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>>MDVN
I think you are grasping at straws here. Trials fail all the time for many reasons other than fraud. Even if there was fraud, more likely it's the Russian investigators rather than MDVN itself. I think the chances of PFE asking for their money back is close to zero.
(No position in MDVN).
Peter
PPCO
I personally disagree with both ends of your analysis here.
I would have been a serious buyer under $70 if the trial had matched the earlier results, with a target of way more than that. Just run the math - this would have been a $2+ billion/yr drug, and MDVN has only 33m shares outstanding.
On the downside, I'd be a definite buyer here in single digits, and a serious buyer at $5 (assuming they don't decide to fritter away more money on Dimebon). Their prostate drug is a very good one.
Peter
In the "Just how competent are analysts at major brokerage firms category?" I present this quote on Dimebon from last month:
Medivation may plunge 35 percent in Nasdaq trading if the study fails, said Ian Sanderson, an analyst at Cowen & Co. in Boston. Success may propel the stock to rise 20 percent, he said.
In my opinion, he would have been even more wrong on the upside had the trial been successful.
Peter
While we are reading tea leaves, is it significant at all that PFE is nowhere to be seen in this announcement of results?
I personally chickened out and sold my remaining MDVN recently.
Peter
It's interesting that Clozapine was actually the most-used single drug in this survey - 32,000 patient-years, vs. 25k for Olanzapine, 19k for Risperidone and only 5k for Quetiapine. (Polypharmacy at 132k was the biggest entry).
In the US, I think everyone was scared-off by the small risk of agranulocytosis. Too bad, because it works better than the other drugs and is more tolerable too, as can be seen in this survey.
I think Aryx had a "safer Clozapine" in their early pipeline, but doubt if that will ever see the light of day given their dire straits.
Peter
Your comments seem reasonable to me - but I think that as overall margins for big pharma drop with changing product mix, so the opportunity for playing tax games drops too.
It's very hard for any outsider to get a handle on tax rates - they will mostly remain a black box. One unpleasant surprise for high-tech companies a few years from now is the treatment of their deductions for gains at option exercise. The new IFRS II rules are much less favorable than existing US rules and will lead to a higher (and more volatile) reported tax rate.
Peter
No Geodon was not included (unless it's included in "other" or in "polypharmacy").
I went back and read the study. As might be expected, Clozapine was generally given only to the sickest patients and it still had the lowest suicide and highest compliance rate by quite a bit.
Unfortunately the tables are not presented as text, so I can't paste the mortality rates by drug. Risperidone, Haloperidol and Quetiapine are all about the same (adjusted HR for mortality of 1.34 to 1.41). Clozapine was 0.74, with the crude rate even better at 0.53
Peter
I think it's part of a new process, which explains why the two regulatory authorities coordinated their decision here:
http://regulatoryaffairs.pharmaceutical-business-review.com/news/fda_ema_to_accept_single_orphan_drug_designation_annual_report_100226/
Hard to believe, but this study in Lancet claims clozapine had the lowest mortality:
Volume 374, Issue 9690, 22 August 2009-28 August 2009, Pages 620-627
doi:10.1016/S0140-6736(09)60742-X |
11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study) Summary
Background
The introduction of second-generation antipsychotic drugs during the 1990s is widely believed to have adversely affected mortality of patients with schizophrenia. Our aim was to establish the long-term contribution of antipsychotic drugs to mortality in such patients.
Methods
Nationwide registers in Finland were used to compare the cause-specific mortality in 66 881 patients versus the total population (5·2 million) between 1996, and 2006, and to link these data with the use of antipsychotic drugs. We measured the all-cause mortality of patients with schizophrenia in outpatient care during current and cumulative exposure to any antipsychotic drug versus no use of these drugs, and exposure to the six most frequently used antipsychotic drugs compared with perphenazine use.
