I was just looking over the phase II data yesterday. I'm still concerned that they are not conducting MARQUEE in an enriched population. A primary endpoint of OS is a tough nut to crack.

NVS/INCY - Jakavi (ruxolitinib) approval in the EU

http://www.reuters.com/article/2012/08/28/idUS41821+28-Aug-2012+HUG20120828

How often do oncologists prescribe expensive cancer drugs off-label?

In both arms or just the bavi arm? The former would not surprise me

I'm pretty much in agreement with you...just pointing out that the longs will undoubtedly try to rationalize the different outcomes in the two trials. I won't be surprised if PPHM execs also come up with some quasi-scientific rationale to explain the divergent results.

I agree for the most part. It does have a supposedly novel MOA, so it's possible that it works better in combination with docetaxel than a platinum doublet. Furthermore, it is generally more difficult to demonstrate OS improvement in front-line clinical trials. Nonetheless, given the purported magnitude of the benefit in the second line trial, one would expect to see at least a hint of benefit in the front-line trial if the signal is "real".

Do you think the EU and other jurisdictions will eventually introduce guidelines on interchangeability for biosimilars? AFAIK, only the FDA has developed guidelines to address this.

IMO, the need to market biosimilars that are not interchangeable may actually be a positive for Sandoz and other big players, as it places a higher barrier to entry than for small-molecule generics. I think there may be several players initially, but being unable to compete on price alone will probably mean that many smaller players will not survive.

Thanks for your input. What are your thoughts on Sandoz's prospects in the biosimilars market?

Interesting...what was the issue, and was it finally resolved?

It's not an assumption; I'm just stating what should be patently obvious: the trial was not explicitly designed to measure overall survival.



I never claimed that they are different, but I would definitely want to see that information before being confident that the OS signal is "real".



I don't claim to know what PPHM's intentions are and haven't accused them of lying per se. Nonetheless, I have seen some misleading PRs from them in the past, and I wouldn't put it past them to be over-exuberant in their reporting of the results of the 2nd line NSCLC trial. While I am probably more skeptical of PPHM than I would be of other companies, I would afford the same level of scrutiny to these "results" even if they came from another company.



One of the points I've been trying to get across is that we probably won't get a definitive answer on whether bavituximab improves OS for 2nd line NSCLC, even once the full results of this trial become available. For that, we would have to have results from a phase III trial with OS as the primary endpoint - and we're not likely to have those results any time soon.

Of course, the share price could get a nice pop when PPHM announce the full results, but that's a separate issue from what I've raised above.



A partnership deal would be positive, but it does not change the scientific validity of the results. There are certain unknowns that a potential partner will not be able to answer even after completely dissecting the data from the trial. If these unknowns did not exist, there would be no reason to conduct a phase III study - which I maintain will be necessary.

I wouldn't be surprised if the share price continues to increase due to over-exuberance. I just hope the longs realize that the phase II results themselves are unlikely to lead to approval, despite what some of the PPHM execs have suggested. They will probably need a phase III trial to confirm the OS results, and I doubt they have enough cash for that.

Robert, I don't think anyone is unduly downplaying the results of the trial. You have to remember that the full results have not yet been presented at a scientific meeting, and there are still many unanswered questions.

Firstly, as others have already pointed out, overall survival was not a primary endpoint of the trial. Thus, self-acclaimed "PPHMites" who describe it as having a "gold standard design" are mistaken. If measuring overall survival was the main objective of the trial, unblinding would not have occured until a pre-specified number of deaths had occured. Measuring OS after unblinding introduces potential bias.

Secondly, there are still a lot of unanswered questions about the trial. For instance, were baseline factors such as performance status, EGFR status, etc balanced between all three treatment arms? Furthermore, were there differences in treatment that patients received post-progression in each arm? Are the OS results consistent across all geographic regions?

If the treatment arms were well-balanced and the results are consistent across different subgroups, then it certainly warrants further exploration in a phase III study that is actually designed to assess OS.

Finally, don't forget that this is still a relatively small trial (only ~40 patients in the control arm). There have been a number of instances where promising results in randomized phase II studies weren't replicated in a larger phase III study.

By the way, has PPHM offered hints as to whether there is a difference in OS in the 1st line NSCLC trial?

If you still have trouble convincing others, try capitalizing a few more words.

What are your reasons for dropping NVS?

Unfortunately, if the OS data are biased it may not become apparent until after the company runs a phase III study with OS as the primary endpoint. It wouldn't be the first time "promising" OS data from a phase II study fails to be corroborated by a larger, more well-designed trial (see KERX, ONTY, etc).

