Replies to post #77206 on Biotech Values

[corpstrat]

10 most promising drugs expected out in next 2 years.
Looks like a PR blurb for Big Pharma
Where are Provenge and Proellex?

[DewDiligence]

Top-10 drug candidates: Here’s the full text of the Business
Week article with some added annotations. Note: the author
is a bond analyst for S&P, so take his views with a grain of salt.

http://www.businessweek.com/print/investor/content/may2009/pi2009051_087752.htm

›Pharma: The 10 Most Promising New Drugs

S&P compiles its list of the most promising late-
stage drugs due out over the next two years

By Arthur Wong
May 4, 2009

The pharmaceutical industry continues to march toward the patent cliff in 2010-2012, when a record amount of drug sales will lose patent protection in the U.S. This means some of the best-selling drugs, including Pfizer's (PFE) Lipitor, Bristol-Myers Squibb's (BMY) Plavix and Avapro, Eli Lilly's (LLY) Zyprexa, Wyeth's (WYE) Effexor [they meant to say Effexor XR — Effexor per se has been sold as a generic since 2006], and Merck's (MRK) Cozaar/Hyzaar and Singulair will be exposed to generic competition.

The industry has gone through previous waves of patent expirations over the past 10 years, and it has largely been able to generate sales and earnings growth via a combination of volume growth, pricing increases, and new product launches. However, research-and-development productivity has fallen off, and as each successive wave of patent expirations washes over the industry, the pressure mounts on the industry's R&D pipelines to produce new, significant products.

Our selection criteria for the top 10 prospects is pretty straightforward—promising late-stage drugs due out over the next two years, where a lack of commercial success may have negative rating implications for the parent company. The failure of a drug prospect to perform up to commercial expectations, or even to reach the market, does not alone necessarily lead to a negative rating action. If a high-profile, high-potential, late-stage drug prospect at a Big Pharma company fails in development, it does not automatically mean that we lower the rating or revise the outlook to negative, if the company still has robust cash flows and a modest financial risk profile. However, the failure may lead the company to adopt a more aggressive financial policy (e.g., acquisitions or share repurchases) to drive future sales and earnings growth and counter negative shareholder sentiment.

The prospects we selected are from a wide range of companies, from top-rated Big Pharma and biotechnology companies to smaller speculative-grade specialty pharmaceutical players.

Denosumab (Osteoporosis)

Amgen (S&P credit rating, A+)

Why it's important: Amgen (AMGN) is facing several years of low sales growth, because its core product portfolio of large molecule drugs is highly mature. The company's top products—Aranesp, Epogen, Neulasta/Neupogen, and Enbrel—contribute more than 90% of sales and are not expected to grow materially (and may even decline slightly) over the next five years because of several factors.

Status: Amgen submitted its request for approval of denosumab to the U.S. Food & Drug Administration in December 2008. If Amgen receives FDA approval in the standard timeframe, we expect denosumab to come to market in late 2009.

Profile: Denosumab is a human monoclonal antibody to Receptor Activator for Nuclear Factor k B Ligand (RANKL), an important molecule in bone metabolism that acts as the primary signal in bone resorption. Amgen has completed Phase III clinical trials for the treatment and prevention of osteoporosis in post menopausal women and in the treatment of treatment-induced bone loss in breast and prostate cancer patients and received positive results. Data from Phase III clinical trials for the prevention of bone metastases in prostate cancer patients and skeletal-related events in breast cancer, prostate cancer, and solid tumors will be available in late 2009 and in 2010. The twice-yearly dosing for the prevention of fractures in patients with osteoporosis makes it likely that the compliance rate would be higher than the current daily or weekly forms of treatment. [However, it’s not clear that Denosumab is better than Zometa/Reclast from NVS, which enjoys the same dosing convenience.]

Brilinta (AZD6140; Arterial Thrombosis)

AstraZeneca (S&P credit rating, AA-)

Why it's important: During the past two years, AstraZeneca (AZN) has made great progress in its late-stage pipeline, which was thin in 2006. The company achieved improvements both from internal development and externalization. AstraZeneca faces some high-profile patent expirations for existing blockbuster drugs—Casodex in 2009, Arimidex in 2010, and Nexium in 2009-10.

