"...as potential partnering discussions continue to advance."
This truly is the one "wild card" in the mix that can't be construed as "baked in"...
Yours is not an easy question, but I have an opinion...
And that opinion is apparently shared by the market. No one knows. In addition to the direct competition in the space provided by the D & T combo, the paradigm has changed quickly and will continue to change as checkpoint inhibition immunotherapeutic technology matures. Cobimetinib is certainly a promising MEK inhibitor - but is it more promising than pimasertib, selumetinib, or binimetinib?
Only time and trial can say for sure... I think the uncertainty of the future treatment paradigm is the most telling obstacle to assigning valuation at this time, and analysts will not upgrade till they see revenue trends that bely clinical acceptance. JMO
I think I found an answer, though not what I expected to find...
I don't think the milestone has anything to do with the PI3k delta program...rather, I think it is payment for a P2 recruitment milestone in the collaboration between Sanofi/ Merck in ovarian cancer. That trial achieved full recruitment in Sept,2015, and is evaluating Merck's MEK inhibitor Pimasertib in combination with XL-765 - also known as SAR245409 - a class 2 PI3k/mTOR inhibitor. Results should review sometime in 2016.
In addition, I found another P2 Sanofi trial of which I was unaware that is evaluating XL-765 in combination with a variety of therapeutics. See NCT01587040...
...reported a $3M milestone payment at the last ER, yet I can find no pubs dated later than Nov 2014, when the NCBI recorded a Merck patent filing evaluation by Norman Consulting. Here's the abstract conclusion:
"The compounds appear to be XL-499 derivatives, some of which are more potent than XL-499. The compounds claimed by Merck are some of the most potent PI3Kδ inhibitors yet described but it is unclear whether a development compound has been identified."
That was a year ago. Has a patient ever been dosed under this PI3k delta program? Why the $3M?
"Thanks for the good news."
Here's the best part - the good news is not a part of the presentation. I figure we are less than 3 weeks away from an EC decision announcing the granting of an MAA for Cotellic. Statsig OS is icing on the cake. An EPAR will publish concurrent with the EC decision, and there is a high probability OS will be addressed in that assessment with corresponding survival benefit noted on the European labeling for combined Zelboraf & Cotellic. Timing couldn't be better...European marketing will hit the ground running with fresh updates in PFS, survival benefit, and biomarker correlates.
Last day, very end of the agenda...
"mproved overall survival (OS) with cobimetinib (COBI) + vemurafenib (V) in advanced BRAF-mutated melanoma and biomarker correlates of efficacy." - Victoria Atkinson 11/21/15. This presentation has wonderful potential. Doc Atkinson is published extensively in adv melanoma with recent authorings including the D&T combo, the V&C combo, updates on nivolumab - with peripheral reporting on treatment-related QOL issues.
Ernie, thanks for posting in depth here, as this is an issue continually coming to light as combo trials reach maturity. A recent posting to the NCBI wrt CNS demyelination as a result of Nivolumab infusion post Ipi in adv melanoma serves to warn of new adverse potentials in stacking checkpoint inhibitors, and I suspect we'll see more on this topic as therapeutic stacking becomes more commonplace. As always, best of luck...
"...that deal expiring in 2015..."
That's no longer correct. According to the 2Q Sobi ER, the deal is extended to Dec 2019.
Just a reminder, there are underlying issues wrt Cometriq marketing in Europe that stand to impact revenue structure in the near term. This SEC filing re-declares and redefines the SOBI agreement, which was set to expire in Dec 2015. I see the following as a very important excerpt:
"Named Patient Use Program
Through our agreements with Sobi, we have established the infrastructure to make COMETRIQ available globally upon physician request under a named patient use, or NPU, program in countries where the drug is not yet commercially approved. An NPU program provides access to drugs unapproved in that country, but approved elsewhere, for a single patient or a group of patients in a particular country."
The recent updated EAU guidelines highlighting Cabo as viable 2nd line therapy in post-VEGF adv RCC will enable evidence-based oncologists to prescribe Cabo within a defined infrastructure of healthcare coverage. I can't see this as a coincidental filing. EXEL knew where Cabo results were headed in mid-July, as only a month later they initiated an application for an accelerated assessment. An application that has succeeded.