In the meantime, PPHM longs probably still have a chance to make hay while the sun shines.

Koch also mentioned that GSK has a p38 inhibitor in a trial for ACS. I believe this is the one:
http://www.clinicaltrials.gov/ct2/show/NCT00910962?term=p38&recr=Open&rank=11

Now you're just making up phrases...

Votrient's sales last year were about $150m, and I think Afinitor sales for renal cell carcinoma are in the same ballpark. Votrient's main selling point at the moment is being better tolerated than Sutent, but it has safety issues such as liver toxicity. Tivozanib is better tolerated than all of the currently approved TKIs including axitinib.

I think a conservative estimate of $150m in annual sales within the first couple of years on the market is reasonable for tivozanib, given what we have seen with Votrient. I think longer term there is potential for tivozanib in other indications - a phase II study in colorectal cancer is underway and they announced during the last CC that they are planning to initiate a study in breast cancer later this year.

I don't pay much attention to the rest of AVEO's pipeline, but I think tivozanib has a very attractive profile. There are a lot of VEGFR TKIs out there, but many of them are multi-targeted. While hitting multiple targets may be desirable in some cases, tivozanib may be more versatile due to its selectivity.

You probably wouldn't get approval from an ethics committee to begin with, but tivozanib was compared to sorafenib so it is a non-issue. I think even marginal efficacy vs. sorafenib is better than showing highly statistically significant superiority to placebo. As far as the FDA is concerned, I don't think they can categorically say that Sutent is better than sorafenib since they haven't been compared head-to-head.

Of course, regulatory approval is necessary but not sufficient for commercial success. That said, I do believe if approved that tivozanib can differentiate itself from the competition based on its side effect profile. A head-to-head efficacy trial may be necessary down the road, but I think it makes sense to wait until the results of COMPARZ are available.

Votrient was approved based on a placebo-controlled trial.

AVEO - I think there is an overreaction to yesterday's news, although somewhat understandable considering that they don't have much else apart from tivozanib.

The FDA raised concerns about one-year survival data which favor sorafenib. However, given that the trial allowed for cross-over, I don't see this as a pertinent issue as far as approval goes. As long as the FDA doesn't have a problem with the PFS data, tivozanib will most likely be approved IMHO.

INCY didn't previously issue any guidance, and AFAIK the earnings beat analyst estimates. That said, I'm assuming there are folks out there who were hoping that Jakafi would be generating $500m in revenue in its first year. The launch hasn't been spectacular, but it hasn't been a disaster either.

I haven't had a chance to listen to the call yet though...I didn't see anything negative in the press release.

From AVEO's Q2 PR:

Personally, I don't think it should be an issue for approval.

The selumetinib melanoma data are expected fairly soon, aren't they?

I've been in and out of this stock a few times over the past nine months or so - it's always been quite volatile. It's hard to arrive at a fair valuation of ARRY given that there are still quite a few unknowns with all their assets, but you would hope that at least one of them will end up becoming a commercially viable product. It's still early days, but I think as they start moving molecules into phase III trials the street will start paying more attention. KRAS mutant lung cancer is a huge opportunity for them, especially since they are behind GSK in melanoma.

Comparable efficacy in a relatively small trial is not much to go by. It's possible that in a larger, non-inferiority trial that ARRY-797 doesn't show comparable efficacy, in which case I believe oxycodone would be preferred, especially since it is likely to be cheaper.



A lack of dependence would be an advantage, but IMO it would be overshadowed by the CV safety concerns. Even if it turns out to be inconsequential, I think regulatory agencies will want to see long-term safety data before approving it for chronic use.

I agree that the QTc issue is concerning, unless they want to target a niche population (e.g. acute use in patients who cannot tolerate oxycodone). I think it will make potential partners think twice about licensing ARRY-797 because cardiovascular issues are bound to be a huge concern for chronic use.

Bristol-Myers Snatches Five-, 30-Year Coupon Records

http://online.wsj.com/article/BT-CO-20120726-723467.html

Another potential application for ponatinib albeit in a small number of patients:

http://www.sciencemag.org/content/early/2012/07/25/science.1220834.abstract

Does anyone know if ponatinib crosses the blood-brain barrier?

I'm not sure it will go up to 70% in the near future, because demand in the US market for Apple products will likely remain strong especially following the launch of the iPhone 5 and a smaller version of the iPad (speculated).