Status: The drug is currently in Phase III of clinical development, targeting a potential launch in the fourth quarter of 2009 in Europe and the U.S.

Profile: Brilinta is an anti-platelet agent and the first reversible oral adenosine diphosphate (ADP) receptor antagonist to prevent more thrombotic events than do currently available thienopyridine therapies in patients afflicted with acute coronary system (ACS). The 11,000-patient trial PLATO has completed recruitment with data to be available in mid-2009. The molecule's reversibility is the key differentiator from competing products Plavix and prasugrel.

Onglyza (Saxagliptin; Diabetes)

AstraZeneca and Bristol-Myers Squibb (S&P credit rating, A+)

Why it's important: AstraZeneca has made great progress in its late-stage pipeline during the past two years, but because the company also faces the high-profile patent expirations noted above, it needs to replace potentially lost sales from generic competition. In addition, AstraZeneca's strategy is to build up a sizable diabetes portfolio, and Onglyza's successful launch would mark the inauguration of that ambition. Given the dynamics of the diabetes market, Onglyza's sales prospects are good even in an increasingly crowded competitive environment.

Status: The molecule has been submitted for regulatory approval in Europe and the U.S., with decision dates expected around midyear 2009. The FDA's advisory committee gave a positive recommendation, however, on Apr. 2, 2009, supporting the molecule's new drug application for the treatment of adults with type 2 diabetes.

Profile: Onglyza is a dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of type-2 diabetes. Upon approval, the drug will be the third DPP-4 inhibitor after Januvia and Galvus, which is still awaiting FDA approval. [Galvus is approved in the EU, but is not selling especially well there; it has been difficult to overcome Januvia’s first-mover advantage.]

Belatacept (Organ Transplants)

Bristol-Myers Squibb (S&P credit rating, A+)

Why it's important: Bristol-Myers stands to lose nearly $10 billion in 2008 sales to generic competition in 2010-12. Key drugs Plavix and Avapro will lose patent protection in the U.S., and Bristol-Myers' marketing agreement on Abilify expires. [Actually, the Abilify agreement with Otsuka calls for BMY to receive declining payments rather than an outright cessation of sales.] We believe, however, that the company does have one of the more promising pipelines in the industry, with at least four major, high-potential prospects in late-stage development: Onglyza, belatacept, dapagliflozin, and Apixaban [the apixaban program is half-owned by PFE]. All are expected to come to market in 2010-12, too late to generate enough sales to replace Plavix, Avapro, and Abilify. But if all goes well, they should become major contributors to the company's growth beyond 2012. We selected belatacept over the others because it is most likely the next to be filed for FDA approval; it is a biologic (which has the advantage of less direct competition); and all earnings will stay in-house, because it was self-developed by Bristol-Myers and not shared with partners, as the other three prospects are.

Status: Late-stage Phase III, with FDA filing expected this year. It has fast-track approval status.

Profile: A fusion protein linked to CTLA-4 that selectively blocks the T-cell activation process, belatacept is designed to reduce organ-transplant rejection with fewer side effects than cyclosporine, the current gold standard in immunosuppressant therapy.

Effient (Prasugrel, Platelet Inhibitor) [For some reason, Effient will go by the brand name Efficent in Europe.]

Eli Lilly (S&P credit rating, AA)

Why it's important: As with almost all the big drug companies, Lilly loses patent protection on its top drugs in the 2010-12 period—specifically, top product Zyprexa (2011). However, 2013-14 is not going to be kind to the company, either, because major blockbuster products will also lose patent protection: Gemzar (for cancer) in 2013; Humalog (for diabetes) in 2013; Evista (for osteoporosis) in 2013; and Cymbalta (for depression) in 2014. Lilly's R&D program has yielded a number of new products over the past five years, so the pipeline has been productive. However, we believe the pipeline does not have enough high-sales-potential prospects. One of the few is Effient, a platelet inhibitor developed by Lilly and Daiichi Sankyo. Lilly's recent acquisition of ImClone adds some intriguing prospects to the company's pipeline, but we believe Effient is Lilly's only drug that could be generating blockbuster revenues by the time 2014 rolls around.

