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Pretty simple; China has over 50% of the worlds pigs. Not a cost issue
It’s kind of stupid. They downgrade from a buy to neutral w a $21 price target. Not sure how that computes but I’m not a sell-side analyst…..here’s the first page
Summary and Highlights
While Teva has yet to gain FDA approval for their enoxaparin, investors have been afraid to own MNTA shares, wanting to wait until “the shoe drops” before getting involved. Similarly, consolidation of the Mylan and Momenta/Sandoz litigation regarding Teva’s Copaxone patents has likely delayed the outcome of that case until 2012. Hence, we are hard pressed to see an obvious path for substantial MNTA share appreciation this year.
The never-ending Lovenox soap opera. Ever since Teva declared last August that they were a month behind Momenta in launching their version of generic Lovenox, Momenta has been in the unfavorable position of having to disprove a negative. First, Teva claimed to be a month behind Momenta. When three months passed, Teva expressed optimism that they would gain approval by the end of 2010. In late January, Teva announced that they had received a “minor deficiency letter” from the FDA, implying that they could gain approval in a matter of weeks or months. We continue to model an April 1 Teva launch, but Teva’s latest FDA Warning Letter suggests that may be optimistic.
Momenta’s 4q10 run rate will last until Teva’s launch. We believe that Momenta’s reported 4q10 earnings of $36.3 million, or $0.79 per 4q10 share, should continue at a relatively stable rate until Teva gains FDA approval. We remind investors that Momenta conducted a 4.2 million-share secondary offering in December, which would imply a forward quarterly EPS of $0.73. Given that Momenta lost 34 and 37 cents in the two quarter preceding the launch of m-enoxaparin, each quarter in which Momenta retains generic exclusivity accounts for an earnings swing of $1.08 or more.
Results of Copaxone trial unlikely until 2012. Given the likely consolidation of the Mylan and Sandoz/Momenta Copaxone lawsuits, we don’t expect resolution of the litigation until the first half of 2012. While Teva believes Copaxone is “safer than ever before,” we believe their optimism is premature. However, as with the Lovenox situation, Momenta
is forced to disprove a negative to investors who otherwise remain on the sidelines.
Key Catalysts: News from Teva on their enoxaparin ANDA; progress on Copaxone patent litigation in 2011.
Valuation. We have projected Momenta’s income streams out to 2017, using a sum-of-the-parts approach, discounting future income by 12%. We assign no value to M-118, a proprietary anti-thrombotic agent with promising phase IIa data.
That's not what IMS is showing
I guess I shouldn't have used the term Wall Street; too specific for you. Let me rephrase; there is not a single reputable analyst in North America or Europe that thinks the CVR will have value. Not sure who the bucket shop in London is that you are linking. Probably fraudulent as it was pulled.
Yes I am short the CVR. Tell me why I shouldn't be.
There is not one analyst at any Wall Street bank that covers FRE that thinks the CVRs will have value. Call them and/or read their research.
Per IMS APP had sales of Propofol of $20.3 million in Q4 compared to $16 million in Q3; hardly enough to get to the threshold.
Also per IMS APP heparin sales are down in Q4 going to $39.3 million from $47 million.
LOL...it's not my opinion it's a fact. Read the CVR agreement. They need to exceed $1.267 billion in cumulative EBITDA for the 3 year period and currently have $997 million. That leaves $270 million. Why do think that is incorrect?
But you should be scared if you own the CVR as it will soon be zero.
That's correct. They need to break $270 million in Q4 for any value
Same way as a stock; get the borrow from you broker. Cover the same way as you do w a stock; buy the CVR. You can also let it expire similar to selling an option. Same maintenance requirements too (shorting below $2.50 a share requires maintenance requirement of $2.50 a share). So if you short 100k shares of the CVR at $0.10 for a $10k position you need $250k of collateral. Because of this you are pretty limited on what you can do. I was looking at ways to get around the $2.50 maintenance offshore but unfortunately it can't be done. If anyone on this board would like to discuss engaging in a private option contract on if the CRV being in the money I would gladly entertain it up to $200k.
Not sure how you think shorting something w zero value is suicide or risky. I would love to hear a reasonable explanation of how you think APP will make $270 million in EBITDA in Q4? Look at the IMS data. It's not going to happen. It won't even be close. Last Q was their highest EBITDA ever @ ~ $150 million and you are talking about doubling it w their largest drugs declining in sales.
The CVR is worthless and has been for 18 months. Not sure how you think they make $270+ million in EBITDA in Q4. Not going to happen; really wont be close. Probably won't break $150 million
You should short APCVZ. It should be zero in a month when Q4 #s are out. Will expire worthless in June.
From Wedbush – saying the same thing as Goldman
“Moreover, we note that the term “minor” is often a misnomer with respect to deficiency letters. For instance, MNTA itself received a “minor deficiency letter” with respect to its immunogenicity data, an issue which eventually took MNTA a full 18 months to resolve to the FDA’s satisfaction. Indeed, for truly simple issues, the FDA has created a telephone amendment pathway through which these issues can be resolved. The FDA’s decision to not employ this telephone amendment path suggests that substantive issues do remain for TEVA.”
