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It's worth noting that labeling discussions are in fact a part of the normal formal ANDA process, even for AB substitutable products.
An AB substitutable generic might have different excipients and different packaging and hence require minor labelling changes. There is also the possibility in some cases (not here) of a so-called section viii "carve-out" where the generic deliberately omits an intended use because of patent issues - this happened in the case of Camptostar.
Of course this doesn't quite square with the "crystal ball" statement, but I thought I should nevertheless mention it.
Peter
ITMN:
>>If the Bosentan trial meets their end point would you be less inclined to approve?
No, as I believe what we call "IPF" is actually multiple diseases, in which case it is likely that different drugs will work for different endpoints.
I think there is a good chance in many of these trials that a fair number of patients have some completely different underlying condition. "True" IPF is supposed to be rapidly progressive and fatal within a few years - that's not always what we have seen in the placebo groups in IPF trials. We really need some biomarkers to figure out the different subgroups.
Peter
ITMN:
>>I don't recall ever seeing such drastically different Phase 3 results for one compound
Drug performed the same in both trials. In the failed trial the placebo patients took a sudden turn for the better right before the endpoint.
I've never understood why companies pick an arbitrary single time for their endpoint rather than looking at a more robust measure like the area between the curves over some time range.
If I was on the AC I'd vote to approve - not that the drug is so great, but because it very likely works to some degree and there is absolutely nothing else out there for these patients.
At the end of the day CRME's drug is for something of a niche indication compared with the wide usage that amiodarone has despite its absolutely miserable side effect profile. Amiodarone is basically the drug of choice in heart failure patients with atrial fib (which is between 15-30% of all heart failure patients) because unlike other atrial fib drugs it has no negative inotropic effects. Amiodarone has to be a candidate for the trickiest-to-use and most toxic widely-used non-oncology drug.
So the comparison isn't really a good one. If Budiodarone is an easier-to-use amiodarone that works in a good percentage of HF patients with atrial fib, it would find wide use as a first-line agent, with amiodarone reserved for patients that don't respond. So it clearly has at least potential as a significant blockbuster, although it's still too early to project its ultimate efficacy and S/E profile and hence how it will actually play out.
CNS side effects of VVUS drug:
I think it would be a miracle if there were no cognitive side effects given the combination includes Topamax (AKA as "Dopamax"). I can personally attest to these as I tried Topamax for migraines - I couldn't think of common words when I was on the drug. But it's important to note that these side effects disappear once you stop Topamax, and the incidence appears to be fairly low - certainly under 5%. Further, the Qnexa doses of Topamax are much lower than those typically used in epilepsy and migraine. So at the end of the day I don't see this as a big issue - some people will not tolerate the drug and will stop. We're not talking about issues like seizures that will cause the FDA great concern. (There are some very-low-incidence side effects of Topamax that are of more concern such as kidney stones and ocular issues).
Somehow nobody seems to be talking about the side effect profile of the OREX drug. Wellbutrin has a suicide black box, and the other constituent (naltrexone) is well known for making people feel out of sorts, perhaps because it blocks endorphins. At the end of the day I believe the Qnexa tolerability and label will be more benign than that of OREX's drug.
Peter
>>question on tryglicerides
Time to do your part and contribute to pharma industry revenues. :)
Obviously there was a marked improvement using your new regimen (what was it?), but only from terrible to bad. HDL still too low, blood sugar somewhat high (was it a non-fasting level in which case it might be OK?), triglycerides still much too high.
Basically you need to also be on a statin (generic Zocor) plus maybe Niaspan (Abbott) to get your HDL up. High-dose fish oil (Lovaza - GSK) might be necessary to get your triglycerides down, or you can just take lots of OTC fish oil or krill oil. Exercise and a better diet will certainly help too but I doubt if they will be enough by themselves. Next time have doctor test HbA1c instead of blood sugar.
Standard "I-am-not-a-doctor" disclaimer applies.
(Note it's spelled "triglycerides" - if you search using your spelling who knows what flaky sites you will find).
I'd never heard of this PCYC program until your post. Btk is indeed downstream of SYK (inasmuch as anything in these systems with feedback loops and redundant pathways can be said to be downstream of something else), so I could imagine inhibiting it might have fewer side effects.
This article gives some insights into the connection between SYK and Btk:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC16561/
On looking further, I would have some long-term tox concerns, as it seems Btk is a negative regulator of the Wnt-beta-catenin pathway:
http://www.ncbi.nlm.nih.gov/pubmed/19471023
The Wnt-beta-catenin pathway is crucially upregulated in initial colon cancer, raising an obvious concern.
