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OT:
Interesting- I thought the protections for breast feeding women were related to FMLA vs being newer and the result of health care reform law.
Takeda purchased them for 25 per share, or about 9 billion.
Just as a reference point, there share price was in the 12-14ish range when Velcade first got approved. I think. It's been a while.
Has any MLNM-originated drug ever been approved? Integrelin and Velcade were both developed elsewhere and tehn acquired by MLNM.
They also said that the business development folks at Onyx are quite arrogant/greedy. Theyre looking for something like Takeda paid for Millenium, which I think is out of the question. MLNM had a much bigger pipeline to offer and some serious research/marketing skills.
Onxx:
If they get approval for carfilzomib, coupled with royalties from a potential regorafenib approval, then they could be looking at some decent cash flow in 2013 and beyond.
One wholly owned and two partnered drugs is not a bad portfolio.
A couple of general impressions from the carfilzomib panel
- The tone of the fda briefing versus the fda's tone at the meeting were very different. Even one of the panel members commented that the briefing documents were much more vehement about safety, in contrast to the FDA's posture at the meeting. My comment here is that the people who worked up the FDA briefing are either going rogue, or they just didn't have the balls to stick to their guns in a live, head-to-head with the panel members.
- A few panel members voted yes on the risk / benefit but noted general unease and said the data were "soft" or almost me-too (referring to velcade). But when they elaborated, it was pretty clear that they're just sad that they're not reviewing an amazing drug but rather one that is incremental. My view on this is two-fold: 1) they're there to assess the data at hand, not what they wish they had, and 2) it almost sounded like the myeloma people had some targeted therapy envy. No gleevec like results for this community seems to be getting to them.
11 yes, 0 no, 1 abstain for the vote on whether the risk / benefit is favourable for carfilzomib.
Was it the "user advocate" on the panel who asked that question?
Wow, one of the ODAC panel members is basically asking how response rates are measured / reported.
Pretty sad.
Onyx can not unequivocally say there is not an effect, since there is no control arm.
I think the confounding of the data with Dex makes it a tough judgement call.
re: ONXX
I think the dexamethasone issue is a red herring. There is a reason why dexamethasone treatment is dosed significantly higher than the small dose that was allowed to be administered to ameliorate the side effects at the time of carfilzomib administration. The concentration is nowhere near therapeutic, unless you have data suggesting otherwise.
As for the tolerability of velcade: if you bring the safety aspect of velcade into it, then you need to acknowledge the efficacy. In this respect, carfilzomib has undeniable activity in those resistant or intolerant to Velcade, which is an unmet need in my book. Also, the improved tolerability of SubQ velcade only applies to the neuropathy... there is no indication that the cardiac events were reduced, which are the salient side effects in play. In that respect, a reference to SubQ Velcade isn't one that makes carfilzomib look worse. The velcade PI has all the same warnings that the FDA was ok with when they gave it accelerated approval.
The protocol violations are disappointing. Most of these appear to be due to patient compliance, which the company needs to take seriously. In a trial of patients who have exhausted most of their treatment options, however, I'm not so outraged by an enrollment error where they missed inclusion / exclusion criteria. It's not like these people don't have myeloma, and it's clear that their previous history was accurately reported (and confirmed) by the FDA. I think this is your most valid point, however. Protocol violations are just poor form.
As to the FDA regulation you copied, I don't really understand the point. The passage is intentionally vague and could be interpreted either way. Are you suggesting that this trial did not test the "safety and effectiveness" of "treating serious or life-threatening illnesses" and that carfilzomib was tested for its ability to provide "therapeutic benefit to patients who are ... unresponsive to, or intolerant of, available therapy?" Even the FDA acknowledges with their efficacy analysis that the response to carfilzomib was independent of the number and type of previous regimen...
I also think point #4 exemplifies the mission creep into the accelerated approval process. If the FDA wants randomized trials for accelerated approval, then we should probably just remove the accelerated approval pathway.
I agree that they won't approve. But I don't think your comments are all that convincing considering the pathway that Velcade followed to approval. It seems to me that you would have been equally disappointed with Velcade's initial NDA application, because it was essentially identical to this carfilzomib application. I guess where you see a poorly run single arm phase 2 trial, I see a trial that is following in the footsteps of a very successful example of accelerated approval.