The question about proportion of sales from Emerging Markets is a good one, but not one I've looked into in any detail. China is evidently a huge growth opportunity for them, but I'm not sure how well they are doing in countries like Brazil, India, Nigeria, etc.

It was also 62% in Q3 2011 for AAPL.

However, I anticipate that it will be slightly higher in the next quarter due to iPad sales in China.

AAPL -5% A/H following 3Q results

http://www.apple.com/pr/library/2012/07/24Apple-Reports-Third-Quarter-Results.html

GILD may also have new single-tablet regimens containing GS-7340 by the time Merck's putative combo is ready to hit the market.

I think it is likely that a decision will be made earlier. Nonetheless, don't you think approval is already baked into the current share price?

SNY and REGN Launch PhIII Program With PCSK9 Antibody

http://investor.regeneron.com/releasedetail.cfm?ReleaseID=693585

Sanofi (EURONEXT: SAN and NYSE: SNY) and Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) announced today that several trials within ODYSSEY, the Phase 3 clinical program of SAR236553/REGN727, have initiated patient enrollment. SAR236553/REGN727 is a potential first-in-class, subcutaneously administered, fully-human antibody that lowers low-density lipoprotein (LDL) cholesterol by targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), an enzyme which binds LDL receptors, leading to their accelerated degradation and increased LDL-cholesterol (LDL-C) levels.

"We are delighted to lead the field of PCSK9 late stage development with the broad global 22,000 patient ODYSSEY clinical trial program, and would like to thank in advance the patients and physicians who will contribute to the first Phase 3 program evaluating a PCSK9-targeted therapy," said Jay Edelberg M.D., Ph.D., Head of the PCSK9 Development and Launch Unit, Sanofi. "This comprehensive Phase 3 program will test the safety and efficacy of SAR236553/REGN727 administered as one single injection every two weeks in multiple treatment strategies and patient types, such as those who are at elevated cardiovascular risk, are unable to tolerate statin therapy, or have familial hypercholesterolemia."

"Lowering LDL-C remains the primary objective for the management of hypercholesterolemia and has been supported by numerous morbidity and mortality trials. Despite the existence of very effective LDL-C lowering therapies, many patients, such as those with heterozygous familial hypercholesterolemia or those with elevated cardiovascular risk, are unable to achieve their LDL-C goals," said Professor Henry N. Ginsberg, M.D., Columbia University Medical Center, New York and Chair of the ODYSSEY Steering Committee. "Sustained PCSK9 blockade represents a potential new option to further reduce LDL-C on top of standard of care statin therapy and help patients achieve their LDL-C goals."

The ODYSSEY program will enroll more than 22,000 patients. This includes over ten clinical trials evaluating the effect of SAR236553/REGN727 on the lowering of LDL-C and an 18,000 patient cardiovascular outcomes (e.g., heart attack, stroke) study. LDL-C is expected to be the primary efficacy endpoint for regulatory filings. The studies will be conducted in clinical centers around the world including the United States, Canada, Western and Eastern Europe, South America, Australia and Asia. Studies are currently enrolling patients with familial hypercholesterolemia or elevated cardiovascular risk, as well as patients unable to tolerate statin therapy.

"We believe that Regeneron's expertise in antibody discovery and development, combined with Sanofi's experience in clinical development and self-injectable delivery systems, will be an advantage as we work to bring this important new therapy to patients who are unable to reach their LDL-C goals with traditional lipid-modifying therapies, as quickly as possible," said George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron and President of Regeneron Research Laboratories.

In parallel, Sanofi announced the creation of a dedicated PCSK9 Development & Launch Unit. Jay Edelberg, M.D., Ph.D. has recently been appointed as Head of the Development & Launch Unit, reporting to Elias Zerhouni, President, Global R&D and Hanspeter Spek, President, Global Operations, Sanofi. The creation of a dedicated unit for this new PCSK9 inhibitor underscores Sanofi's commitment to develop this potential first-in-class therapeutic agent.

About PCSK9

PCSK9 is known to contribute to circulating LDL-C levels, as it binds to LDL receptors resulting in their degradation so that fewer are available on liver cells to remove LDL-C from the blood. Moreover, traditional LDL-lowering therapies such as statins actually stimulate the production of PCSK9, which limits their own ability to lower LDL-C. Inhibiting the PCSK9 pathway is therefore a potentially novel mechanism for lowering LDL-C.

About SAR236553/REGN727 and the Phase 2 Program

SAR236553/REGN727, created using Regeneron's VelocImmune® technology, is a fully human monoclonal antibody directed against PCSK9, administered via subcutaneous injection. By inhibiting PCSK9, a determinant of circulating LDL-C levels in the blood, SAR236553/REGN727 increases the number of free LDL receptors which can clear circulating LDL-C from the bloodstream.