One other bullet
"TEVA describes the issues as minor, but company’s track record is questionable here. TEVA’s press release appears to portray the unresolved issues as relatively insignificant and easily resolved. However, we caution investors from taking this at face value: Recall that upon MNTA’s approval in July 2010, TEVA responded by saying it expected to receive approval of its own generic Enoxaparin in late August. When August passed with no approval, the company then stated that it believed an approval was imminent in the autumn of 2010. When that failed to materialize, TEVA said it would be “disappointed” if they did not receive approval by year end. After failing to receive approval in 2010, TEVA disclosed at an analyst conference earlier this month that the FDA would provide a response by the end of this month, and that TEVA expected the decision to be an approval. While TEVA describes the FDA’s letter as having a short-list of minor issues, we note that the company has a growing history of being unrealistically optimistic regarding the timing of approval. In our view, TEVA’s past history raises the possibility that the unresolved issues could be more substantive and take longer to resolve than TEVA’s press release suggests. That said, because the public is unable to review TEVA’s ANDA itself, it is impossible for us to say with any confidence that approval will never occur. For this reason, we continue to expect approval in Q4:2011."
They had been buying API from a fake manufacturing plant in China and got busted by the FDA. I can see why the FDA is reluctant to let them import anything.
I would like to see them resume work on their generic Fragmin (Dalteparin). Not a very big drug but they’ve already done a lot of work on it and it’s a LMWH so there should be no issue w approvability. It would be a small but nice revenue stream.
oldberkeley-
Yes Lupenox was tested in this study. If you look at slides 26-36 you can see the different generics listed by name.
The way I read it none of the generic LMHWs tested in this study could pass the FDA criteria for sameness.
I’m not sure on the exact date of the study but I presume it is 2008. That is when the abstract was written.
Generic low molecular weight heparins. Are there any guidelines!
Well this is interesting. The here is the link to the full Loyola University Medical Center presentation comparing Lovenox and different versions of generic LMWH.
http://www.sasat.org/documents/powerpoint/Development_of_Generic_lmwh-what_are_the_guidelines.ppt
I’d like to first point you to slide # 7.
“Is Chemical Characterization of Branded LMWHs Sufficient to Satisfy Assure Pharmacodymamics Equivalence?”
Answer: “No. Because LMWHs are hybrid products of biologic origin with chemical modifications. Moreover the starting material is more important to characterize for product consistency.”
Assuming Dr. Fareed knows what he’s talking about, I would say Teva’s comments on achieving chemical sameness are somewhat inconsequential. It sure did sound good though.
I would next like to point you to slides 29-36 comparing Pharmacodymamics of several generic LMWH. Seems like they are different from a Pharmacodymamics perspective.
Many other good slides to review as well but these are the most relevant in my opinion.
You should ask Teva IR the question. Make them put it in writing
Teva's comments today about the FDA make no sense. Anyone who has ever dealt w the FDA knows they don't provide you w tacit verbal approval for portions of an application. They never really tell you anything. They ask questions and more questions and move on. You are always open to additional questions, data requests and studies. Then one day you get a letter and you are either approved, denied or need to provide more info.
Complicating the situation for generic enox is the fact that many different divisions of the FDA are involved. The OGD may be totally fine w the drug and then another division, like biologics, can review and ask for all sorts of additional information. In fact, this is what played out several years ago w the request for immunogenicity studies. OGD was fine w the applications and biologics stepped in and requested more work. Word on the street at the time was OGD was ready to approve all 3 of the applications and Amphastar was gearing up for an IPO….looks like that didn’t happen.
The analyst community is shockingly bad.
That's what they said in the intro when they were updating on US ops
The Immunogenic Potential of Generic Version of Low-Molecular-Weight Heparins May Not be the Same as the Branded Products
Jawed Fareed, PhD, DSc, Rodger L. Bick, MD, PhD, Gundu Rao, PhD, Samuel Z. Goldhaber, MD, Arthur Sasahara, MD, Harry L. Messmore, MD, Debra A. Happensteadt, PhD, and Andrew Nicolaides, MD, on behalf of the IACATH, IUA, SASAT, and NATF*
Heparin-induced thrombocytopenia (HIT) is a catastrophic adverse reaction associated with the use of heparins and related products. Although the incidence of HIT with low-molecularweight heparins (LMWHs) is much lower than with unfractionated heparin (UFH),1 these agents are capable of triggering immunogenic responses in 10% to 20% of the patients treated for different indications. The generation of these antibodies depends on the dosage, duration of treatment, patient population, and underlying comorbidities. Differences in the immunogenic responses among different branded LMWHs have been noted. These differences are due to the structural composition of the LMWH and the interactions with endogenous platelet factor 4 (PF4) and other proteins.
Low-molecular-weight heparins have been differentiated on the basis of several biophysical, biochemical, and pharmacologic properties. These differences translate into their safety and efficacy profiles in a given clinical indication. Therefore, the United States Food and Drug Administration (FDA) and other regulatory bodies consider each of the commercially available LMWHs as a distinct drug and require clinical validation for the approval of each of these in specific indications. The introduction of generic versions of the branded LMWHs has challenged the regulatory bodies to develop specific guidelines for their approval. The current guidelines for generic drug approval are not adequate because of the complex nature of the LMWHs due to biologic origins and chemical modifications of a polycomponent mixture of glycosaminoglycans.
