"A team at The Institute of Cancer Research, London, found that Hsp90 inhibitors countered the effect of malfunctions in the androgen receptor, which often occur in resistance to hormone treatments.
The research suggests that Hsp90 inhibitors could be effective in prostate cancers that have become resistant to treatment and started spreading round the body."
"Study co-leader Professor Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research, London, said:
"We have demonstrated for the first time that Hsp90 inhibitors can block the production of the most common abnormal androgen receptors that cause many prostate cancers to stop responding to current treatments.
"These drugs are already in clinical trials for several types of cancer, and I am excited that our work suggests they could also benefit men with prostate cancer who have otherwise run out of treatment options."
I have no idea which Hsp90 inhibitor was used for this study but I know that EXEL has a an Hsp90 inhibitor (xl888) and has been the subject of other studies for resistant melanoma in the past.
"Leerink Partners reiterated an Outperform rating on Exelixis (NASDAQ: EXEL), and raised the price target to $8.00 (from $7.00), after the FDA recently approved Cabometyx (Cabo). Leerink believes that Cabo is well positioned to capture significant market share in 2nd/3rd line treatment of renal cell carcinoma (RCC). Leerink also believes that it’s likely that the FDA will require a confirmatory Phase III trial for lenvatinib before FDA approval. However, expect limited competition for Cabo if lenvatinib receives accelerated approval based on the Phase II results.
Analyst Michael Schmidt commented, "We're reiterating our OP rating on EXEL. We believe that recently FDA approved Cabometyx (Cabo) (LINK) is well positioned to capture significant market share in 2nd/3rd line treatment of renal cell carcinoma (RCC). We think the Cabo data and label are impressive and the stock's current valuation only reflects a modest opportunity for the product in RCC. We believe the pending PDUFA date for Eisai's lenvatinib (multi-TKI) in 2L RCC on Monday, May 16, has created an overhang on the stock. Based on our due diligence highlighted here, we believe that (1) the approval probability of lenvatinib is very low, despite breakthrough therapy designation (BTD), and (2) if approved, we don't think lenvatinib would compete with Cabo. At the same time, our recent checks with RCC key opinion leaders (KOLs) indicate that Cabo could actually capture a decent share of the 2L RCC market, reflecting upside to our estimates. We are reiterating our OP rating on EXEL and are raising our PT to $8 from $7 previously."
Sentiment: Strong Buy
Under the agreement, Exelixis will receive a $200 million upfront payment. Exelixis is eligible to receive regulatory milestones, including $60 million upon the approval of cabozantinib in Europe for advanced renal cell carcinoma (RCC) and $50 million upon the filing and approval of cabozantinib in Europe for advanced hepatocellular carcinoma (HCC), as well as additional regulatory milestones for potential further indications. The agreement also includes up to $545 million of potential commercial milestones and provides for Exelixis to receive tiered royalties up to 26% on Ipsen's net sales of cabozantinib in its territories.
The BIB chart is again a relative mirror of EXEL today. Six months ago BIB was trading at $81, today's close $41. A 50% decline. Six months ago EXEL was trading at $5.91, today's close $4.04. A 32% decline. When questioning the current PPS, look at BIB and appreciate that EXEL has had nothing but good news in the last 6 months. Suggesting "the market" is discounting EXEL for lack of transparency on OS, manipulation by the CC holders, etc, is ignoring the facts. EXEL got sucked down with all the bio's and fortunately all the recent positive news has actually prevented more damage. Once EXEL exits the world of speculation on FDA approval (soon) and further with growing RCC and Cotellic revenues (cash flow), this correlation will be greatly reduced. EXEL will be judged on it's merits and not it's race (sector).
Sentiment: Strong Buy
Couple O' Snippets, full article out. Wabizzle.....
The overall survival for Cabometyx was included on the label approved by the FDA, and suggests that the drug works at least as good as, if not better than, Bristol-Myers Squibb's (NYSE:BMY) Opdivo, which was approved for the same kidney cancer patients a few months ago.
Obviously, the launch of Cabometyx -- and its competition with Bristol-Myers Squibb's Opdivo -- is the most important event for Exelixis in 2016; but there's some upcoming clinical trial data that could increase Cabometyx's peak sales that investors should be looking out for. This year, we'll get phase 2 data in first-line kidney cancer. It won't be enough to get approved for earlier-stage patients, but if the data is solid enough, it could induce off-label use for first-line treatments.
Exelixis is also expecting data from a phase 1b trial testing Cabometyx in combination with Bristol-Myers Squibb's Opdivo this year. If the combination works better than either drug alone, it should alleviate concerns about the competition dampening sales.
Finally, next year, we'll get data from the Celestial phase 3 trial testing Cabometyx in liver cancer, which would add substantially to the market potential.