Status: An FDA advisory committee recently voted 9 to 0 to approve Effient for heart attack patients undergoing percutaneous coronary intervention. The overall positive tone from the committee leads us to believe Effient could reach the market by the end of 2009, although the company still has to discuss labeling with the FDA before final marketing approval.

Profile: Prasugrel is a platelet inhibitor that is a member of the thienopyridine class of ADP receptor inhibitors, the same class as Bristol-Myers' Plavix, the leading anti-platelet inhibitor and one of the world's largest-selling drugs. Data released from Lilly's Phase III Triton clinical study, comparing Effient with Plavix, showed that Effient was more potent at reducing the number of heart attacks—but also that it caused increased bleeding incidents. The key to Effient's commercial success is whether doctors and patients believe the increased potency outweighs the higher risk of fatal bleeding. [This is the case for all antiplatelet drugs and anticiagulants!]

Embeda/Remoxy (Morphine/Oxycodone, For Pain) [Note: these are two different drugs that are purportedly “tamper resistant.”]

King Pharmaceuticals (S&P credit rating, BB)

Why it's important: The approval of one or both therapies would greatly enhance King's (KG) presence in the $20 billion pain management market, because it competes against new formulations of existing drugs, generics, and other abuse-resistant products. King recently bought Alpharma for approximately $1.6 billion, a price that assumes Remoxy's approval by the FDA. Moreover, the loss of King's Altace product in December 2007, and the potential loss of Skelaxin to generic entry, have placed more reliance on gaining approval of these pipeline products.

Status: King received a nonapproval letter by the FDA for Remoxy on Dec. 10, 2008, citing that additional nonclinical data could be required. In November 2008, an FDA panel narrowly recommended Remoxy for approval but suggested the drug be labeled tamper-resistant, rather than abuse-resistant. Separately, the company filed a new drug application (NDA) for Embeda and should receive a response from the FDA shortly.

Profile: Embeda is an abuse-resistant, extended-release, morphine-based drug for moderate to severe pain and is a follow-on product to Kadian, which was divested as part of King's acquisition of Alpharma. A sequestered naltrexone hydrochloride inner core is designed to mitigate euphoric effects of the morphine upon tampering. Remoxy is an abuse-resistant, extended-release oxycodone-based drug for moderate-to-severe pain. Its dosage form and gel-like consistency resist "dose-dumping" and unapproved routes of administration to prevent abuse.

Cordaptive (Atherosclerosis)

Merck (S&P credit rating, AA-)

Why it's important: Merck faces patent expirations on Cozaar/Hyzaar in 2010 and Sigulair in 2012, following the loss of patent protection on Zocor in 2008. Each of the three products generated more than $3 billion in annual sales in their last full year's worth of branded sales. Merck's product pipeline has been relatively productive, launching a number of significant new products, such as Gardasil and Januvia, in the past few years. Concerns remain, however, regarding Merck's future sales and earnings growth outlook through the 2010-12 period. The need to improve R&D productivity contributed in part to Merck's recent decision to acquire Schering-Plough for $41 billion. [I would argue that leveraging the balance sheet—not improving R&D productivity—is the impetus for the SGP merger.] The companies' combined pipelines would bring the number of late-stage Phase III candidates to 18 (nine from each company), giving Merck a chance to offset the bulk of the looming sales decline because of patent expiration.

Status: Cordaptive received a nonapprovable letter from the FDA in April 2008, although the product is approved in Europe. The reasons for the nonapprovable letter are unclear, with few specifics, but it may relate to the generally more conservative stance by the FDA for approving new products. We assume Cordaptive has a higher-than-average chance of being approved in the U.S., because of the Europen approval, but the timing is very uncertain.