Although the incidence of HIT is rare with the use of LMWHs and heparinomimetics such as fondaparinux and idraparinux when used for prophylactic and therapeutic indications, these agents are capable of generating antibodies to heparin-PF4 complex, which are measurable by using immunologic methods. 2-11 The relative prevalence of these antibodies is method-dependent owing to different capturing probes. Moreover, the relative proportion of antibody subtypes (immunoglobulin G, A, and M) differ from product to product.12-14 Up to 20% of the patients treated with LMWHs generate these antibodies. The pathophysiologic role of these antibodies remains unknown at this time.15-20 However, this immunogenic response is comparable to autoimmune responses observed in the case of the antiphospholipid syndrome. Additional data are needed to identify the role of these antibodies in various pathologic states and their impact on clinical outcomes.
The FDA has been visionary in identifying the immunogenicity of LMWHs as an important criterion to differentiate and demonstrate the bioequivalence of generic LMWHs to the branded products. The agency has made a determination that the immunogenic responses of LMWHs occur because of the interactions of the components of the generic products with PF4 and other proteins, that result in the formation of complexes that lead to an immunogenic response. Therefore, if a generic product has identical composition and similar proportion of the oligosaccharide components as the branded product, then the generic product would exhibit a similar quantitative and qualitative immunogenic profile. Such a bioequivalence can only be demonstrated in well-designed, population-balanced clinical trials that include critically ill patients with multiple pathogenic etiologies. The FDA is to be commended for this very clear directive. This underscores the concerns on the use of biologics that have multiple components and mechanisms of action.
Although the generic LMWHs may exhibit similar molecular profile and anti-factor Xa potency, some of the currently available generic versions of LMWHs have been found to differ in their biochemical and pharmacologic profiles.21 Therefore, the additional recommendation to profile these agents for other biologic actions and their interactions with cells beyond the immunogenic profiling should also be taken into consideration to assure therapeutic equivalence. As the different regulatory and professional organizations are moving ahead in developing recommendations for the therapeutic and generic interchange of these drugs in different indications, the FDA’s action to require immunogenic profiling of these drugs is not only timely but also prudent in establishing approval guidelines which will have an International impact.
Heparin and LMWHs are also capable of binding to several other endogenous proteins. It is likely that these interactions can also result in the generation of neoepitopes. The physiologic implications of such responses are not known. Most of the immunogenic response data currently available are based on the use of 2 methods that use enzyme-linked immunosorbent assay.22With the advances in technology, several other methods have recently become available. Therefore, it is important to have standardized methods to compare the immunogenic potential using valid methodologies with particular reference to the specific antibodies to be profiled. At the present time, the immunogenic profiling is focused on the antibodies that are generated against the PF4 neoantigen formed upon complexation of heparin oligosaccharides and PF4.
The International Academy of Clinical and Applied Thrombosis and Hemostasis (IACATH), the International Union of Angiology (IUA), the South Asian Society of Atherosclerosis and Thrombosis (SASAT), and the North American Thrombosis Forum (NATF) will review and consider endorsing this requirement in conjunction with the white paper that is currently being prepared on the International Summit on Generic Antithrombotic drugs that was held in New Delhi under their auspices on October 12, 2007. This white paper will be published in the journals of the sponsoring societies and posted on their respective Web sites
References
1. Walenga JM, Prechel MM, Jeske WP, Bakhos M.
Unfractionated heparin compared with low molecular
weight heparin as related to heparin-induced thrombocytopenia.
Curr Opin Pulmon Med. 2005;11:385-391.
2. Warkentin TE, Levine MN, Hirsh J, et al. Heparininduced
thrombocytopenia in patients treated with lowmolecular-
weight heparin or unfractionated heparin.
N Engl J Med.. 1995;332:1330-1335.
3. Amiral J, Peynaud-Debayle E, Wolf M, Bridey F, Vissac
AM, Meyer D. Generation of antibodies to heparin-PF4
complexes without thrombocytopenia in patients treated
with unfractionated or low-molecular-weight heparin.
Am J Hematol. 1996;52:90-95.
4. Bauer TL, Arepally G, Konkle BA, et al. Prevalence of
heparin-associated antibodies without thrombosis in
patients undergoing cardiopulmonary bypass surgery.
Circulation. 1997;95:1242-1246.
5. Pouplard C, May MA, Iochmann S, et al. Antibodies to
platelet factor 4-heprin after cardiopulmonary bypass in
patients anticoagulated with unfractionated heparin or a
low molecular weight heparin: clinical implications for
HIT. Circulation. 1999;99:2530-2536.
6. Lindhoff-Last E, Eichler P, Stein M, et al. A prospective
study on the incidence and clinical relevance of heparininduced
antibodies in patients after vascular surgery.
Thromb Res. 2000;97:387-393.
7. Prechel M, Bano A, Drenth AF, Messmore HL, Walenga
JM. Assay selection and interpretation for laboratory
testing of heparin-induced thrombocytopenia: diagnostic
implications. Blood. 2001;98:36a.
8. Gruel Y, Pouplard C, Nguyen P, et al, the French
Heparin-Induced Thrombocytopenia Study Group.
Biological and clinical features of low-molecular-weight
heparin-induced thrombocytopenia. Br J Haematol.
2003;121:786-792.
9. Francis JL, Palmer GP III, Moroose R, Drexel A.
Comparison of bovine and porcine heparin in heparin
antibody formation after cardiac surgery. Ann Thorac
Surg. 2003;75:17-22.
10. Gluckman TJ, Segal JB, Fredde NL, et al. Incidence of
anti-platelet factor 4/heparin antibody induction in
patients undergoing percutaneous coronary revascularization.
Am J Cardiol. 2005;95:744-747.
