In melancholy tone, CEO Scarlett stated that, "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..."
Balderdash I say!!!
CEO Scarlett knows full well Mayo Clinic's Ayalew Tefferi, M.D. already established that MF recovery just begins to start at week 12, and it is optimal only when patients reach the week 24 mark. Suggesting any information about efficacy before this throws imetelstat under the bus.
So why did CEO Scarlett showcase the 12 week data as a failure when he knows that CR's are established to occur only at the 24 week mark? Was he trying to feed Adam Feuerstein false information so Adam could shoot down imetelstat at 9.4 mg/kg and call it a failure?
I think Adam knows very well the CRs identified by Mayo Clinic's Ayalew Tefferi, M.D. are real. Adam was just trying to shoot down imetelstat because it only saves the lives of 20-30% of patients and has to be respected properly for toxicity like all chemo.
For proof of the 24 week time point requirement, go to video "Current Developments in Myelofibrosis Treatment", start at minute 22, go to graphs of the two CR patients presented. It is very clear that MF recovery only begins at week 12 and is optimal ONLY AT THE 24 WEEK MARK.
The questions asked during the conference call were sophomoric at best. No one challenged CEO Scarlett about how legitimate his comments about efficacy at 12 week were light of the established Mayo data proving 24 weeks is the proper time frame. None of the callers asked about Geron's viability and the JNJ collaboration if myelodysplastic syndromes (MDS) succeeded alone.
Finally, Janssen's absence is an outrage. Imetelstat is very much a medicine meant to be paired with a subpopulation of patients using biomarkers associate with efficacy. Instead, Janssen is trying to apply the "one size fits all cut-off rules" of the past when we know the mystery is why only a subpop. benefits
Opt -In rights for the develop and commercialization of imetelstat worldwide for ALL INDICATIONS, INCLUDING HEMATOLOGIC MYELOID MALIGNANCIES, AND ALL OTHER HUMAN THERAPEUTIC USES. NOTE: This includes imetelstat delivered by liposomes or by other means for pancreatic and other cancers.
-Buyer pays 20% of costs or provides 20% of US selling effort with sales force personnel and Janssen pays the remaining 80% of costs.
-Buyer gets a $65M payment from Janssen for continuation.
-Buyer gets $470M in dev/reg milestones from Janssen.
-Buyer gets up to $350M in sales milestones.
-Buyer gets royalty from mid-teens to low twenties on worldwide net sales for ALL INDICATIONS IN ONCOLOGY, INCLUDING HEMATOLOGIC MYELOID MALIGNANCIES, AS WELL AS ALL OTHER HUMAN THERAPEUTIC USES
-In addition, both we and Janssen may propose to the joint development committee imetelstat development for any new indications not then provided for in the joint clinical development plan and if we and Janssen agree such development should be conducted outside of the joint clinical development plan, both we and Janssen would be entitled to independently undertake such development at the developing party's own cost, subject to the other party's obligation to provide reimbursement for its specified portion of the development costs plus a premium following marketing approval of imetelstat in such newly proposed indication as a result of such independent development. In the event that we do not exercise the U.S. Opt-In Rights following Janssen's Continuation Decision, the joint governance structure under the Collaboration Agreement would be dissolved, a joint oversight committee would monitor the progress of the collaboration, and we would have no further rights to conduct any independent imetelstat development.
Sentiment: Strong Buy
There is no way Geron could develop a new drug candidate(s) without massive dilution, so this new Janssen agreement is all gravy. All gravy indeed.
Also, new telomerase inhibitors that would compete with imetelstat as well as all bone and blood cancers are off-limits to Janssen when using Geron's technology, so Janssen is married to imetelstat as a telomerase inhibitor and for all bone derived cancers.
Geron is sitting pretty if the imetelstat results are good. They can even get in on imetelstat 2.0 in liposomes.
But, the wild card is the opt-in rights. This will give Chip bargain power for the buyout endgame.
"If we exercise the U.S. Opt-In Rights, then we and Janssen will share U.S. development and promotion costs on a 20/80 basis (Geron 20%, Janssen 80%), we will receive a $65 million milestone payment at the time of the Continuation Decision, and will be eligible to receive additional potential payments of up to $470 million in development and regulatory milestones, up to $350 million in sales milestones, and tiered royalties ranging from a mid-teens up to a low twenties percentage rate on worldwide net sales of imetelstat in any countries where regulatory exclusivity exists or there are valid claims under the patent rights exclusively licensed to Janssen."