Profile: Cordaptive is a combination of extended-release niacin with laropiprant, a chemical that prevents the side effects of niacin, such as flushing and hot flashes. Cordaptive is a cholesterol-lowering medication that reduces LDL-cholesterol, raises HDL-cholesterol, and reduces triglyceride levels. The drug is deemed to be effective and has the potential to generate blockbuster sales.

Afinitor (Everolimus; Oncology) [See #msg-37269397 for a profile of Afinitor in Forbes.]

Novartis (S&P credit rating, AA-)

Why it's important: Novartis (NVS) has one of the deepest pipelines of the sector, resulting in a promising list of newly approved and to-be-approved drugs. Afinitor could be highly important for the evolution of the group's oncology exposure, because of that market's strong growth rates and the drug's oral administration.

Status: Novartis meanwhile received FDA approval for Afinitor on Mar 30, 2009, as a first treatment for patients with advanced kidney cancer after failure of either Sutent or Nexavar-based treatments. Other future filings of the molecule are likely for neuroendocrine tumors, lymphoma, hepatocarcinoma, and gastric, non-small cell lung and breast cancer, which are all in Phase III development.

Profile: Afinitor is an oral inhibitor of the mTOR pathway for patients with advanced kidney cancer. The drug could be the first therapy to demonstrate significant benefit for patients after standard kidney cancer treatment fails.

Liraglutide (Diabetes, Obesity)

Novo Nordisk (S&P credit rating, A)

Why it's important: Novo Nordisk (NVO) is the world's leading producer of insulin and related diabetes medications. Market approval of its insulin analogue Liraglutide would further cement its position in the global insulin markets, especially as competitor Eli Lilly's product, Byetta, has been approved in the U.S. since 2005.

Status: Liraglutide was submitted both in Europe and the U.S. in 2008 as an anti-diabetic. While the FDA's advisory committee has stated safety-related concerns with regard to interpretation of C-cell tumors in rodents, a majority of voters attested that the molecule has an acceptable cardiovascular safety profile [see #msg-36777418 for the confusing voting at the advisory panel]. The FDA will now complete its review of liraglutide's application and potential approval, which has become more uncertain, while the European regulatory decision is expected by mid-2009.

Profile: Liraglutide is a once-daily glucagon-like peptide (GLP-1) analog of human insulin, stimulating the release of insulin from the pancreas only when glucose levels become too high. The drug class explores new territory between traditional metformin-based oral anti-diabetics and insulin-based medication, which is injected. The drug was also developed as an anti-obesity medication, for which it is in Phase III trials.

Multaq (Dronedarone; Atrial Fibrillation)

Sanofi-Aventis (S&P credit rating, AA-)

Why it's important: Sanofi-Aventis' (SNY) two main existing blockbuster drugs, Plavix and Lovenox, will be threatened by generic competition over the next few years [perhaps sooner that that for Lovenox :- )]. In addition, the group had to withdraw anti-obesity drug, Acomplia, from the market in 2007 because of safety concerns, so the company needs potential new blockbusters to replace lost sales volume elsewhere.

Status: Sanofi-Aventis filed Multaq with the European regulator EMEA in June 2008. In the U.S., the FDA advisory committee voted 10 to 3 in favor of approving Multaq, but the recommendation had qualifications that will affect the labeling and potentially temper the drug's commercial prospects.

Profile: Multaq is an anti-arrhythmic agent, planned as a first-line therapy for the treatment of atrial fibrillation patients without severe heart failure. Atrial fibrillation remains the main cause for cardiovascular hospitalization, with about 7 million patients in Europe and the U.S. Multaq appears to be the only anti-arrhythmic drug that has shown a significant reduction of mortality in atrial fibrillation patients, and it has a favorable safety profile.‹

[Smooth]

With so many blockbuster drugs coming off patent between 2010-2014 as the article states, who are some of "the best" generic drug makers likely to prosper? Any ideas?