11. Warkentin TE, Maurer BT, Aster RH. Heparin-induced
thrombocytopenia associated with fondaparinux. N Engl
J Med. 2007;356:2653-2654.
Ahmad S, Untch B, Haas S, et al. Differential prevalence
of anti-heparin-PF4 immunoglobulin subtypes in patients
treated with clivarin and heparin: implications in the HIT
pathogenesis. Mol Cell Biochem. 2004;258:163-170.
13. Ahmad S, Haas S, Hoppensteadt DA, et al. Differential
effects of clivarin and heparin in patients undergoing hip
and knee surgery for the generation of anti-heparin-platelet
factor 4 antibodies. Thromb Res. 2003;108:49-55.
14. Ahmad S, Bacher P, Lassen MR, et al. Investigations of
the immunoglobulin subtype transformation of antiheparin-
platelet factor 4 antibodies during treatment with
a low-molecular-weight heparin (Clivarin) in orthopedic
patients. Arch Pathol Lab Med. 2003;127:584-588.
15. Chilver-Stainer L, Lämmle B, Alberio L. Titre of antiheparin/
PF4-antibodies and extent of in vivo activation of
the coagulation and fibrinolytic systems. Thromb Haemost.
2004;91:276-82.
16. Mattioli AV, Bonetti L, Sternieri S, Mattioli G. Heparininduced
thrombocytopenia in patients treated with unfractionated
heparin: prevalence of thrombosis in a 1 year
follow-up. Ital Heart J. 2000;1:39-42.
17. Williams RT, Damaraju LV, Mascelli MA, et al. Antiplatelet
factor 4/heparin antibodies. An independent
predictor of 30-day myocardial infarction after acute coronary
ischemic syndromes. Circulation. 2003;107:2307-12
18. Fareed J, Iqbal O, Nader H, et al. Generic low molecular
weight heparins: a significant dilemma. Clin Appl
Thromb Hemost. 2005;11:363-366.
19. Hoppensteadt D, Jeske W, Ahsan A, Walenga J, Fareed J.
Biochemical and Pharmacologic Profile of Defined
Molecular Weight Fractions of Heparin. Sem Throm
Hemost. 1993;19:12-19.
20. Untch B, Ahmad S, Jeske W, et al. Prevalence, isotype,
and functionality of antiheparin-platelet factor 4 antibodies
in patients treated with heparin and clinically
suspected for heparin-induced thrombocytopenia: the
pathogenic role of IgG. Thromb Res. 2002;105:117-123.
21. Jeske WP, Ackerman P, Drenth A, Walenga J, Bakhos M.
Generic versions of branded low molecular weight heparins
can be differentiated in biologic and pharmacologic assays.
J Thromb Haemost. 2007;5(suppl 2):P-M-647.
22. Izban KF, Lietz HW, Hoppensteadt DA, et al. Comparison
of two PF4/heparin ELISA assays for the laboratory
diagnosis of heparin-induced thrombocytopenia. Semin
Thromb Hemost. 1999;25(suppl 1):51-56.
That's great. These fools are going to get crushed
FDA Says It May Tighten Standards for Generic Drugs
By Anna Edney - Oct 20, 2010 4:52 PM CT
The U.S. Food and Drug Administration may tighten standards for how closely generic drugs resemble brand-name equivalents, said Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research.
Patients and employees of generic-drug makers have told the FDA that some of the medicines don’t work as well as the originals, Woodcock said today in an interview after speaking to the Generic Pharmaceutical Association in Bethesda, Maryland. The FDA is discussing tightening the limits "so there is less variability," she said.
Regulators are focusing on the issue because more prescriptions are filled with lower-cost copies of medicines as insurers try to cut costs and name-brand drugs lose patent protection. Woodcock raised the issue in a speech, and said later that her agency is considering tighter standards.
“Although Dr. Woodcock did not elaborate on her comment relating to therapeutic equivalence, we are always very concerned about any potential problems and look forward to following up with her,” said Bill Head, senior vice president of government affairs for the pharmaceutical association, which represents Mylan Inc. and Novartis AG’s Sandoz division.
Patients have complained about generic anti- seizure medications not working as well as brand-name counterparts, Woodcock said.
Use of generic nervous-system medicines, which include anti-seizure drugs, generated $250 billion in health care savings from 1999 to 2008, according to data from the generic association that Woodcock presented. The savings were the most of the 14 categories of drugs presented, totaling $733 billion.
Generic Competition
Brand-name drugs stay on the market an average of 12.8 years before facing generic competition. By the end of their first year, generics can capture nearly 60 percent of market share.
Woodcock told industry executives and employees their colleagues have approached her with concerns at similar conferences. They said some generic drugs have spurred quality concerns that went unnoticed in the approval process because clinical testing includes too few patients.
“They say, ‘I know there are products out there that aren’t equivalent,’ and typically they’re manufacturing folks,” Woodcock said in her speech. “I’ve heard it enough times from enough people to believe that there are a few products that aren’t meeting quality standards.”
Unspecified Drugs
The lower-level employees don’t specify which drugs have sparked quality concerns, she said in the interview.
Given the high rate of generic-drug use in the U.S., it’s important for the Food and Drug Administration to continue ensuring that generic products are as safe and effective as the innovator products they copy, said Wes Metheny, senior vice president of the Pharmaceutical Research and Manufacturers of America in Washington, the brand-name drugmakers’ lobby.