I think the bottom line is that there are unknown risks involved in chronically intervening in any of these complex immunological pathways in non-fatal conditions. (Tysabri is of course a poster child for just such an unknown risk.) So maybe second or third to market with a better drug is the smarter general strategy.
Whether I might ever be tempted to even remotely consider investing in PCYC depends on how thoroughly they fumigated the place after the previous management departed. :)
Peter
The RIGL fans appear to be away from their desks
Well at these levels I previously qualified as a RIGL fan myself, although I currently don't own any. But this article certainly has given me second thoughts by at very least raising the already high safety bar here.
At the end of the day maybe their drug belongs in their oncology indication rather than in RA.
Peter
I posted on SI about a potential negative for RIGL:
http://siliconinvestor.advfn.com/readmsg.aspx?msgid=26043521
Peter
I looked at the Rigel presentations briefly, but only caught a small part of their presentation.
The one new thing they present is that for TASKi3 (the failed trial) there was a significant difference between patients that entered via an elevated CRP (where the drug was on the border of being statistically superior and was p<.002 superior on DAS28) and those that entered via an elevated ESR but normal CRP, where the placebo was numerically dramatically better than the drug.
This may well just be a statistical artifact, or it may be indicative that the ESR was fudged by some trial sites to get patients who didn't really have active disease into the trial. (The CRP was measured at a central site, the ESR locally).
I'm pretty sure this is an active, partnerable drug. But at this point it does have some warts because of the hypertension issue and the failed TASKi3.
>Fusilev
This is a quite misguided article. The FDA does not consider the eventual cost of the drug in making its decisions. The cost isssues emerge only when payors decide whether or not to cover the drug.
I did some research on Fusilev last year. For some reason this version of the generic has good sales in Europe, but its practical (rather than theoretical) advantages over the generic seemed quite unclear to me.
Note SPPI must have gotten some temporary sales boost because of the previous shortage of the generic leucovorin:
http://chocgpo.files.wordpress.com/2009/01/leucovorinshortage.pdf
Correction:
What I do find weird about her analysis is the way she has linked what happens with M-118 and Copaxone. I grant that if the FDA rejects M-118
That should of course be:
What I do find weird about her analysis is the way she has linked what happens with Lovenox and Copaxone. I grant that if the FDA rejects M-Enoxaparin
Peter
>>1. Robyn Karnauskas (the lead Deutsche Bank analyst assigned to MNTA) says MNTA is worth $18/sh without any contribution from Lovenox while also arguing that the share price will fall to $6 or less if the FDA approves more than one generic Lovenox (which would, of course, provide MNTA some economic value attributable to Lovenox). This is so bizarre that I need to state it again: Karnauskas says MNTA would be worth $18/sh if the Lovenox program did not even exist, but she expects the share price to fall to $6 if the FDA approves multiple generics. A real head-scratcher!<<
That's not the way I read the report. She does assign a $9 NPV to M-118, plus $1 cash, plus (a generous) $2 to pipeline, plus $2 NOL. The NPV of Copaxone is variable - she links it to different scenarios, but overall it is $4. She then subtracts a variable amount between $9 and $14 for the costs of the base business. Thus you are missing the NPV offset for the cost to run the business.
In her "no generics" Scenario 1, she assumes no contribution from Copaxone or M-Enox, and hence a $5 fair value. In the "several generics" scenario she favors, she assigns $9 to M-Enox and $4 to Copaxone, ending up with a $18 fair value.
What I do find weird about her analysis is the way she has linked what happens with M-118 and Copaxone. I grant that if the FDA rejects M-118, then the NPV for Copaxone would also be reduced. But it makes no sense to me to reduce the NPV for Copaxone if there are multiple M-118 generics - no way there will be multiple Copaxone generics.
The other complaint I have about her analysis is I think she overestimates the likelihood of multiple generics. This statement of hers is key:
We believe Xa: IIa activity will likely be the primary analysis required by the FDA to show bioequivalence because so little is known about the other activities of Lovenox. While Sanofi-Aventis argues there are other functional components of Lovenox (many unknown) we believe they do not fall under the FDA’s definition of being proven clinically meaningful. As evidence, these functional components are not outlined in the USP.
(emphasis added)
The issue here is that it is incumbent on a would-be generic to prove that the other components are not clinically meaningful if they cannot completely characterize the compound and show they are the same. Just look at Premarin for a good precedent. If "so little is known about the other activities" of the drug, that, to my mind is a good reason for the FDA to be cautious here.
Except for these two issues (the conflation of the M-118 and Copaxone scenarios and her over-estimate of the likelihood of multiple generics), I think the report is pretty reasonable, with NPV's in the different scenarios not that different from your ranges.
