"Takeda Pharmaceutical Company Limited they once were talking to them for an Asian market connection.If I remember correctly."
Takeda has frequently been mentioned as a possible geographic partner. We could see a geographic partnership or a monetization of the GDC 973 asset. Toward mid 2014, they will have made a big dent in the cash hoard and be looking for fresh capital.
Not sure who it belongs to...
Kazuhide Nakamura, Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 2-26-1, Muraokahigashi, Fujisawa, Kanagawa, 251-8555, Japan
Guess that answers that q.
"....too much of coincidence. Don't you think?"
Not sure who it belongs to, but it is a different compound.
"Ernie, what's your opinion about the likelihood of JNJ or Astellas making a bid for EXEL in light of JNJ's recent acquisition?"
It's been a while since I've given much thought to EXEL takeover. It's obvious that the long term goal here is to sell the company. There is no R&D left to backfill the pipeline. I think there was a window for 5-6 months following the initial presentation of the 19 of 20 BSR's back in 2010/2011. We will probably never know how close we came to being sold, but the deal did not get done and EXEL set us on this path to prove the commercial viability of the XL 184 asset. I think we are always "for sale" for the right price, but my feeling is that we need to see some of the pivotal results due out in 2014 before we enter another window of opportunity for a deal getting done. The acquirer will be a large player and Cabo will fit into their oncology portfolio of products without cannibalizing any existing products. That eliminates a few companies, but not many. I do not see J&J as being any more or less likely than any of the other large oncology players.
Regarding Cabo pre-chemo. It is a rapidly changing landscape, Abi and MDV will hold the high ground for a while, but there are more drugs coming plus different combinations. Moving a drug into earlier indications is a way to greatly enhance commercial potential, but EXEL is not the only company strategically looking at various drug combinations in order to move pre-chemo. The revenue potential makes it an attractive prospect worth exploring, but I see other opportunities that may have a better risk/reward profile. It hasn't been hardly discussed, but there are three NCI sponsored randomized trials about to start in frontline RCC, Ovarian and Uveal melanoma comparing Cabo to Sunitinib paclitaxel, and Temo respectively.
Cabo may be the current forerunner in TKI cMET inhibition, but the recent advent of "breakthrough designation" may potentially make the FDA decision-making policy the other "gorilla in the closet" we'd want to be wary of...
First, read the following and you will perhaps see the attraction for J&J. "Is ARN-509 (Aragon) potentially better than MDV-3100 (Medivation) in advanced prostate cancer?"
Here's my read on consensus thinking. MDV 3100 has a big advantage over abi because it does not require concomitant steroids. Besides having their own SA profile, steroidal use causes many to question the advisability of abi in combination with Provenge or any upcoming other immunotherapy drugs. Sequential use of abi/MDV or MDV/abi has been disappointing. The KOL's are hopeful for an abi/MDV combination. I think Bif nailed it, J&J would rather see a proprietary Abi/ARN combo, or if abi is supplanted by an AR antagonist, they would prefer for it to be by a drug in their pipeline vs MDV.
This really does make moving Cabo into a pre-chemo combination a bit more problematic and we haven't even looked at TAK 700 yet. The refractory space that EXEL is staking out isn't going to move and the double trial design is going to put a formidable moat around Cabo's indication, assuming the two Comet trials are successful.
"Ten investigators for a handful of patients seems unusual to me."
Resume building. When the trial is over, they will all be coauthors when the results are published.
"1) What are your hot leads besides EXEL?"
I'll politely decline. I'm not comfortable with this. From time to time I have offered opinions on stocks, ONTY, DNDN and ARQL negatively, and I did post my speculative buy and sell on DVAX, but the older I get and the more I see, the less inclined I am to give specific recommendations or endorsements.
"Hope you are enjoying your summer thus far."
Well thank you I am, but you're still a snake. That aside, I don't wish you ill and hope your summer is going well also.
I occasionally see comments regarding the moral correctness of investing in companies that seek to develop cancer therapies. Investing is about making money, not doing charity work. Besides, take a look at the perks CEO's and BoD's give themselves and then decide if their first priority is improving patient outcomes or enhancing their own lifestyle. This isn't like rooting for the Seahawks, Giants, or Fortyniners. We give them our favorite sports team some degree of loyalty and tolerance for failure. We should hold our investments to a much higher standard and on a daily basis question whether they still merit inclusion in our portfolios.