David Rosen, an attorney at Foley & Lardner LLP in Washington who served as a top-level generic official at FDA between 1980 to 1989, said questions have long been raised about generic compounds’ effectiveness based on anecdotal evidence. He wondered what is different now.
No Timetable
“I was surprised to hear that Woodcock was questioning the quality without identifying specific products, and I have confidence in the agency’s rigorous review process,” Rosen said.
Woodcock said she didn’t know when the agency would come to any conclusions about generic standards of equivalence. The standards assure the generic is absorbed at the same rate and extent as the brand-name version.
The absorption problems aren’t necessarily harmful, Woodcock said. FDA permits generic drugs to absorb at a 25 percent different rate and extent than the originals they copy.
In April, a group of outside FDA advisers, the Pharmaceutical Science and Clinical Pharmacology Advisory Committee, voted 11-2 that the agency’s equivalence requirements aren’ sufficient for certain medicines. They didn’t offer an alternative, and suggested the FDA list “critical dose drugs,” or drugs where a small difference in concentration can change patients’ reaction, that may need new standards.
Stricter Standards
At the time, Gary Buehler, FDA’s acting deputy director in the office of pharmaceutical science, suggested such drugs included digoxin for various heart conditions, lithium used to treat manic episodes, phenytoin for a certain type of seizures and the blood-thinner warfarin.
Australia, Canada, the European Union, Japan and South Africa have stricter bioequivalence standards for critical dose drugs, according to slides from Buehler’s presentation to the advisers.
Woodcock also urged generic-drug makers to put more emphasis on “product presentation.”
“Manufacturers need to think beyond therapeutic equivalence,” Woodcock told the industry group.
She urged generic drugmakers to aim to make their pills look more like the original versions. Consumers complain that the low-cost pills often are larger or have rougher coatings, she said.
Molecular Profiling of Generic Versions of the Low Molecular Weight Heparin Enoxaparin and Their Digestion by Heparinase-I.
Melanie Clark, He Zhu, Debra Hoppensteadt and Jawed Fareed
Pathology, Loyola University Medical Center, Maywood, IL
ABSTRACT
Generic versions of the low molecular weight heparin (LMWH) enoxaparin (Lovenox, Sanofi-Aventis, Bridgewater NY) are available in Southeast Asia and South America. The purpose of this study was to compare Lovenox with two generic versions, Lupenox (co. name) and Loparin (co. name). The molecular weight (MW) profile of these agents and unfractionated heparin (UFH) was determined using HPLC prior to and after heparinase-I digestion. The MW of the generic versions of LMWH ranged from 3.9 to 4.7 kDa. Lupenox exhibited the lowest mean MW (3.9 kDa), whereas Loparin was 4.7 kDa. UFH had a MW of 17.1 kDa. Heparinase-I digestion resulted in marked decrease in the MW of all agents studied. UFH was the most susceptible to the actions of heparinase-I digestion (> 50% reduction in MW) whereas the LMWHs exhibited a 20–30% reduction. Loparin was more susceptible to heparinase-I digestion (30%) compared to Lovenox and Lupenox. The molecular components with a MW > 7.5 kDa ranged from 3–10% for the LMWHs and >90% for UFH. The molecular components with a MW < 7.5 kDa ranged from 90 to 97% for LMWHs and 9% for UFH. These results suggest that the generic versions of LMWHs exhibit differences in their molecular profile and digestion by heparinase-I. Moreover the studies indicate that relative to UFH, both generic and branded enoxaparins are less susceptible to heparinase-I digestion.
Strong Support for Generic Drug User Fees
Agency Caution and Industry Disagreements May Delay Enactment
Recently, the Food and Drug Administration (FDA) held a public meeting to obtain stakeholder input on developing a generic drug user fee program in advance of a formal recommendation to Congress. Such a program would likely parallel the Prescription Drug User Fee Act (PDUFA), which authorizes the agency to set user fees for brand prescription drug applications, and sets specific goals for FDA review times. The agency would likely use generic drug user fees to supplement congressional appropriations for FDA and support a more rapid review of applications through the Office of Generic Drugs (OGD).
Marwood believes that broad support for a generic user fee program has formed among the generic drug industry, the FDA, and lawmakers. This broad support will likely translate into a generic user fee provision in the PDUFA V reauthorization legislation in 2012, so long as industry infighting does not hamper its progress in that legislative debate. Different than in years past, the Generic Pharmaceutical Manufacturer’s Association (GPhA) will now have to negotiate alongside a breakaway group of large generic manufacturers. Given the diverse constituency of GPhA, that association’s agenda may at times run counter to that of the large manufacturers that are no longer part of the group.
Below are some of the central issues that agency and stakeholder groups must negotiate:
• Fee Scope—Determining which generic drug applications should subject to the fee and how to handle existing applications;
• Fee Construction—Options include a standard fee or varying the fee according to some metric, such as company size or application complexity;
• Yearly Fees—The industry is likely to oppose annual fees for approved products;
• Agency Performance Metrics—A review period of approximately one year or less seems a likely proposal, but no consensus exists on a phase-in relative to the timing of new OGD resources.
From Marwood
Nope, not Lonza.
Folks need to ask questions about their "manufacturing partner". I would bet they get nothing near 100% of profit
That's what I heard too
I think you are missing my point. I don’t think Teva has recreated MNTA’s technology. I’m not really sure how they would do that and to your point would be in violation of every MNTA patent. My point is that MNTA has a lot of patents and some of them may be broad, I don’t really know. My question (as an example) is can one characterize LMWH to FDA standards without doing chain profiles or chain mapping? If no, then how many ways can one chain map a LMWH? Are the MNTA patents broad enough to prevent any other chain mapping? If they are Teva and any other generic player will have IP issues. I think it would be similar to MNTA having patents on certain assays or testing methods that are required for lot release.