Findings
Although the proportional use of second-generation antipsychotic drugs rose from 13% to 64% during follow-up, the gap in life expectancy between patients with schizophrenia and the general population did not widen between 1996 (25 years), and 2006 (22·5 years). Compared with current use of perphenazine, the highest risk for overall mortality was recorded for quetiapine (adjusted hazard ratio [HR] 1·41, 95% CI 1·09–1·82), and the lowest risk for clozapine (0·74, 0·60–0·91; p=0·0045 for the difference between clozapine vs perphenazine, and p<0·0001 for all other antipsychotic drugs). Long-term cumulative exposure (7–11 years) to any antipsychotic treatment was associated with lower mortality than was no drug use (0·81, 0·77–0·84). In patients with one or more filled prescription for an antipsychotic drug, an inverse relation between mortality and duration of cumulative use was noted (HR for trend per exposure year 0·991; 0·985–0·997).
Interpretation
Long-term treatment with antipsychotic drugs is associated with lower mortality compared with no antipsychotic use. Second-generation drugs are a highly heterogeneous group, and clozapine seems to be associated with a substantially lower mortality than any other antipsychotics. Restrictions on the use of clozapine should be reassessed.
Adverse effect reports - top culprits:
Table 1. Most frequently reported drugs in 2009 Q3 from all sources
Drug Name* Brand Name Cases Rank
ROSIGLITAZONE AVANDIA 1218 1
QUETIAPINE SEROQUEL 977 2
BACLOFEN LIORESAL 796 3
FENTANYL 688 4
ETANERCEPT ENBREL 495 5
INFLIXIMAB REMICAIDE 395 6
ADALIMUMAB HUMIRA 353 7
DEFERASIROX EXJADE 294 8
ZOLEDRONIC ACID 287 9
TERIPARATIDE FORTEO 278 10
ACETAMINOPHEN 276 11
DULOXETINE CYMBALTA 266 12
IBANDRONATE BONIVA 249 13
LEVOFLOXACIN 242 14
IMATINIB GLEEVEC 239 15
*Generic drugs shown in bold face
Direct Reports
Full report at:
http://www.ismp.org/quarterwatch/2009Q3.pdf
Be interesting to normalize this based on number of scripts - certainly Baclofen must be up there as I don't think it is all that widely used.
Also notable are the three RA biologics, and the three osteoporosis drugs, although I guess they are more widely used (but maybe not Forteo). Gleevec is surprising too, given it isn't that widely used. Exjade is a known problematic drug, and it's not surprising to see Levaquin here as it's still widely used and has known issues. Cymbalta is surprising to me - wonder what the issue is.
Hard to know if Avandia is on top because of all the publicity or because it belongs there. Seroquel is widely used and has lots of side effects - in a large 10-year observational study it showed the highest mortality of any of the second-generation antipsychotic drugs. (Anyone want to guess which drug showed the lowest mortality?)
Targanta (oritavancin ) was a close (10-8) negative decision by the AC. I think the principal issue was that one of their two trials missed a 10% non-inferiority margin - I believe that trial was powered for 15%. It didn't help that it seemed to do worse than vanco for patients with MRSA, and there were some lingering safety concerns - it has a very long half-life, which is always a bit scary.
So I don't believe the issue was that they tested against vanco - it's just that they didn't demonstrate non-inferiority to the required standard.
One of the FDA's statistical concerns with these antibiotic trials is that they often don't really know how well the old drug works in a given patient population. So conceivably if the old drug is only marginally better than placebo in some difficult patient group, then if your new drug is say 15% worse than the old drug, then conceivably the new drug doesn't do anything at all. On the other hand, these are serious conditions, so you can't try them against placebo.
Peter
Here's a copy of a post I made on SI:
Depressing article in NYT about resistant gram-negative bacteria:
http://www.nytimes.com/2010/02/27/business/27germ.html
The drought of new drugs isn't just because big pharma has given up - it's also a reflection of the FDA's statisticians who are antagonistic to non-inferiority studies.