ONXX / FDA Concerns:
All known on study deaths were 38 in total, with 21 due to disease progression. That leaves 17 deaths in play.
Of those, 10 were due to cardiac (n=7; 5 identified by applicant, 2 additional by FDA) or "cardiac possibly contributory to death" (n=3, only identified by FDA). So 10/526 = 1.9%. Of the 7 deaths, 5 died on cycle 1 of drug administration, 1 on cycle 2 and 1 on cycle 4.
The other one the FDA appears to have pointed out is Hepatic Failure, which occurred in 2 patients out of 526. I'm not sure why they've actually singled this one out, since it is on par with the other found causes of death (multi-organ failure, sepsis, intracranial hemorrhage, pneumonia, renal failure). The company did a small study to show that carfilzomib did not influence the PK of CYP3A4 substrates (the only one that carfilzomib was found to "moderately" inhibit, in vitro).
They do make a bigger deal of "cardiac disorders" in the briefing (30/526 patients, 6%), although I'm unsure how certain findings would relate given that the patient is on drug for a relatively brief period of time versus the typical trajectory of the disease (example: aortic valve stenosis). If I squinted hard to see a pattern, I would say exclude people with coronary artery disease from the drug. In the real world, the safety signals here should ideally be compared to Velcade, which also has cardiac effects. The disadvantage, in the case of these single arm trials, is that you don't have a comparator arm for safety. In one velcade trial, treatment-emergent cardiac disorders were 15% and 13% in the velcade and dexamethasone groups, respectively. Doesn't look as bad in that light, especially considering that patients in the carfilzomib trial did have the option of receiving low dose dexamethasone occasionally.
All in all, you can tell by the way that the FDA is wording their document that they are not intending to approve. They say things such as the patients who were "unresponsive or intolerant" to all known drugs "was a very small fraction off the ITT population (69/266; 26%)" or that the ORR in the primary efficacy study was "only 22%" while making a very big deal about adverse events that were present at or less than 1%. In a sense this is their mandate to keep patients safe, but the tone seems to be one where they're stacking the deck against the drug a little bit.
It's too bad, because this appears to be a reasonable case of the sponsor following the accelerated approval guidelines. The phase 3 studies are under way, so the sponsor is acting in good faith.
These were 10b5 sales, so there was no choice but to make them if the stock hit the predetermined criteria.
Legally their right, but I'm amazed at how few biotech executives understand how unpleasant these sales look ahead of company-defining pivotal events.
They just don't seem to care.
I prefer in-your-face graft a la the Biancos rather than this cowardly behaviour practiced by most executives.
OT:
Dr. Olson came to talk here last year.
Their labwork is impressive. Very impressive. My personal hunch / bias is that this isn't going to do that much in the clinic. But I guess we'll see
Here is something I'm a little more hopeful about:
http://www.trevenainc.com/pipeline.php
I think the biased ligand concept is attractive.
My view is that the holy grail would be to prevent the remodeling that occurs in the first place, that is associated with or responsible for heart failure.
holy grail in cardiology
OT:
I'm not aware of what you are referring too
OT:
The rate isn't surprising and I expect that the rates will continue to decline until things settle down.
What threw me was the use of the phrase "protein activity". Your first example is correct but not accurate due to semantics. The activity of each single protein has not been altered by the mutation, but rather levels of the protein in the cell are reduced resulting in physiologic or metabolic changes. The second example is not correct as removing an entire exon will change the primary sequence of the protein.
I will take that bet, but on the side that the twin study will have limited value. I think we had previously discussed the issue of epigenetics and how this impacts gene expression.
CLDX:
I actually think the consistency among triple negetive, high GPNMB, triple negative and high GPNMB groups is positive. I don't know where you get the information ORR rarely seem to scale with the degree of overexpression. The boundary between high and low expression is always going to be a cutoff - that's what a dignostic is all about - people can always say it is arbitrary. Even if you think so, triple negative fills in nicely to me.