I am frequently chided for being pessimistic and overly negative. I don't have a problem with this. I visit other biotech mb's from time to time and try to keep up with industry gossip. I take a particular interest in watching a train wreck in slow motion. I've followed Biomira/Oncothyrion for over a decade and my interest in that company is what gave me my first look into cancer immunotherapy. Several years ago I came to the conclusion that they were on the wrong track. History has validated that opinion twice, yet somehow the company manages to survive and recapitalize. I also watched the recent DVAX debacle. The company crashed after a bad Adcomm recommendation inconsistent with FDA's briefing documents. I traded into the stock on that basis. I did more research, came to the Adcomm's point of view, and cashed out with a nice profit. Still following the stock, I noted inconsistencies and oddities in the company's public portrayal of events, yet the stock crept back up. This was a case in which the outcome was swift and predictable when the full story finally came out.
I'm rambling, but here's my point. Train wrecks in biotech happen all the time. Watching the mb's as they occur is enlightening. Lot's of disbelief, denial, finger pointing (usually blaming FDA), but rarely an acknowledgment that the result was foreseeable or that the poster made a misjudgment and shared in the responsibility for his/her loss. My takeaway lesson from this is that as an investor, I need to be more of a watchdog than a caretaker or curator. Biotech CEO's enjoy a great lifestyle and will aggressively tell the best story they can to keep the investment dollars coming. Hiding data, telling half truths, and sometimes outright lying are all too common in the industry. If you are going to be successful, think of yourself as a sheepdog, your account as the sheep herd, and the CEO's doing the conferences are the wolves trying to steal your sheep. I have more...
"1) The PSA levels of patients who respond to Cabo don't show a decrease as with the AR pathway inhibitors. Why?"
Cabo PSA response is erratic. Some patients do have a PSA response, some level off and some progress. Overall, my impression looking at the scatter plot, was that Cabo had a positive effect on PSA, but it was not consistent and did not uniformly correlate to other markers of efficacy. So, be careful about generalizing. The question is not why don't patients have a PSA response it is rather, why do only some patients have a PSA response and why do some patients with obvious antitumor activity not also have a PSA response?
"What is going on in the cell when it develops Cabo resistance?"
Great question and I have not seen it discussed to any degree. I did see one slide that showed an observation that Cabo treatment appears to leave a core of relatively unaffected tumor cells that forms the basis for disease reemergence when resistance occurs. It was actually Dr. Legothetis who showed the slide at another conf.
"I would imagine that there is this cooling of KOL sentiment for Cabo in monotherapy if the OS benefit really is as small as about 1 month."
Let's roll the clock back a few years, to when the bone scan phenomenon first emerged. The first obvious question that popped into everyones' minds "Is it real?" Next thought would be "If it is real, how long does it last?" I think the first question is answered in the affirmative, although not to everyone's complete satisfaction. And I think the second question got answered at ASCO. The 10.8 month OS put a cap on the BSR benefit at 3-4 months of survival in terms of median OS. Some patients may push considerably further out on the right side of the curve, I hope so. I think 3-4 months is a bit disappointing and deflating. When the first 20 before and after bone scans were presented in the fall of 2011, I think consensus expectation was for a more durable outcome.
"Which makes me wonder, what determines when patients halt abiraterone treatment?"
Great observation. The intended use part of the label does not address this question, so the logical fallback is to mimic the pivotal trial use instructions, which were:
"Patients randomized to either arm were to continue treatment until disease progression (defined as a 25% increase in PSA over the patient’s baseline/nadir together with protocol-defined radiographic progression and symptomatic or clinical progression), initiation of new treatment, unacceptable toxicity or withdrawal."
For reference, when chemically castrate patients progress, standard of care is to continue Lupron treatment until death. The rationale, although not fully verified by clinical trial, is that withdrawing treatment would accelerate the downward spiral. I suspect many clinicians use the same logic to give their abi progressors some extra time on drug.
"Dr. Beer expressed doubts about this in his comments; my memory isn't totally clear but I think DeBono as well."
They did. Let me muse a bit too. The body of knowledge is increasing rapidly. Each new drug, trial result, and pure exploratory research like that going on with CTC's provides new pieces to the puzzle. It is tempting and even appropriate for the KOL's to take this incomplete picture and brainstorm new theories as to what the whole picture looks like and where the missing pieces will fit, That doesn't mean that each new theory is going to be the aha!! moment and the remaining pieces rapidly fall into place. I think Legothetis is out to lunch. He may be accurately describing a small subset, but he is overreaching and claiming his concept is a one size fits all and is generally applicable. I think Beer and DeBono share my view, although they were uncomfortable saying so in a straight forward manner.