This press release really got me thinking this morning. MNTA has many patents and pending patents around the analytics used to characterize heparins. This chain mapping one must be pretty important because I can't recall them doing a press release over a patent. What if there is no way to analytically characterize enox to FDA standard w out infringing on one of these patents? Teva could try to copy their science but would be infringing and couldn't get to market. Under this scenario the FDA could approve other generics but they couldn't get to market due to the IP.
I think I have it. The ANDA was filed in 2007. FDA agreed to review in 2008
Theravance – Any thoughts?
Relovair looks promising in COPD w some upside from Vibativ.
I find it interesting that Buapost holds a decent position and Blue Ridge just took a small position (last 13F)
M356 – Wedbush 9.7.10 Update – Pretty positive IMO
M356 – Generic Copaxone
We believe that an even more compelling justification for owning MNTA is presented by M356, MNTA’s generic candidate of blockbuster drug Copaxone. Copaxone is marketed by TEVA for the treatment of Relapse-Remitting Multiple Sclerosis and brought in $1.9 billion in US revenues in 2009 (with Q2:10 US revenues up 21% y/y). While M-Enoxaparin is a complex mixture of sugars, Copaxone is formed from a complex mixture of amino acid polymers.
Given Copaxone’s market size, and the license agreement between MNTA and Sandoz, we believe that M356 will likely become an even more important drug for MNTA than M-Enoxaparin. Regarding the latter point, while MNTA enjoys a profit split for MEnoxaparin only while it is the only generic on the market, MNTA enjoys a profit split for M356 regardless of the presence of other generics. As a result, we predict peak royalties to MNTA of $420 million in 2015.
MNTA and Sandoz filed an ANDA for M356 on July 11, 2008, and TEVA responded on August 28 of that year with a lawsuit alleging infringement of 4 related patents.
In late December 2009, a motion seeking summary judgment for invalidity of the Copaxone patents was filed by Sandoz/Momenta on the issue of indefiniteness (35 U.S.C. section 112). Moreover, a Markman Hearing for the ongoing lawsuit between TEVA and Sandoz/Momenta was held in late January, and we expect a ruling by the court in the near future (the decision has already taken far longer than we already expected). The Markman Ruling should provide a strong indication of the ultimate outcome of the trial, which may proceed to a full jury trial in the second half of 2010.
Having reviewed the patents-at-issue, as well as the publicly available court filings, we strongly believe that MNTA has a better-than average chance of winning this litigation. We plan on watching developments here very closely. Of note, recent activity appears focused on one of Teva’s expert witnesses who unfortunately for Teva, was belatedly discovered by the parties to have been convicted of fraud. Understandably, Teva appears to be making every effort to find a replacement, which the court will likely permit.
In any event, this scenario can do nothing but benefit Sandoz and Momenta in their litigation efforts against Teva. Indeed, these sorts of last minute pre-trial disasters not infrequently force the associated party to settle.
Finally, we note that on September 7, 2010, the court denied Sandoz and MNTA’s motion for summary judgment on the issue of indefiniteness. This motion argued that the evidence was so clear that the patents-in-suit were invalid, that trial was simply unnecessary.
Courts are typically reluctant to grant motions for summary judgment (given the high burden of showing no facts in dispute), and we do not read anything into this particular ruling. Instead, we believe the most likely outcome will be victory for MNTA and Sandoz at trial, after a favorable Markman ruling is offered. Should this ruling appear negative, however (which we view as unlikely), MNTA and Sandoz’s chances of winning at trial will be greatly diminished. The court’s recent ruling on summary judgment may suggest that a Markman ruling can be expected in coming weeks.
Great info. Not a perfect comp but I have some old IMS data for unfractionated heparin going back to 2004. There appears to be a little seasonality w the strongest months typically being December, November, January and June. July and August are about the same in volume w August slightly higher. So if there is a correlation that should bode well for nvs/mnta.
I'm pretty sure they did not. At least not for some period of time.
If Teva didn’t modify their application significantly (include the rings, etc.) I don’t see how they can get approved….ever.
What are folk’s thoughts on MNKD?
I think you have a few $ of downside from these levels but long term upside is mid 20s. My near-term concern is more clinical data need for the Dreamboat device. General concern is use of inhalable insulin. However, I can see the need and the efficacy data looks pretty good.
Here’s an interesting old article I found on how the Premarin situation played out. There seem to be many similarities….also some differences.
The Strange Case of Premarin
By Jim Kling
The closer the FDA looked at the problem of generic equivalence, the muddier it appeared.
Until 1986, Premarin wasn’t such a big deal. Isolated from pregnant mares, the complex mixture now known to contain more than 50 estrogens was introduced in 1942 by Wyeth Ayerst (now a division of American Home Products, based in Philadelphia) as a treatment for hot flashes and other symptoms of menopause. It was a successful product for the manufacturer, but its best days were yet to come.
In 1986, the FDA announced that Premarin and other short-term-acting estrogens were effective in combating the bone loss associated with osteoporosis. Suddenly, a drug that women were taking over the short term was the treatment of choice for a long-term, chronic problem.