The sponsor of both trials is legally assigned to: Janssen Research & Development, LLC.
CEO Scarlett had no authority to conduct a conference call. He had no business doing this.
Janssen should have put out a press release themselves simply stating that the 4.7 mg/kg dosing arm is proving inferior to the higher 9.4 mg/kg and will be discontinued with the low dose patients being given the option to move to the higher dose if their physicians advise.
Chip's 8a.m. Monday morning threat released on a weekend was uncalled for.
There was absolutely no reason for him to comment about efficacy know his comments were premature for 12 weeks data.
He crashed the PPS knowing full well a response would not be expected until 24 week (the established time frame) based on Mayo's data and the Janssen trial design.
It makes you wonder who CEO Scarlett is working for and why he wanted the PPS to crash.
Geron's oligonucleotide drug technology is the imetelstat "chassis"
What does Janssen get with the imetelstat "chassis"?
They get the following:
1. Enhances binding affinity of therapeutic RNA to its mRNA target
2. High resistance of therapeutic the RNA to resist cellular nucleases
3. A lipid conjugated to the therapeutic RNA that improves cell permeability of the therapeutic RNA
***4. ALERT Sen H. Zhuang MD, PhD Vice President Janssen Onco Clin Res is HIGHLY LIKELY to put the therapeutic RNA (including imetelstat in an agreement with Geron) in an immunoliposome delivery system based on past Zhuang et al. publications and Janssen's current liposome technology on the market.
Janssen Pharmaceuticals gets exclusive worldwide rights for the development and commercialization of the imetelstat "chassis" based on Geron technology, excluding the therapeutic RNA built on this "chassis" which we all know as "imetelstat":
In other words:
1. Janssen cannot make new imetelstat-like therapeutic RNA therapeutic targeting cancers originating from the blood or bone marrow which is currently the focus of the imetelstat agreement
2. Janssen cannot make a new imetelstat-like telomerase inhibiting RNA therapeutic because they are currently under an agreement which uses imetelstat for this purpose
This is a real committment:
"Janssen Pharmaceuticals is required to use reasonable efforts to perform research, development and commercialization activities to obtain at least one licensed product to be researched, developed and commercialized under the License Agreement, at Janssen Pharmaceutical’s sole cost." AGAIN: Sen H. Zhuang MD, PhD Vice President Janssen Onco Clin Res is HIGHLY LIKELY to put the therapeutic RNA (including imetelstat in an agreement with Geron) in an immunoliposome delivery system
Competition: "Alnylam’s RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNA, thereby preventing disease-causing proteins from being made.
I respectfully disagree with you, and I think you are aware this was a setup for someone to short GERN. You are attempting to paint it with innocence.
CEO Scarlett said the MF trial, even at the 9.4 mg/kg is currently failing, knowing full well Tefferi's CR data for MF demonstrated improvement only at 24 weeks.
It was as if CEO Scarlett said, "Investors would lose all of their money if we used today's data, but just maybe tomorrow might be different if we wait until the the 24 week point...but don't hold your breath folks...the trial could be terminated all together...we must wait and hope."
All he needed to say was the 4.7 mg/kg is behind 9.4 mg/kg based on current metrics and the low dose will be discontinued with the option of low dose patients to convert to high dose which is showing safety in line with Mayo's findings and better metrics. That's it.
He did not stop there though, did he?
CEO Scarlett planted a seed of doubt by trying to interpret the 9.4 mg/kg efficacy data at a premature time point of 12 weeks which is already established to be too early, which is especially true in this more experience Janssen trial population. CEO Scarlett did this knowing the positive signal would not appear until 24 weeks. Yes, he mentioned more time was important, but he stated the current data would fail at today's point in time.
Planting this negative spin crashed the stock PPS, and anyone with any knowledge of the market would have expected this to happen. Why Janssen and JNJ allowed this negative spin, I do not know, but they did approve it no doubt.
This was a perfect "go short" opportunity for someone out there. Do not pretend otherwise. This was not an innocent statement of fact. It was a seed of doubt without proper context or explanation.
The damage is done.
Now, the next question is why Janssen did not show up and explain why they are not moving forward with the biomarkers to pair with imetelstat patient success????