For us as EXEL investors, the real story here is the discomfort this particular group had discussing Cabo. DeBono gave a weak endorsement and he has since published affirming his belief that the bone scan effect represents real disease regression. The skepticism and reluctance to embrace the result is largely due to the fact that it was totally unexpected. There activity does not fit any of the preconceived models describing the disease and the basic research at the molecular microenvironment level is still incomplete.
A couple other quick observations. Dr Legothetis is not a "friend" of Cabo. He recently went on record stating that it was his belief that the bone scan response phenomenon is an imagery quirk and not reflective of a patient benefit. When patients progress on Abi or MDV, treatment is halted, so in a sense androgen independence is almost irrelevant, tumors are going to get as much T as they can handle. Legothetis took a swipe at Cabo in favor of Dasatinib in effect saying it was nice to have a defined MOA before a trial result as opposed to having a trial show unexpected activity and trying to figure out an MOA after the fact. I felt smug knowing that the Dasatinib ph 3 in CRPC which he was promoting failed.
"You don't seem to directly address the last "micro-environment" state of PC where does sound like it is indeed distinct from the various direct and indirect forms of AR signaling you state."
I have no business commenting on this, biology is not a strong point for me, but I'll press on anyways. First, thx for pointing me to the presentation. It is already a bit dated, but well worth the time to listen and there were some interesting references to Cabo. The notion advanced was that tumors typically go through a three stage evolution, the third stage of which was termed a micro-environment stage in which the tumor truly becomes androgen independent with increased aggressiveness. I'm not sure if you picked up on it, but this notion was not a majority view. The majority view was that AR signaling still occurs. perhaps through alternative nonCYP 17 mediated production or by alternative AR activation in the absence of testosterone. Dr. Legothetis (not Sartor) hypothesized that SRC mediated cross activation with AR's accounted for much of this androgen independence. They were anxious to see the results of a Dasatinib (SRC inhibitor) trial. With the benefit of 20/20 hindsight, I can tell you the Dastinib trial failed. That some tumors are unresponsive to both Abi and MDV is not surprising. As Dr Metro repeatedly emphasized, PC is a heterogeneous disease. We can discuss "typically" and "commonly" but each patient presents with a genetically distinct disease.
"The reason I suspect that AR might be being re-expressed is precisely because PSA levels in patients on Cabo aren't being reduced and in fact seems to increase in some cases."
I think your theory needs a little more polishing. Abiraterone does not reduce androgen receptor expression, instead it inhibits androgen synthesis. In fact, androgen receptor expression has been reported to increase with abi treatment. I suggest "Resistance to CYP17A1 inhibition with abiraterone in castration resistant prostate cancer: Induction of steroidogenesis and androgen receptor splice variants." It is a murine study looking at means of reisistance using 2 typical cell lines. It hypothesizes that (at least in these cell lines) resistance is not mediated by finding alternative pathways, but by using alternatively produced testosterone and/or achieving AR signaling in the absence of testosterone. You can see what a bind this puts a patient in when he progresses on Abi and treatment is withdrawn. Testosterone synthesis resumes and the PC cells are waiting with upregulated AR expression.
Enzalutamide (MDV 3100), on the other hand is an AR antagonist and would better fit your proposed scenario. You can see the rationale for investigators wanting to see the effect of an abi/MDV combination. Deplete the ligand and simultaneously inhibit the receptor.
....as patients become refractory to ADT, they often do so because their CTC levels go up and those CTC’s contain more MET, and MET makes those CTC cells more invasive, more metastatic. So mechanistically it makes sense, cabo decreases CTC levels,..."
This statement is pretty significant. We have known about the work identifying CTC's as a marker for poor prognosis and the reduction of CTC's as a marker for improved outcome. However this remark goes quite a bit further. It is identifying increased CTC levels as a means of ADT resistance. Markers can be merely an artifact or they may be a link in a pathway that is integral to a cause/effectIt relationship. He is also identifying the increased CTC MET expression as the likely means by which Cabo reduces CTC's and hypothecates that Cabo mediated reduction of CTC's will delay ADT resistance. Pretty interesting.
He also identified two new randomized trials to start later this year, Cabo/abi and cabo/MDV. It's pretty interesting stuff, but results are literally years away. Of more immediate concern are MTC OS topline data, initiation of HCC and MET NSCLC trials, GDC 971 decision, full enrollment for Comets, and Comet 2 topline results.