A registered NPU program with the blessing of the EAU guidelines could make a significant revenue impact prior to RCC approval. Going forward, this is good news for both patients and shareholders. GLTA
From the SABCS website:
"OT1-03-18 COLET: A multistage, phase 2 study evaluating the safety and efficacy of cobimetinib in combination with paclitaxel as first-line treatment for patients with metastatic triple-negative breast cancer
Kim S-B, Miles D, Rhee J, Yan Y, Hsu J, Brufsky A. Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Mount Vernon Cancer Centre, London, United Kingdom; Genentech, Inc., South San Francisco, CA; University of Pittsburgh, Pittsburgh, PA."
Posted in today's (11/9/15) OncologyNurseAdviser - a little expansive discussion on the preclinical workup that has been previously discussed on this MB -
"New Therapy for TNBC Shows Promise..." By Kathy Boltz, PhD
"One target of cabozantinib is the MET protein, which drives many of the processes that make cancer aggressive and challenging to treat, including invasion of other tissues, proliferation, and survival of cancer cells. MET is overexpressed in 20% to 30% of all breast cancer cases, and is typically associated with a poor outcome. In a 2009 paper, Graveel and VARI's George Vande Woude, PhD, demonstrated that MET is expressed in triple-negative breast cancer and is a potential therapeutic target.
In addition, cabozantinib, discovered and developed by Exelixis Inc, is the subject of ongoing clinical trials in advanced kidney and liver cancers, and is approved to treat metastatic medullary thyroid cancer."
...the Way of the Future" posted on Onclivedotcom 11/7/15. Interview with Oncodoc Greg Riely:
"Right now, we have a couple retrospective analyses looking at a handful of patients which demonstrate that cabozantinib, crizotinib, as well as investigational drugs that are MET inhibitors, can lead to significant shrinkage of MET exon-14 skipping mutations. This is all based on biology where we know that MET exon-14 skipping leads to protein stability. Therefore, we need to study tumors in mouse models and in human systems, so we understand that the MET exon-14 skipping mutation matters, and we know that we can target that by a particular drug." Good discussion. Cabo gets mentioned a few times. As NCI MATCH data matures, I suspect Cabo treatment will find its way into varied aspects of the paradigm, perhaps with emphasis on bone involvement. JMO
"For a small company like EXEL, every possible detail possibly affecting competitiveness is a big deal..."
With that said - I'm expecting shareholders to get tossed a rare bone at next weeks' ER. It could be as simple as acknowledging acceptance of accelerated assessment for Cabo in RCC by EMA; as nebulous as some positive NCI P2 results ; as boisterously positive as the announcement of a productive JV. Even a a Celestial recruiting update would be constructive...
We're long overdue some management posturing in a direction of positivity...
Take a moment to consider the possibilities...
If Shkreli pulls a Hoffa...
...and Seymour pulls his Peter...
...and the President decides to be in attendance, and also decides to bring the First Lady...
Who encourages everyone to bring along swimming trunks for an open-bar poolside luncheon...
The Senate could witness the first ever...
Obama MamaYama Odd-Job Mob-Job Drunken Pharma Bro Poolside Peter Pull
Sounds somewhat historic...Seymour, et al on the History Channel...
Wouldn't yer Mama be proud, Seymour?
Heads up. Dec 9th could be a dark day for biotech...
I expect irreverence, conceit, and contempt...
JMO - I think the twirp needs a public spanking.
#1) Substantial OS improvement has been noted in RET 918T mutated MTC treated with Cabo.
#2) FAK inhibition with PF-562271 has been noted as a worthy component in resistance to Cabo therapy.
Both can be accessed thru PMC. From the MDACC SPORE study conducted by Chris Logothetis...
Sorry - all I've got time for today... GLTA
Put yourself in MMM's shoes. For the first time in the history of your 20-odd year old company, speculative value is on the verge of becoming structured revenue. It could become very real in the next couple quarters...
As a result, your drug development platform has the potential to be a player, your flagship drug is being taken quite seriously. What sort of questions must be satisfied before an outside deal is struck, and how willing are you to divulge value-critical information in a fickle market?
Subsequent to those thoughts...
If I am also correct in that we may see a recruitment spike in Celestial due to the recent successes of Meteor, it's also possible that we see the 2nd interim "peek" coming to maturity in 2016 as well. Good luck to everyone holding. We should have some big puzzle pieces in the coming week.