In the EMEA, resistant gram-negative infections actually have a greater cost than gram-positive. The two biggest problems are gram-positive MRSA and gram-negative Carbapenem-resistant Pseudomonas aeruginosae
From an investment perspective, Polymedix's compounds exhibit good in vitro activity against many gram-negatives. But very early stage yet, and I don't know if they are focusing on gram-negatives.
I found a paltry list from an EMEA document of all new drugs in the clinic for gram-negative infections:
Tomopenem [Phase] II (Sankyo?)
hLF1-11 II (these are all some sort of immunomodulatory drug)
Lactoferrin I
Talactoferrin-alfa II
Opebacan III (Xoma)
NXL 104/ceftazidime I (Forest)
Don't personally know much about any of them.
Peter
I actually posted a reference here to this analysis a few weeks back:
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=46443959
Personally I recently decided to take my MDVN profits (I've held the stock for quite a while) and run. I'd call this trial a 50:50 shot, and the stock will move quite dramatically in one direction or another depending on the results. Options are all very expensive, so I'm intending to wait for the results and maybe trade the stock if the market either doesn't react fully or overreacts to the results.
Peter
That link is about interclonal tumor cell cooperation in fruit flies. Is that what you meant to link to?
Peter
Here is GSK's rebuttal memorandum:
http://link.reuters.com/bar62j
I'm guessing that if their methodology is the standard chop-it-up-into-little-bits and then use software to put the individual sequences back together, they need to know if the sample is from normal tissue (there's just going to be one sequence) or from a tumor (likely lots of variants and mutations within any tumor sample). If the latter, they probably have to work much harder.
[OT quiz]
Correct. (As is Jbog's response).
http://autos.aol.com/article/LED-lights-snow
[OT - LEDs]
There's a thread on SI about this "White light from LED" (not very active though):
http://siliconinvestor.advfn.com/subject.aspx?subjectid=27260
OT Quiz: Many towns have replaced their incandescent traffic lights with LED lights. The LED lights last much longer and are of course much more efficient. But in some areas, these LED lights have turned out to have what might be seen as a serious drawback. What is it?
Peter
An interesting side note - Plexxikon was co-founded by Yale professor Joseph Schlessinger - he was the "S" in Sugen. Tough guy - ex-Israeli army commando.
This is hands-down the private company I would most like to have stock in.
Peter
Seems like the big pharma check out this drug/drug interaction fairly commonly:
http://clinicaltrials.gov/ct2/results?term=midazolam+AND+Pharmacokinetics+
But agreed it has to be a good sign.
Peter
SLXP -
This is a tough condition to run a trial in, and I think the clinicians on the panel will be sympathetic to that.
Remember this is just a label expansion (albeit with a higher dose I think) - this is an approved drug.
Here's some discussion of existing treatments:
http://content.nejm.org/cgi/content/full/337/7/473
Peter
Here's the key negative paragraph from a review by the neurology folks:
There's another error, although maybe it's just carelessness:
not anticipating that oil prices would tumble nearly $150 a barrel
Well it tumbled from nearly $150, but it didn't tumble by nearly $150.
[OT FIOS]
The FIOS people came by and "signed me up" with a good deal to move me from Comcast - I took that offer to Comcast and they matched it, throwing in some premium channels for free. When I called Verizon to cancel, they offered me an even better deal, which I declined.
The Comcast Tivo (now they finally have the bugs out) is superior to Verizon's DVR, and Comcast on-demand has a much better free movie selection than Verizon does (I suspect because Comcast owns content).
Quality is essentially equivalent. I have Comcast business-class internet and phone which gets me quick response if the cable goes down. It's been very reliable the last year or so.
Peter
>>Micromet
From a purely medical perspective, given MRD-positive patients don't miraculously become MRD-negative without additional chemo, if they meet their primary clinical endpoint (based on conversion to MRD-negative), they will have demonstrated efficacy.
Whether they can get the FDA to agree, I am not at all sure. I'm sure the FDA will let them run this trial in the US as well as Europe, but that doesn't mean the FDA will necessarily agree that this qualifies as a pivotal trial.