Peter
>>MNTA’s Valuation in the Single-Generic Lovenox Scenarios
This particular analysis seems quite reasonable to me, but I do have one concern with your overall methodology.
In my view, the single most likely outcome is that MNTA's generic gets approved but we are left hanging as to whether other generics will ever receive approval or not. So then you would essentially have a blend between the single generic case and the multiple generic case, and the stock will trade as some blend of the two outcomes. Even though in that scenario MNTA's drug would be the only approved generic (at least for some time), there would always be an overhang of doubt about the possibility of later approvals of competitor drugs that would prevent it reaching the "single generic" range you are projecting.
FWIW, my take on the possibility of an "authorized generic" is that Sanofi launching an authorized generic would be quite unlikely in the "single generic" case but likely in the "multiple generic" case. The reason for this is that in the single generic case there would be duopoly pricing, and Sanofi would have little reason to further undercut the price.
MNTA has been a frustrating stock for me over the years. I was long for a while shortly after they went public, then eventually gave up in frustration, but re-entered after the heparin contamination publication and then stayed in the stock too long. Right now I have a modest net-long option position.
Peter
>>MNTA now has about 49.1M diluted shares for valuation purposes.
You just hit on a pet peeve of mine. You are calculating "diluted shares" ignoring the dollars the company gets for the option exercise, which exaggerates the dilutive impact.
The correct way to do it is to use the so-called Treasury Stock Method, which uses the assumed proceeds of the hypothetical exercise to buy back a portion of the assumed to be issued shares. As a first approximation, you can use the strike price of the option as the assumed proceeds, although the actual calculation is quite a bit more complex as unamortized compensation expense and any tax benefit credited to APIC are also included.
If you do the calculation correctly you will see that the dilutive effect of an option that is only barely in-the-money is minimal, while the dilutive effect of unvested restricted stock (which is basically an option with a zero or $0.01 strike price) is much greater.
>Abraxane
"Definitive studies to show it is better than Taxol have yet to be done," says Eric Winer, a top breast cancer researcher at the Dana-Farber Cancer Institute.
See abstract below. For some reason I don't fully understand the academic centers have been resistant to the drug.
Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer.
Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J.
Northwestern University, Breast Oncology, Division of Hematology/Oncology, Department of Medicine, Chicago, IL 60611, USA. w-gradishar@northwestern.edu
PURPOSE: ABI-007, the first biologically interactive albumin-bound paclitaxel in a nanameter particle, free of solvents, was compared with polyethylated castor oil-based standard paclitaxel in patients with metastatic breast cancer (MBC). This phase III study was performed to confirm preclinical studies demonstrating superior efficacy and reduced toxicity of ABI-007 compared with standard paclitaxel. PATIENTS AND METHODS: Patients were randomly assigned to 3-week cycles of either ABI-007 260 mg/m(2) intravenously without premedication (n = 229) or standard paclitaxel 175 mg/m(2) intravenously with premedication (n = 225). RESULTS: ABI-007 demonstrated significantly higher response rates compared with standard paclitaxel (33% v 19%, respectively; P = .001) and significantly longer time to tumor progression (23.0 v 16.9 weeks, respectively; hazard ratio = 0.75; P = .006). The incidence of grade 4 neutropenia was significantly lower for ABI-007 compared with standard paclitaxel (9% v 22%, respectively; P < .001) despite a 49% higher paclitaxel dose. Febrile neutropenia was uncommon (< 2%), and the incidence did not differ between the two study arms. Grade 3 sensory neuropathy was more common in the ABI-007 arm than in the standard paclitaxel arm (10% v 2%, respectively; P < .001) but was easily managed and improved rapidly (median, 22 days). No hypersensitivity reactions occurred with ABI-007 despite the absence of premedication and shorter administration time. CONCLUSION: ABI-007 demonstrated greater efficacy and a favorable safety profile compared with standard paclitaxel in this patient population. The improved therapeutic index and elimination of corticosteroid premedication required for solvent-based taxanes make the novel albumin-bound paclitaxel ABI-007 an important advance in the treatment of MBC.
And this interesting preclincal study suggesting it may be better in HER2 negative tumors:
1: Anticancer Drugs. 2008 Oct;19(9):899-909. Links
Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status.
Desai NP, Trieu V, Hwang LY, Wu R, Soon-Shiong P, Gradishar WJ.