[DewDiligence]

Brilinta Bests Plavix in Phase-3 ACS Study

[This PR has no data, but it confirms that the trial met its primary endpoint by showing a statsig reduction in the composite of CV death + non-fatal stroke/MI for Brilinta relative to Plavix. Brilinta, from AZN, is one of the “top 10” drug candidates in late-stage testing cited by the Business Week article in #msg-37566691. AZN is up about 3% in London on this news. The potential damage to SNY and BMY, the companies that market Plavix, is mitigated by the fact that Plavix goes off-patent in the next couple of years. Perhaps a bigger adverse impact will be felt by LLY and Daiichi Sankyo, the companies who will market Effient/Efficent.]

http://www.astrazeneca.com/media/latest-press-releases/brilinta-plato?itemId=5837126

›AstraZeneca Announces Top Line Results From Pivotal Phase III Study for BRILINTA

11-May-2009

AstraZeneca today announced top line results from the phase III trial, PLATO (A Study of Platelet Inhibition and Patient Outcomes), which demonstrate that BRILINTA (ticagrelor), the investigational oral antiplatelet treatment for acute coronary syndromes (ACS), has achieved a statistically significant primary efficacy endpoint versus clopidogrel, in the prevention of cardiovascular (CV) events in patients with ACS. The primary efficacy measure was time to first occurrence of any event from the composite of myocardial infarction, stroke, and CV death.

In PLATO, the overall safety profile for BRILINTA was in line with the safety data observed in the phase II studies. Given the size of the PLATO trial, further analysis of the entire database, secondary variables, and subgroups is ongoing. AstraZeneca and the PLATO Executive Committee’s aim is to submit the PLATO data to a peer-reviewed medical journal and present at the European Society of Cardiology (ESC) annual meeting in August 2009.

It is estimated that one in three ACS patients will die, have a recurrent heart attack (also known as myocardial infarction), or be readmitted to hospital within six months of their first cardiovascular event so preventing reoccurrence is vital in ACS patient treatment.

PLATO was a head-to-head outcomes study of BRILINTA versus clopidogrel to establish whether BRILINTA could achieve meaningful cardiovascular and safety endpoints in ACS patients. The study involved 18,624 ACS patients in 43 countries and was designed to provide a comprehensive analysis of efficacy, safety and tolerability of BRILINTA. The PLATO study was led by the Executive Committee co-chairs, Professor Lars Wallentin, Sweden (Uppsala Clinical Research Center) and Professor Robert Harrington, USA (Duke Clinical Research Institute).

The submission of BRILINTA to regulatory authorities remains on schedule for the fourth quarter of 2009.

BRILINTA is the first reversibly binding oral adenosine diphosphate (ADP) receptor antagonist and is chemically distinct from thienopyridines like clopidogrel. It selectively inhibits P2Y12, a key target receptor for ADP. ADP receptor blockade inhibits the action of platelets in the blood, reducing recurrent thrombotic events.

AstraZeneca has proposed the name BRILINTA. If approved by the FDA and the EMEA, it will serve as the trade name for ticagrelor/AZD6140.

The study design of PLATO was published in the April 2009 edition of the American Heart Journal (James, S. et al. in Am. Heart J. 2009; 157: 599-605).

BRILINTA Phase II studies include DISPERSE and DISPERSE2. DISPERSE was published by Husted, S. et al. in Eur. Heart J. 2006; 27: 1038–1047. DISPERSE2 was published by Cannon, C.P. et al in J. Am Coll. Cardiol. 2007; 50: 1844-1851 and by Storey, R.F. et al in J. Am. Coll. Cardiol. 2007; 50: 1852-1856

About AstraZeneca

AstraZeneca is a major international healthcare business engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and supplier for healthcare services. AstraZeneca is one of the world's leading pharmaceutical companies with healthcare sales of US$ 31.6 billion and is a leader in gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infectious disease medicines. For more information about AstraZeneca, please visit: www.astrazeneca.com.‹

[DewDiligence]

FDA Panel Endorses BMY’s Belatacept by 13-5 Vote

[See below for a description of belatacept’s indication and MoA.]

http://finance.yahoo.com/news/FDA-Advisory-Committee-bw-3356848747.html?x=0&.v=1

›FDA Advisory Committee Recommends Approval of Belatacept, an Investigational Agent for Prophylaxis of Acute Rejection in De Novo Kidney Transplant Patients