The standard for single-arm trials is unmet medical need and no alternative approved treatment, and they meet that standard. You couldn't really blind this trial either, because 100% of the patients on the infusion get fever. So they could run something like a 2:1 randomization against "watchful waiting" I guess. Only disadvantage would be that they need a bigger trial but seems to me it would be worth it.
Peter
FWIW, Dimebon is an even more potent 5-HT7 inhibitor (Ki=8nM vs Ki=56nM for 5-HT6). HT7 is an interesting target in migraine prophylaxis.
It's surprising to me how benign its side effect profile has been given how promiscuous the drug is - it hits a whole slew of receptors, although maybe not at high enough concentrations for most of them to have much effect. Tightest affinity is to H1 by far, followed by HT7, HT6, and alpha1A adrenergic.
Peter
I posted that Bloomberg article on SI with a derogatory comment comment about this analyst's competence:
Now valued at $1.13 billion, Medivation may plunge 35 percent in Nasdaq trading if the study fails, said Ian Sanderson, an analyst at Cowen & Co. in Boston. Success may propel the stock to rise 20 percent, he said. Sanderson rates the shares “neutral.”
If I had an opportunity to buy at +20% after a successful trial result, that would be the only stock I owned. And an opportunity to sell at -35% after a failure would be fairly inviting too. Just look at the pricing of the options to see that the actual market disagrees strongly with this so-called analyst.
Peter
Dimebon/HD
I certainly didn't notice anything substantive and new in the paper. It includes discussion (more like speculation) about why a result on the MMSE scale and not on the others. One suggestion they made was that the MMSE scale was much more stable than the other two scales for the untreated patients over 6-12 months, but they also acknowledge it could simply be a random result because of multiple comparisons. (Of course if you are going to claim victory based on any one of three independent endpoints you need to reduce the p value accordingly).
Peter
Note these Dimebon HD results are just the publication of the top-line results first presented last year.
The only nugget in the paper that I don't think was mentioned last year was that the improvement on the MMSE was even better for the patients with more severe cognitive improvement (p=.008 in this post hoc subgroup analysis vs. p=.03 for the whole group). Note also fewer dropouts among the placebo group.
This top-line result when it first came out did give me some small amount of additional confidence that the drug wasn't just a Russian version of a placebo. But given the stock's substantial advance since then I've taken more than half off the table. The prostate drug should act as something of a backstop if the AD trial fails, but really I have no good feel for how the AD trial will come out - call it 50:50.
Here's a bearish analysis which amounts to "something doesn't smell right here:"
http://www.foursquarepartners.com/pdf/MDVN_2009_02.pdf
Peter
>>a primary-care salesforce of the kind operated by FRX is a less valued asset than it once was
Can't deny that.
>>3x the roughly $2B Dainippon Sumitomo paid
But Astellas and Daiichi Sankyo have 3x the sales of Dainippon, and Takeda must be something like 5x, so within reach.
Peter
>>FRX
The other asset FRX has is its primary care sales force. So another Japanese pharma might find that attractive (cf. Sepracor).
Peter
>>These are techniques that seem to be working for Merck with Maxalt
That's a silly statement by that author, although the rest of the article may have some validity. None of these issues apply to triptans. It's worth noting that MRK's non-instant-dissolving Maxalt tablet comes similarly packaged (except a bit smaller to account for the difference in size between the tablet and the MLT).
All the triptans come in individual packaging. The main reason for this in my opinion is pricing and insurance dosing limits. Typically insurance will only pay for 9 doses a month, and those cost around $150. So if you bulk up the packaging the patients are less likely to freak out when they receive a mostly empty pill bottle with a handful of pills lurking at the bottom.
(Incidentally the PK disclosed for Maxalt MLT shows it is actually slower than the tablets).
>>ACOR
Note there is a competing drug from Sanofi called Nerispirdine that I think is currently in Phase II.
There's a little about it at the end of this article:
http://pubs.acs.org/cen/coverstory/87/8714cover.html
I own a little ACOR - seems reasonably priced at these levels.
Peter