Abraxis BioScience, LLC, Los Angeles, California 90025-1506, USA. ndesai@abraxisbio.com
Nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) is an albumin-bound 130-nm particle form of paclitaxel that demonstrated higher efficacy and was well tolerated compared with solvent-based paclitaxel (Taxol) and docetaxel (Taxotere) in clinical trials for metastatic breast cancer. Nab-paclitaxel enhances tumor targeting through gp60 and caveolae-mediated endothelial transcytosis and the association with the albumin-binding protein SPARC (secreted protein, acidic and rich in cysteine) in the tumor microenvironment. The overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer has been shown to correlate with resistance to paclitaxel. To evaluate the importance of HER2 and SPARC status in determining the relative efficacy of nab-paclitaxel compared with polysorbate-based docetaxel, nude mice bearing six different human tumor xenografts were treated with nab-paclitaxel (MX-1: 15 mg/kg, once a week for 3 weeks; LX-1, MDA-MB-231/HER2+, PC3, and HT29: 50 and 120 mg/kg, every 4 days three times ; MDA-MB-231: 120 and 180 mg/kg, every 4 days three times) and polysorbate-based docetaxel (15 mg/kg). HER2 and SPARC status were analyzed by RT-PCR and immunohistochemical staining. MDA-MB-231 and MX-1 breast and LX-1 lung cancers were HER2 negative and low in SPARC expression. Nab-paclitaxel at submaximum-tolerated dosage was significantly more effective than polysorbate-based docetaxel at its maximum-tolerated dosage in these three HER2-negative tumors. The HER2-positive tumors had variable SPARC expression, with MDA-MB-231/HER2+ <PC3 <HT29. In these HER2-positive tumors, nab-paclitaxel was equal to or better than polysorbate-based docetaxel in tumors with medium to high SPARC levels (PC3 and HT29), but not in MDA-MB-231/HER2+ tumors with low SPARC expression. These results demonstrated that the relative efficacy of nab-paclitaxel was significantly higher compared with polysorbate-based docetaxel in HER2-negative tumors (three of three) and in HER2-positive tumors with high levels of SPARC. HER2 and SPARC expression may be useful biomarkers in determining antitumor effectiveness for taxanes.
>>Wonder how and why this poster, who registered 2.5 years ago, wants to jump in and is able to remember the posting password never used or even needed before<<
That would be me. I'm Biomaven on Silicon Investor, and Dew posts not infrequently on the Biotech Valuation board on SI I have moderated for many years and I returned the favor here.
Ihub has a very simple "recover your password" feature.
Peter
Looks to me like you are getting your information from Wikipedia, which in this rare case happens to have very weak entries. Using "dilutive" vs. "non-dilutive" to differentiate between primary and secondary offerings indicates to me that this entry was written by an amateur. (Not all offerings that increase the number of shares outstanding are dilutive - indeed they could theoretically be anti-dilutive).
The legal terminology is actually quite precise and simple:
IPO vs. Follow-on offering: The first public sale of securities is an IPO; any subsequent sales are follow-on offerings.
Primary vs. Secondary: If the company is selling shares, it is a primary offering. If existing shareholders are selling shares, it is a secondary offering.
This MNTA offering was a primary, follow-on offering.
In many cases an offering will be a mixed primary and a secondary - both the company and existing shareholders are selling shares.
I do grant that some non-lawyers use the term "secondary" more broadly to cover all sorts of follow-on offerings.
As to your initial point, any member of this board that happens to have a strong relationship with the underwriters could have gotten shares. That's the same for an IPO, or for any underwritten offering. No member of the public can automatically acquire shares in an underwritten offering - it's up to the underwriters to decide who gets them.
MNTA offering was not a PIPE or a registered direct offering. Technically it was an underwritten follow-on offering by the company. The fact that the underwriters felt no need for a road show and likely offered it only to institutional investors doesn't make it a PIPE. The underwriters can stabilize the market post offering should they so desire.
By contrast, registered direct offerings are not underwritten. They are still considered public offerings under the 1933 Act however, and require a registration statement or an existing shelf. The placement agent (in lieu of underwriter) cannot inventory the shares and cannot intervene post-offering because of Reg M.
In both underwritten offers and registered direct offers, the ultimate purchasers of the offering sign no offering documents and are not subject to any Sec. 144 resale restrictions. That provides the biggest distinction with PIPEs. Often in PIPEs the buyers are locked-up for some period and the registration statement is only filed post-offering. Only accredited investors can typically invest in PIPEs.
Underwritten offerings are the most expensive (legal and underwriter fees), but they offer the least discount from the market. Registered directs are somewhat less expensive (particularly if there is an existing shelf), but involve a bigger discount. PIPEs are the cheapest but have the biggest discount.
Right now, the trend is very much away from PIPEs and towards registered directs.
Peter