Sentiment: Strong Buy
Finally.....Over the next several quarters the data won't be speculation on how good the drug works (better than expected across the board) but on how quickly it ramps up sales. While the "gamble" of biotech is quite exciting for the thrill seeker, the "financial fundamentals" will now kick in. It's hard not to like the potential in RCC with all the data in hand. This is the most derisked EXEL as an investment has ever been. The company is trading at just over $1B, with revenue potential estimates in RCC alone anywhere from $300M to $700M. It doesn't need to be said, but there is some serious runway left on the valuation here. The market has been very skeptical (think Adam F's article about OS) about Cabo's efficacy. Now the data is clear. Will the market continue to be skeptical...now about the financial fundamentals...will it wait to value the company based on financial results over time....or will astute investors, with data in hand, and the company derisked...get ahead of the curve....we shall see.
Sentiment: Strong Buy
"Beyond evidence-based data: scientific rationale and tumor behavior to drive sequential and personalized therapeutic strategies for the treatment of metastatic renal cell carcinoma"
Lorena Incorvaia, et al... Oncotarget 2/8/2016
See Figure 4... These guys have done some great theoretic and evidence-based research here, and propose that values of induced resistance and rates of disease progression (slow vs rapid) may be deciding factors in determining treatment choices in 2nd and 3rd line mRCC. Note that Cabo is clearly the first choice following rapid progression on sunitinib or pazopanib, and also note that in slow progression axitinib might share 2nd line treatment space with nivolumab. Good read...
If BMY offered $10B for the whole shebang...
It seems we would revisit the $2s...
Welcome to share price du jour, a wonderland of unknown market capitalization...
Who's the Bozo driving this bus?
Get ready for a number of negative spin articles at or around that time. There does seem to be a concerted effort among some investors on SeekingAlpha, Twitter, and Motley Fool who shorted the stock in anticipation of a METEOR failure.
Nivolumab and Cabo make it seem like a crowded market but their orthogonal mechanisms of action makes both attractive choices even after one has been tried in light of both of their demonstrated OS benefits. Success is also more rare than it seems: "AZD2014 Inferior to Everolimus for VEGFR-refractory RCC"
Sumanta Pal's point seems to be that you want to use Cabo for a healthier patient population where you might get much result w/ a TKI in favorable to intermediate risk patients than compared with Nivolumab where there's close to none, but Cabo's trial was directed at a sicker patient population and Nivolumab's earlier approval will make it the first choice in second line. Still, there's definitely a subset of patients where cabo will be preferred second-line; actual PFS and pill form would make for better quality of life for patients with debilitating mets.
More ongoing support for Cabo combo treatment rationale...
Nearly 90% clinical benefit rate when combined w Temo & beva in refractory uterine LMS - LBA 226/6
"Further, in a novel and surprising discovery, we found that cabozantinib alters the immune microenvironment by reducing the M1 macrophages. However, cabozantinib depleted both basal and luminal epithelial progenitor cells in vivo. Taken together, we found that cabozantnib can have a tumor potentiating role by limiting M1 macrophages, yet the down regulation of carcinoma associated fibroblasts and associated epithelial progenitors could suggest interesting combination therapies. A lower dose of cabozantnib with traditional anti-proliferative therapies, like taxanes or radiation is supported by the pre-clinical experiments" - LBA 274/12
"The positive outcome of CABOSUN is extremely exciting, as it marks the very first time that a therapy has shown a progression-free survival benefit over standard of care first-line treatment sunitinib for patients with previously untreated advanced renal cell carcinoma,” said Toni K. Choueiri, M.D., Clinical Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and chair of the CABOSUN study. “Based on these findings, cabozantinib may have the potential to become a new gold standard for previously untreated patients following their diagnosis with advanced kidney cancer.”
“All of us at the Alliance for Clinical Trials in Oncology are very gratified to have successfully demonstrated the potential of first-line cabozantinib to benefit patients with renal cell carcinoma in the CABOSUN study. This trial exemplifies how NCI-sponsored studies can be efficient, accrue rapidly, and yield results highly relevant to the field,” said Michael J. Morris, M.D., medical oncologist at Memorial Sloan Kettering Cancer Center, and Chair of the Alliance Genitourinary (GU) Committee."
Ouch....Shorts going to take this one in the shorts! lol
Check the timing. The "contributor" for MF just happens to drop these ridiculous and poorly conceived articles on EXEL on days the stock is coming off solid up moves. On the 15th he dropped the comparison to BMY and then today's absurd lineup. There is clearly malice in his intentions. The articles are so absurd my guess is that no one really pays any attention excepting the few loyal fools remaining from days gone by.
Sentiment: Strong Buy
Very nice write-up for shorties to gnaw & gnash their teeth over this weekend.
To those who sacrificed & their families, God bless. This letter from Abe is so appropriate & poignant. GLTA
Washington, Nov. 21, 1864.
I have been shown in the files of the War Department a statement of the Adjutant General of Massachusetts that you are the mother of five sons who have died gloriously on the field of battle.
I feel how weak and fruitless must be any word of mine which should attempt to beguile you from the grief of a loss so overwhelming. But I cannot refrain from tendering you the consolation that may be found in the thanks of the Republic they died to save.
