did not derail the study and may still provide as yet publicly unknown endpoints re symptom reduction and late spleen volume reductions. What is known is that a meaningful MOS improvement exists. Phil's great post outlines all of the reasons we might anticipate MF approval well before MDS. In MDS its pretty clear that the path forward will require a P III study which is on the launch pad, but AA certainly could apply for MDS. I think outright approval for MF is a strong possibility but I have gotten push back from some of the most respected posters in this regard before so I remain humble. Regards, bp

j6proulx
Posts: 23
Joined: Mon Jun 25, 2018 10:20 pm

Re: Why Imbark gets approved

Post by j6proulx » Thu Sep 20, 2018 3:36 am

Timely question. Janssen is certainly willing to try:
https://www.janssen.com/janssen-submits-new-drug-application-us-fda-seeking-approval-erdafitinib-treatment-metastatic
"HORSHAM, Pa., Sept. 18, 2018 -- The Janssen Pharmaceutical Companies of Johnson & Johnson announced today that a New Drug Application (NDA) has been submitted to the U.S. Food and Drug Administration (FDA) seeking approval of erdafitinib for the treatment of patients with locally advanced or metastatic urothelial cancer (UC) and certain fibroblast growth factor receptor (FGFR) genetic alterations whose tumors have progressed after prior chemotherapy. <snip>
"The NDA submission is based on data from the BLC2001 (NCT02365597) Phase 2 clinical trial, which evaluated the efficacy and safety of erdafitinib in the treatment of adult patients with locally advanced or metastatic UC, whose tumors have certain FGFR alterations. The primary endpoint of this study was the percentage of participants with objective response, defined as Complete Response or Partial Response based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1* criteria. The study results were recently presented at the American Society of Clinical Oncology (ASCO) 2018 Annual Meeting in Chicago (Abstract #4503) and were recognized as a "Best of ASCO" selection."

In fact, Janssen has achieved FDA approval based on Phase 2 studies a number of times, including this:
https://www.jnj.com/media-center/press-releases/us-fda-approves-imbruvica-ibrutinib-for-the-treatment-of-waldenstroms-macroglobulinemia-first-fda-approved-therapy-for-this-disease

Back in July, I posted information about two articles writted by a top FDA oncology official, on the topic of the FDA's philosophy of supporting NDA's based on something short of full Phase 3 trials with control arm, especially for indications with no alternative therapies when the prospective drug shows great promise, with high response rates and sustained responses in early clinicals:
http://imetelchat.imetelstat.eu/viewtopic.php?f=1&t=690

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