“There was not a large market for anyone to do anything about until Premarin was granted the osteoporosis indication,” says Kenneth Phelps, vice president of clinical operations at Duramed Pharmaceuticals, Inc. (Cincinnati, OH). Duramed had a generic version of Premarin, known simply as conjugated estrogens USP, which it hoped to exploit in this newfound niche. “The market burst open, and Premarin seized the day. [There was talk that] literally every postmenopausal woman should take Premarin for the rest of her life,” Phelps says.
The new indication promised a staggering market, but it also touched off a scientific debate. Suddenly, the FDA was faced with a witches’ brew product that had been demonstrated safe and effective for short-term use but was otherwise poorly understood. Initial testing showed that Premarin tablets followed a slow-release bioavailability pattern, while the existing generics were immediate release. “They said, ‘whoops, we can’t have that because there could be a lot [of unknown long-term ramifications of different modes of release],’” says Phelps.
“We had certified that the generics were interchangeable with Premarin, but when we looked at it from the point of view of the science, that was not the case,” says Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research (CDER).
The agency immediately set about determining the bioavailability of Premarin and its pharmaceutical properties. The results led to a long struggle between members of the generic industry, Wyeth Ayerst, and the FDA. Women’s advocacy groups got in on the act too, because the battle’s outcome would determine the future alternatives to a drug whose sales to American women exceeded $1.5 billion in 1999.
A different standard
When Premarin was introduced in 1942, federal law required Wyeth Ayerst to prove only its safety, not its efficacy. But in response to the 1962 amendments to the Food, Drug, and Cosmetic Act, the FDA examined existing products. In 1972, the agency published a Federal Register notice announcing that Premarin and other estrogen products had been effective in the treatment of menopausal symptoms. The agency also decided that two estrogens—estrone sulfate and equilin sulfate—were primarily responsible for Premarin’s activity, and it laid the groundwork for Abbreviated New Drug Application (ANDA) submissions of generic versions.
But the scrutiny of the 1980s painted a different picture. The immediate finding was a disparity in bioavailability between Premarin and its generic versions, but the complexity of the mixture—Premarin may contain 50 or more estrogens with some level of biological activity—soon cast doubt on whether the generic versions of the drug were true pharmaceutical equivalents.
The FDA conducted detailed analyses of the blood and urine concentrations of estrogens in women taking Premarin and eventually concluded that the synthetic generics then on the market could no longer be considered generics.
In 1991, the FDA dropped the bomb and withdrew approval of all ANDAs for generic estrogens, leaving Premarin once more alone on the market. That left companies such as Barr Laboratories and Duramed, which had been producing generics of the drug, out in the cold. In 1992, the U.S. Pharmacopeia released a monograph stipulating that three additional estrogens must be included in any generic version.
The lure of a share of Premarin’s huge market drove Duramed and Barr to try again, and both companies submitted new ANDAs in 1994 and 1995, respectively. “[We knew] it was going to be a difficult accomplishment to get a product that would be bioequivalent to Premarin. It was costly and high-risk, and Barr and Duramed were the only two combatants that were interested to give it a shot,” says Duramed’s Phelps.
The good news was that the ANDA required only the demonstration of bioequivalence and adequate manufacturing controls, and no additional evidence of efficacy.
The bad news was that more roadblocks lay ahead. By 1995, Barr Laboratories had developed a synthetic that included estrone sulfate and equilin sulfate and submitted an ANDA in July of that year. But in November 1994, Wyeth Ayerst—which had been conducting its own research into the components of Premarin—filed a citizens’ petition with the FDA, claiming that it had found another critical component of Premarin: delta-8,9-dehydroestrone sulfate (DHES). The company had been working on the project even before the FDA asked it to characterize Premarin’s ingredients in the early 1990s, says Mike Dey, president of ESI Lederle (St. Davids, PA), a division of Wyeth Ayerst, whose parent company is American Home Products.
“We were concerned that the agency would apply a different standard for conjugated estrogens than they required for other generics, because of the complexity of the product . . . that they would look at resolving this by lowering the standards as opposed to working through the difficult scientific questions to make sure the standards were consistent across all products,” says Dey. Osteoporosis is a particular problem because it is a so-called silent disease that doesn’t reveal itself until the onset of bone weakness. “Because it is silent, women are unaware if the therapy isn’t working until their bones fracture. If the agency were to relax its standards, women could no longer be sure they were getting the efficacy needed to protect them from osteoporosis,” says Ley.
The company had collected preclinical evidence and conducted two clinical trials that showed DHES had a unique clinical profile. The FDA took the new information under consideration, and in July 1995, the agency’s Fertility and Maternal Health Drugs Advisory Committee declared that no one had demonstrated whether estrone sulfate and equilin sulfate were sufficient to account for Premarin’s activity. The agency then took an unusual stance by deciding to put the burden on generics manufacturers to prove that their products were pharmaceutically equivalent to Premarin.
By 1997, “FDA again changed its position and said only a natural product will do,” says Bruce L. Downey, chairman and CEO of Barr Laboratories.
That position was outlined in a May 1997 memo. Still, the FDA didn’t come to that decision lightly. A philosophical debate raged within the organization, according to Roger L. Williams, who was the director of the Office of Generic Drugs in the early 1990s and later a deputy director of the CDER from 1994 until this year, when he was named CEO and executive vice president of U.S. Pharmacopeia.