Sen H. Zhuang MD, PhD
Johnson & Johnson
Head of Hematology Clinical Development
Oversee the global development of ibrutinib, daratumumab, IMETELSTAT, and other emerging late stage compounds for hematologic malignancies
NOTE THE ACTIVITY OF DR. ZHUANG'S RESEARCH WITH LIPSOMES.
Sen H. Zhuang MD, PhD was a co-author of:
"Efficacy and Safety of Pegylated LIPOSOMAL Doxorubicin in Combination With Bortezomib for Multiple Myeloma: Effects of Adverse Prognostic Factors on Outcome"
"Pegylated LIPOSOMAL Doxorubicin Plus Docetaxel Significantly Improves Time to Progression WITHOUT Additive Cardiotoxicity Compared With Docetaxel Monotherapy in Patients With Advanced Breast Cancer Previously Treated With Neoadjuvant-Adjuvant Anthracycline Therapy: Results From a Randomized Phase III Study"
This was a bold statement by CEO Scarlett:
Janssen saw the 12 week initial data, and CEO Scarlett made a specific point of telling us that Johnson and Johnson now wants to showcase part 1 of the results of Imerge at a medical conference.
You can find this statement at min 10:50 of the Conference Call given at 8:00 a.m. EDT on September 12th, 2016.
The title of Imerge is: Study to Evaluate Imetelstat (JNJ-63935937) in Subjects With International Prognostic Scoring System (IPSS) Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS).
Keep in mind, the Imerge dose is a lower dose than that being administered for MF. For Imerge, it is 7.5 milligram per kilogram (mg/kg) given intravenously every 4 weeks instead of 9.4 mg/kg every 3 weeks for MF.
It is nice to see we will finally have the Johnson & Johnson brand on imetelstat and the MDS indication will help a lot of patients as it will some of those (20-30 percent) with MF.
Myelodysplastic syndromes (MDS)
12,000 cases diagnosed per year in the US
60,000 people in the US living with MDS
Anemia is predominant clinical problem in lower risk disease (70%)
Drug therapies for lower risk patients with anemia: ESAs, lenalidomide, HMAs
In this design the subjects detected to have received inferior treatments at the interim analysis can be dropped out. Based on the findings of the interim analysis, additional treatment arms can also be added at this stage. This design is useful in Phase II clinical development, especially when there are uncertainties regarding the dose levels. Typically, drop-the-loser design is a two-stage design. At the end of the first stage, the inferior arms will be dropped based on some pre-specified criteria. The winners will then proceed to the next stage. Some prefer to term these designs as pick-the-winner designs."
Biom J. 2005 Jun;47(3):257-68; discussion 269-81.
Indian J Pharmacol. 2010 Aug; 42(4): 201–207
So, apparently the 9.4 mg/kg dosing arm's encouraging trends in efficacy data was sufficient to pick it as the WINNER in the "Drop-the-loser design".
Not only this, but Janssen thought the data was good enough to encourage the 4.7 mg/kg patients to switch to 9.4 mg/kg. So "encouraging trends in the efficacy" would have to be substantial to make this request.
A marginal improvement might justify continuation of the 9.4 mg/kg cohort. But asking the 4.7 mg/kg patients to cross over to the high dose suggests more than simply encouraging.
What did Janssen say, "Doc, the low dose arm sucks, but the high dose arms sucks less...interested in crossing your low dose patients over to the high dose???"
Probably not, Janssen probably said, "Doc, the high dose signal is convincing. We highly recommend crossing your low dose patients over to the high dose?"
I am not sure the safety committee would allow the trial to even continue if there was no efficacy. Asking patients to move to a higher dose is a bold move.
The FDA, Geron, and Janssen are likely working toward approving imetelstat for 15 to 20 percent of myelofibrosis patients paired for success using biomarkers (ASXL1, SF3B1/U2AF1, among others come).
Times have change. We live in a combination, personalized medicine world and recognize cancer as being plural (many diseases under any label) and dynamic. Old school silver bullets are out, and personalized combinatorial shotguns are in, with long acronyms like "FOLFIRINOX". Biologics, microbes, and gene editing are on the horizon.