SAR236553/REGN727 has been studied in three Phase 2 clinical studies: two in patients with primary hypercholesterolemia and one in patients with heterozygous familial hypercholesterolemia (heFH). In the primary hypercholesterolemia trials treatment with different dose regimens of SAR236553/REGN727 on top of statin therapy significantly reduced LDL-C from baseline by 40% to 72% over the 8 or 12-week treatment period. A third Phase 2 study was in patients with heFH whose LDL-C levels remained elevated despite statin therapy with or without ezetimibe. Across the four tested doses of SAR236553/REGN727 administered for up to 12 weeks, patients achieved a mean reduction in LDL-C from baseline of 28% to 68%. In the Phase 2 program, injection site reactions were the most common adverse events with SAR236553/REGN727. Rare cases of hypersensitivity reaction were also reported. There were five serious adverse events (SAE) in the active treatment arms (1.8%, 5/275) and two SAEs in the placebo groups (2.6%, 2/77).

About the Phase 3 SAR236553/REGN727 Program

The Phase 3 ODYSSEY program will include over ten clinical trials designed to test the efficacy and long-term safety of SAR236553/REGN727 both as monotherapy, and in combination with other lipid-lowering agents. ODYSSEY will enroll several patient populations including patients with heFH who are inadequately controlled by current lipid-modifying therapy, and high cardiovascular risk patients with primary hypercholesterolemia. The primary efficacy parameter will be LDL-C; however, multiple lipid parameters will be evaluated. The global Phase 3 program will be conducted across more than 2,000 study centers across the United States, Canada, Western and Eastern Europe, South America, Australia and Asia. The Phase 3 ODYSSEY program will include the following studies:

ODYSSEY FH I, FH II and HIGH FH: The primary objective of these three studies is to demonstrate the efficacy and safety of SAR236553/REGN727 as an add-on therapy in patients with heFH who are not adequately controlled with their lipid-modifying therapy.
ODYSSEY COMBO I and COMBO II: The primary objective of these two studies is to demonstrate the safety and efficacy of SAR236553/REGN727 as an add-on therapy in patients with primary hypercholesterolemia at high cardiovascular risk who are not adequately controlled with their lipid-modifying therapy.
ODYSSEY MONO: The primary objective of this study is to demonstrate the safety and efficacy of SAR236553/REGN727 as monotherapy in comparison with ezetimibe in patients with primary hypercholesterolemia.
ODYSSEY ALTERNATIVE: The primary objective of this study is to demonstrate the safety and efficacy of SAR236553/REGN727 in comparison with ezetimibe in patients with primary hypercholesterolemia (heFH and non-familial hypercholesterolemia) who are unable to tolerate statins.
ODYSSEY OPTIONS I and OPTIONS II: The primary objective of these studies is to evaluate the safety and efficacy of SAR236553/REGN727 as an add-on therapy in patients with primary hypercholesterolemia at high cardiovascular risk or with heFH who are not adequately controlled on statins, in comparison to several second line lipid lowering strategies.
ODYSSEY LONG TERM: The primary objective of this study is to evaluate the long-term safety and tolerability of SAR236553/REGN727 in patients with hypercholesterolemia at high cardiovascular risk or patients with heFH inadequately controlled with their current lipid-modifying therapy.

In addition, the ODYSSEY program will also include ODYSSEY OUTCOMES, a Phase 3 cardiovascular outcomes trial which will enroll about 18,000 patients and evaluate the effect of SAR236553/REGN727 on the occurrence of cardiovascular events.

Not sure LinkedIn is always a good indicator. My previous manager didn't update his LinkedIn page for six months after he left the company.

I'm selfishly hoping that the selling continues. I sold a few weeks ago (so unfortunately missed the recent run-up), but am hoping to get back in at some point.

Any news on PCYC (-11.65%), or have the momentum traders decided to check out?

Let's not forget that targeted therapy is not the only approach. I think there is definitely merit in that approach for certain tumor types, but I'm personally quite interested in seeing how the immunotherapy field develops. Immunotherapy may turn out to be more feasible than using multiple targeted agents at once, especially for tumors where several pathways are involved.

I have no sympathy for KV.A. I think the FDA is caught between a rock and a hard place.

But even if Eylea were to hit $1b in peak sales, does that justify the current valuation? Are there really other products with blockbuster potential in their pipeline?