They are still sticking to the guidance for Comet 1 in 2014. My best guess is that this actually refers to an interim analysis. Interim analyses are typically powered to only show highly significant results, so it may be optimistic to expect 2014 unblinding for Comet 1, but we will see.
You always have to take the seeking alpha transcriptions with a grain of salt. Here is what was actually said;
"MM: We're very interested in moving cabo up in the lines of therapy. We've talked about doing abiraterone-cabo combinations pre-chemo, enzalutamide cabo combinations pre-chemo. And those Phase 2 trials, randomized Phase 2 trials, will start sometime in the second half of this year. Mechanistically it makes sense, as patients become refractory to ADT, they often do so because their CTC levels go up and those CTC’s contain more MET, and MET makes those CTC cells more invasive, more metastatic. So mechanistically it makes sense, cabo decreases CTC levels, cabo can resolve existing bone lesions by bone scan, so it’s got the right clinical/biological profile I would think, to combine in terms of that early early stage effort. So we had some Phase 1 data at AACR from Dana Farber combining abi with cabo with decent and a small patient population but we're ready to go with that and we're not that much farther behind with the enzalutamide-cabo combination."
"I did not see any open market purchases. Are you sure someone bought shares?"
Nobody bought anything, they just received their annual issuance of options for all the hard work they do.
"In addition, all non-employee directors receive an annual option to purchase 30,000 shares of common stock on the day following each Annual Meeting of Stockholders. Options granted under the Directors’ Plan are not intended to qualify as incentive stock options under the Internal Revenue Code of 1986, as amended (the “Code”). The exercise price of options granted under the Directors’ Plan is equal to 100% of the fair market value of a share of common stock on the grant date."
"If the cancer has moved on to a different stage of its life cycle that relies on a different pathway, AR pathway inhibition as a strategy might be much less effective."
It's the same pathway, but blocking it at a different checkpoint. Just as Abi is addressing the same pathway at which physical or chemical castration is directed. It isn't a totally unexpected result and the parallel to Cabo is much less than perfect, but I do think expectations were higher than the observed outcome and that's the point I was trying to make. Just because you can make a theoretical argument for a positive result, more often the clinical outcome is disappointing.
"There is reasonable theoretical rationale for using Cabo with one of the AR inhibitors since it's addressing precisely how prostate cancer eludes AR inhibition, but we'll only see after relevant trials are unblinded. "
I don't think we can say that there is a single pathway to Abi resistance or that Cabo precisely addresses that pathway. I agree more with the reasonable rationale part and there is some preclinical work to support that line of thinking, but so far it's still largely conjectural as to how it will play out in the clinic. The trial is open label and the group doing the study seems to be willing to publish regular interim results. It isn't a very large study and what happens if the results are not definitive in either direction?
"Your reliance on historical metrics to evaluate efficacy and probability of commercial success may be correct but I still view cabo as something special. How special will depend, in part, on clinical trials. But will also depend on how broadly cabo is prescribed."
Let me share my thoughts a bit more. When I look at Cabo and try to "evaluate efficacy and probability of commercial success" I see Cabo being groomed for 3 different market segments. 1. RET driven disease including MTC, RET NSCLC and possibly DTC. 2. RCC and HCC where it will primarily be competing for market share with other TKI's. 3. CRPC
Of these, CRPC is certainly the most complex. There are now all these approved drugs with so many different MOA's. The treatment landscape is evolving so rapidly, that there are major questions on optimizing the use of the approved treatments, let alone speculation regarding potential use of unapproved and off label drugs. The initial turf EXEL is claiming is at the tail end, the fully refractory patient. That looks like a pretty good strategy. If Comet 1 shows good results, perhaps we could see Cabo vs Taxotere in a post abi population. That would be a doable trial which would yield an uncontroversial result and substantially increase the commercial opportunity in CRPC. There is a good rationale for this trial as it is now being realized/postulated/observed that Abi and Taxotere confer cross resistance. Abi pretreatment appears to diminish Taxotere efficacy.
Maybe Abi/Cabo will hit a home run and produce durable deep responses that are clearly superior to Abi monotherapy results. I would love to be proven overly skeptical on this. As I recall the trial has moved to the 60mg dose and by the end of this year perhaps we will see some detailed individual results on the participants.
"all the best - thanks for all...." Likewise