It does not help when a CEO invokes an old clinical trial mentality by saying, " an insufficient number of patients met the protocol defined interim criteria". What, we only cured 15% so far? I guess there is a cutoff for the significant of one person's life. Wall Street likes silver bullets, and Scarlett, especially at the 12 weeks, knowingly damaged GERN PPS...for what end we do not know.
Janssen is aware of using liposomes to put chemo on target. This, however, would be gold that they do not want to share. My best guess is Janssen will walk away with imetelstat on the cheap and then work on liposome delivery for MF but also pancreatic cancer for which imetelstat has shown efficacy in cell cultures.
There is a solution to the toxicity problem (liposomes) that CEO Scarlett is being coy about. His melancholy is an act. Unless we see dramatic changes in his actions, I agree, he is just a do nothing, greedy guy who will go for his own wealth with JNJ, while letting shareholders eat cake. I do not sense any hustle to or drive in him. He acts sullen or depressed. If he is battling depression, he needs to get help because we are dealing with life and death of patients when it comes to imetelstat.
Imetelstat is potent an must be put on target.
JNJ intends to do just that!
Sentiment: Strong Buy
These findings suggest that combination therapy of imetelstat and DNMT inhibitors may have synergistic anti-leukemic efficacy in high risk AML patients. Blood 2015 126:1267
"Janssen has an industry-leading pipeline in heme malignancies," Pamela Van Houten, a spokeswoman for Janssen, told BioWorld Today. "The addition of imetlestat strategically complements our growing myloid portfolio, including Dacogen [decitabine]," a Janssen-backed therapy approved for the treatment of patients with myelodysplastic syndromes in May 2006.
Sentiment: Strong Buy
Janssen see something they like.
The number of nucleotides they put on to the imtelstat chassis is up to them 13, 20, 25, whatever.
It should function for RNAi.
There are other possibilities as well....instead of RNAi to take it out, how about mRNA to put it in?
Messenger RNA (mRNA) Therapeutics™ hold the potential to transform medicine across multiple drug modalities and therapeutic areas. As the first mover and leading company in the space, our responsibility is to simultaneously advance promising internal development programs, while also mobilizing an entire ecosystem capable of propelling the field forward for patients."
Janssen knows this and plans to put imetelstat on target by liposome delivery.
" Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors."
Sentiment: Strong Buy
"Compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, multilamellar vesicles and the like. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, phosphatidylcholines and the like."
Sentiment: Strong Buy
The Janssen trial MF patients are sicker than the ones who participated in Ayalew Tefferi, M.D.'s imetelstat trial at Mayo, and you think it is appropriate for CEO Scarlett to indulge in interpretation of efficacy at 12 weeks when Dr. Tefferi demonstrated that his CR patients took 24 weeks to reach improvement. The same patients you are saying are not ask sick as the Jansssen patients?
What CEO Scarlett did with these eleven words: "an insufficient number of patients met the protocol defined interim criteria", in reference to the MF patients on high dose, was reckless. It casts great doubt on the ongoing imetelstat trial, so much so that it could influence a low dose patient's decision to convert to high dose. The trial now relies on these patient converting to high dose to address the statistics needed to prove the data is a success.
You do not see a problem here because there certainly is one.
It will take more time.
Trust Irishtrader52 on Wed Sep 14, 2016 1:06 pm.
"Clinical trials with telomerase inhibitors have established telomerase as a viable target, but the time lag between drug administration and clinical response is long. Continued treatment is required for successful clinical outcome...." -Genome Medicine20168:69, Department of Cell Biology, University of Texas Southwestern Medical Center
Scarlett knows it will take more time, but he and Janssen chose to deceive to push the PPS down.
The trigger statement:
"an insufficient number of patients met the protocol defined interim criteria".
Why choose to opt-in?
Much higher world-wide royalty, and if Geron does not opt-in they will have no further rights to conduct any independent imetelstat development.
This is why they need to sell the opt-in rights to another big pharma or opt-in themselves because the mega pay will come when imetelstat is put in a liposome for delivery to put 95% of drug on target for higher efficacy and much better management of side effects.
Sentiment: Strong Buy
This was CEO Scarlett's communication objective for Monday Sept 12th: "an insufficient number of patients met the protocol defined interim criteria"
Damage done. Mission accomplished.
Now why he communicated this very premature and reckless statement is the question, but the damage is done.
The "opt-in rights" finish line and buyout is in sight!
Liposomes on the way too.
Enjoy the ride...