CLDX:
The result is very promising to me, especially in triple negatives. Even if GPNMB testing/selection was biased, the triple negative cases showed (even though small sample size) the drug hit the target - patients at this stage usually with confirmed triple negative status already.
OT:
I would just ask you to read through your posts.
4 trading days ago you said PCYC had broken out, but noted today that, in retrospect, it didn't break out then because some one / some people decided to sell lots of shares.
Now you say it broke out today because there was no one to sell lots of shares.
Tautology anyone?
Net-net, it appears the relevant information is to know whether or not someone will decide to sell shares, and your posts provide definitive proof that you can't tell when a seller will step in.
(yes, this is my annual "TA sounds silly when described" post... apologies)
This was really the breakout that should have happened last week before the large seller(s) stepped in and so rudely sold a 1.5 million shares
I find the disambiguation of terminology based on normal vs abnormal function to be more useful than the one based on the arbitrary 1% frequency of the least common allele. As your citation in #msg-75807204 notes with respect to the sickle-cell gene, classifying by function is not entirely clear-cut; however, normal vs abnormal function would seem to provide a reasonable workable definition for the terminology in almost all cases without the need for employing an arbitrary frequency threshold.
OT:
Here's a new surrogate competing with the "positive inflection in the CEO's voice" endpoint that many investors use to gauge program success:
The board is dead, and so is the stock. But implied volatility is rocketing today, and no one seems to notice. The market makers, of course, know all, and adjust prices accordingly. Look at the June 50 calls - up 50% today, with the stock actually down. Fairly decent volume in the 44 and 47 strike, too. Phase III lung data is due out, literally and day between now and the end of the quarter. Since no one is expecting anything positive, could ONXX see a VRTX-style pop of 50 or 60% on good data.
I called IR at Onxx the other day. They answered the phone on the first ring, which they never do. They weren't waiting for my phone call, but could it be that something is afoot, and IR is at the ready??
So the move to the 40s is going to happen unless it doesn't?
ASCO:
The Array data look good, but for some reason I feel like there should be a larger difference in OS for a 37 to 0 response rate advantage. But that's just a weird gut feeling.
ONXX's carfilzomib data look good in that the drug appears to be equally efficacious in bortezomib failures. The Regorafenib data looks good but the PFS is curious... I guess we don't know what the curves look like but that's a big HR for a 0.2 month PFS advantage.
The ONTY data look like crap.
Otherwise why would the fda bother with the REMS and not just require new data (ie new trials ) period.tia.
PYMX:
Just curious about financial shape. Do you know how long their existing cash will last them?
PYMX:
FWIW I bought more this morning.
I never cared about the reversal program, so this just ended up being an unplanned purchase simply due to the low price.
Darapladib
http://clinicaltrials.gov/ct2/show/NCT01000727
http://clinicaltrials.gov/ct2/show/NCT00799903
Still ongoing as far as I know.
While I basically agree with you, ONXX trying to prove you wrong:
ONXX:
Anyone else surprised they're getting an ODAC meeting?
Proteasome inhibitors aren't new, and it's in the same indication as the approved drug Velcade.
I'd given up hope on the carfilzomib application on this round, but perhaps this suggests that the FDA does want a meaningful discussion on efficacy vs. safety? In other words, is there a chance that the use of surrogate endpoints for efficacy are overcome by the increase in safety (especially peripheral neuropathy) versus Velcade? Will the agency have more confidence in the surrogates presented by ONXX given the known data for Velcade in the same indication?
Or is this just going to be a public forum where many people say "wait for survival data" and the FDA can subsequently dismiss the possibility of accelerated approval.
No, it’s not insider trading because it’s not trading.
The change constitutes modest evidence that the BoD is at least thinking about the company’s being acquired.
LOL
Ariad's drugs just got renamed: Pony-trip and Radio-formalus.
iwfal, do you think any time soon we're going to reach that point where, by sheer brute repetition, you'll be able to declare: Well, I think I've made my argument.
The horse is dead, all the flesh has been flayed from every quarter, the flies have finished up and are all gone, and the bones are now loose and scattered.
You've run your 5kb Excel spreadsheet that takes 4 parameters and you've figured out the next local maxima for sunspots and typhoons in Malaysia. We get it. Thanks.