I pray that our Heavenly Father may assuage the anguish of your bereavement, and leave you only the cherished memory of the loved and lost, and the solemn pride that must be yours to have laid so costly a sacrifice upon the altar of freedom.
Yours, very sincerely and respectfully,
Sentiment: Strong Buy
From the 4/28/16 Q1 conference...
"Marc de Garidel added: “We are fully committed, upon regulatory approval, to preparing the upcoming commercial launches of cabozantinib in advanced renal cell carcinoma in Europe..."
Any guesstimates on Euro approval? My hat's in ring for 7/1/16...
From practice update:
"Although there certainly are toxicity considerations to factor into second-line therapy, which can cloud the decision between cabozantinib and nivolumab, the lack of PFS benefit with nivolumab is concerning. Furthermore, the data for nivolumab are somewhat complex. Subset analyses show that there is no benefit with nivolumab in patients with good- or intermediate-risk disease. Rather, benefit appears to be most profound among those patients with poor-risk disease. In contrast, the benefit with cabozantinib appears to be principally among those patients with good- or intermediate-risk disease, who constitute the majority of patients seen in a kidney cancer clinic. With this in mind, I feel that the data associated with cabozantinib in mRCC are perhaps more practice-changing."
In Checkmate 025 for RCC, Nivolumab vs Everolimus, HR for the OS event in favorable to intermediate risk patients was 0.89 and 0.76 respectively which was not stat-sig for favorable patients and looks barely statsig for intermediate. I don't think Pal's going to change clinical opinions about which treatment to use first. There was a recent article by Sznol that declares checkpoint to be the "mainstay" in RCC second line therapy, and an article by Luke about melanoma stating“PD-1/PD-L1 inhibition has now become the foundation of therapy in melanoma and, eventually, it will likely be in all of cancer," he says. "Adding PD-1 to almost anything is likely to make it better.”
However, Pal's point makes is that in the likely scenario they are given Nivolumab first , most patients will need another option shortly. Subpopulations with mets, especially bone related mets will probably also be given Cabo first.
There are some conditions under which the existing short positions, even if hedged, can be squeezed. From the bond prospectus:
"At any time on or after August 15, 2016, we may redeem all or part of the notes, except for the notes that we are required to repurchase in connection with a fundamental change (as defined in this prospectus supplement), for cash, but only if the last reported sale price of our common stock for 20 or more trading days in a period of 30 consecutive trading days ending on the trading day prior to the date we provide notice of redemption exceeds 130% of the conversion price in effect on each such trading day. The redemption price will equal 100% of the principal amount of the notes to be redeemed, plus accrued and unpaid interest, if any, to, but excluding, the redemption date. No sinking fund will be provided for the notes."
That makes it 130% of $5.31 or $6.90 afaict. So provided the share price hovers above ~$7 for 20 days out of 30 (I interpret that this period could begin as early as mid July), Exelixis could do some serious damage to short positions by redeeming the face value principal and remaining interest on those bonds in cash and then doing a stock buyback.
I think this could realistically happen if 1) they have a great US launch in RCC; 2) CELESTIAL hits on interim and they get a Japanese partner with cash upfront; 3) strong takeover rumors. There needs to be a new support level for the stock, but there's enough investors who bail like scalded chimps whenever shares hit $7 that this may never materialize. There may not be much of a squeeze if shares gradually head toward $7 since lots of shorts probably had a basis of under $7 and would gradually cover along the way, and the additional secondaries since the converts were issued would also blunt the effect of any buyback.
I was considering what joeflow said about the insurance and it occurred to me that I’d not seen the NIVO PFS. I got to wondering about 1 vs 2 prior anti-angiogenic therapies. Correct me if I’m wrong here but NIVO missed PFS but hit OS by a few months. The HR on 2 prior treatments was no different than everolimus. Cabo killed NIVO on the PFS and NIVO was actually exactly the same Everolimus on PFS. Cabo killed NIVO on PFS with 9 months; that is a breakthrough. The only reason NIVO got approve was on OS; it was DOA with PFS and it’s second line only. It’s dead as third line. The paper below has the data broken down a bit.
“The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P = 0.11).” -- n engl j med 373;19 November 5, 201
The interim Kaplan Meier curve showed cabo outperforming everolimus and I’d really like to see the subpopulation of sunitinib only prior therapy. The Kaplan–Meier Curve for Overall Survival for NIVO looks a lot like the Cabo curve. As long as there is not something unexpected like a fierce resistance to Cabo at 25 months, I think NIVO is going down. They’re down playing the PFS and trying to shine light on the OS. Those that think NIVO has “beat” cabo have blinders on. If METEOR has been completed prior the checkmate-25, I wonder if NIVO would have been approved at all. If you have 2 drugs that have a similar OS and one gives better PFS and is a pill vs. an injection… The only thing NIVO seems to have going for it is that’s it’s approved and a bit less toxic.