“[The agency] concluded that . . . the burden falls on the generic [manufacturer] to demonstrate pharmaceutical equivalence,” says Williams. “I would argue that the pioneer always has the burden of proof, that whatever is in there is what’s creating safety and efficacy. Part of the problem was that Premarin was approved at a time when (the government) only required proof of safety, not efficacy. When FDA upgraded Premarin’s efficacy status in 1971, the agency concluded that two primary ingredients created the efficacy.”
Williams couldn’t persuade his colleagues. “So in some respects the burden is on the generic manufacturer if they wish to leave things out (of a generic), but we won’t reduce that to absurdity and require trace contaminants,” says Woodcock. “But . . . there is an issue of sheer potency, because you might have small amounts of 10 or 20 estrogens and you have to add them up to have the same estrogenic potency as your innovator product.”
A tall order for generic producers? Woodcock admits that it is. “We said in the memo that we thought it was more plausible that a naturally derived estrogen product could be found to be pharmaceutically equivalent to Premarin—it’s hard to imagine a synthetic one,” she says.
Forging ahead
That pronouncement effectively ended the generic scramble, at least for the moment. In March of this year, the FDA released a draft guidance document for chemical analysis of Premarin, which could spark another round of generics (www.fda.gov/cder/guidance/3668dft.pdf). Still, Williams thinks the prospects for a Premarin generic are bleak. “There are a lot of products available to treat vasomotor symptoms of menopause. . . . I think people are trying to develop natural-product generics [isolated from a different source than Premarin], but it will be difficult.”
Duramed decided to push on, filing an ANDA for its product—dubbed Cenestin—that was eventually approved in March 1999 for the treatment of hot flashes. It doesn’t have the status of a generic, however, which dampens its prospects. Still, Phelps is optimistic. Cenestin is based on a controlled-release delivery system that he believes is superior to the bioavailability properties of Premarin and could reduce side effects such as breast soreness. “Perhaps with Cenestin’s more favorable blood level profile, women might find better tolerance of our drug,” he says, noting that women often stop taking Premarin because of side effects such as breast tenderness, bleeding, or concern about developing breast cancer.
Not surprisingly, Downey is irritated at the outcome. “I can think of no other case where the standards were changed in this way, and this happened twice. I think that American Home Products has paid an extraordinary amount of attention in the political arena and have armed themselves with an extremely gifted legal and lobbying talent. It was a triumph of politics over science,” he says. Nevertheless, Barr continues research on synthetics in hopes that the FDA will change its position, as well as on alternative natural sources that may have a better shot at being considered as a generic.
Duramed’s Phelps is more sanguine. “As a stockholder you feel that FDA pulled the rug out from under us. Is that fair? There’s a sense that you invested based on the best advice of the government, and then you lost because of the process. But as a scientist, you learn something every day . . . to fix standards is impossible. The best understanding holds until you learn something new. From a scientific point of view, Wyeth Ayerst took advantage of that [by continuing to search for new active elements and challenging approvals],” he says.
Woodcock is sympathetic but firm. “I know there’s some bitterness because the community went along for a long time [developing generic candidates] from an existing monograph [the 1972 document]. Meanwhile, the science had changed quite a bit, and our knowledge of estrogens and receptors increased. . . . That was not fair to the people who had developed a new product based on the monograph,” she admits.
Lessons learned
As with all facets of drug discovery, the science marches on. And although the controversy over Premarin has been painful for both the industry and the FDA, it may yet bear fruit.
Estrogens have applications far beyond relieving the symptoms of menopause and osteoporosis—studies suggest protective effects against cardiovascular disease, Alzheimer’s disease, and other conditions. And, a more intricate understanding of estrogens could assist in the fight against estrogen-responsive forms of breast cancer.
In 1995, researchers discovered a second estrogen receptor in rats, ER-b. Its physiological role hasn’t been pinpointed, according to Dey, but it generally resides in different tissues than ER-a.
“Some researchers believe they can modulate the effects of one over the other, while others believe that they are distinct receptors that function independently . . . if we can establish selectivity for the beta receptor, we can compare what genes are turned on compared to the alpha receptor. Many of the components of Premarin have different binding affinities to the two receptors,” says Dey.
That suggests that all of the hand-wringing over a Premarin generic may not have been entirely in vain. The efforts to tease out compounds and understand the biological activities of myriad components of the witches’ brew could pay big dividends as the significance of the two receptors in disease becomes increasingly clear. “If we can find a molecule or molecules that are selective for alpha or beta and can enhance the efficacy and minimize the side effects, then that would be a very exciting outcome of all of this,” says Dey.
Other osteoporosis drug therapies
Althought the time-honored treatment to help prevent and alleviate postmenopausal osteoporosis is estrogen replacement therapy, questions about the hormoneÕs effects on other body systems have led to the development of other drugs. Among these are selective estrogen receptor modulators (SERMs), one of which, raloxifene, has recently been approved by the FDA for the prevention of osteoporosis. In 1995, alendronate, a bisphosphonate compound, became the first nonhormonal prescription medicine used to treat osteoporosis in postmenopausal women. By helping to inhibit bone breakdown, the drug leads to a cumulative increase in bone density. In recent clinical trials, risedronate, another bisphosphonate compound, reduced by up to 58% the risk of hip fracture in women with low bone mineral density. As their principal side effect, bisphosphonate compounds can cause digestive disorders.
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Jim Kling is a science writer living in Bellingham, WA. Comments and questions for the author can be addressed to the Editorial Office by e-mail at mdd@acs.org, by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.