Monday March 1, 2010, 7:49 pm EST

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY ) today announced that the U.S. Food and Drug Administration’s (FDA) Cardiovascular and Renal Drugs Advisory Committee has voted 13 to 5 to recommend approval of belatacept, a selective co-stimulation blocker, for the prophylaxis of acute rejection in de novo kidney transplant patients. The belatacept Biologics License Application was submitted to the FDA for an indication of prophylaxis of organ rejection and preservation of a functioning allograft in adult patients receiving renal transplants with use in combination with an interleukin-2 (IL-2) receptor antagonist, a mycophenolic acid (MPA), and corticosteroids.

“Bristol-Myers Squibb is encouraged by the Committee’s recommendation. We will continue to work closely with the FDA to support the review of belatacept, which has the potential to provide another treatment option for kidney transplant patients,” said Brian Daniels, senior vice president, Global Development and Medical Affairs, Bristol-Myers Squibb.

The FDA Cardiovascular and Renal Drugs Advisory Committee based its recommendation on review of data from the belatacept clinical development program, which included more than 1,000 patients who received belatacept. Data presented included safety and efficacy results from three similarly designed clinical studies in adult de novo kidney transplant patients: a Phase 2 study (IM103100) and two Phase 3 studies, one in standard criteria (living or deceased) donor kidney transplants (IM103008) and one in extended criteria donor kidney transplants (IM103027). Belatacept is being studied in other ongoing and planned clinical trials.

The FDA is not bound by the recommendations of its Advisory Committee, but takes its advice into consideration when reviewing new drug applications. The Biologics License Application for belatacept was accepted for filing and review by the FDA in September 2009 and the Prescription Drug User Fee Act goal date for FDA action is May 1, 2010.

About Belatacept

Belatacept is an investigational agent under development by Bristol-Myers Squibb to prevent graft rejection and maintain kidney function following renal transplantation. Belatacept is being studied to assess its efficacy and safety as an immunosuppressant agent in solid organ transplantation.

Belatacept is a fusion protein designed to be a selective co-stimulation blocker that binds to a specific site on certain cells of the immune system (i.e., antigen presenting cells) to block the second signal necessary to activate naïve T-cells, which coordinate immune-mediated rejection of transplanted organs.‹

[DewDiligence]

FDA Issues CRL for BMY’s Belatacept

[This is yet another case where the FDA contravened the vote of the advisory panel, who voted 13-5 in favor of approval (#msg-47249910 ). In three phase-3 trials, Belatacept met the co-primary endpoints by showing superiority relative to cyclosporine on a measurement of renal function and non-inferiority relative to cyclosporine on acute graft rejection, each measured after 12 months of treatment. However, the advisory panel voiced some dissatisfaction with the width of the non-inferiority margin allowed by the FDA on acute graft rejection; had a narrower and more typical NI margin been used, Belatacept would not have met the NI threshold. This and lingering doubts about long-term safety has caused the FDA to ask for the 36-month (final) data from two of the phase-2 trials, which are not yet mature.

BMY considers Belatacept one of its five most consequential new drugs—see the prologue of #msg-47502391.]

http://finance.yahoo.com/news/BristolMyers-Squibb-Receives-bw-1903800508.html?x=0&.v=1

›May 1, 2010, 6:54 pm EDT

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has issued a complete response letter regarding the Biologics License Application for belatacept in kidney transplantation.

While no new clinical studies have been requested, the complete response letter requests the 36-month data from the ongoing Phase 3 studies to further evaluate the long-term effect of belatacept. The company will work with the FDA to provide the data as soon as they are available. The Biologics License Application submitted for belatacept included 24-month data from the Phase 3 studies.

Other requests raised in the letter primarily relate to information to support the manufacturing of belatacept and the proposed risk evaluation and mitigation strategy (REMS).

“Bristol-Myers Squibb is committed to belatacept as a potential new therapeutic option for kidney transplant patients,” said Brian Daniels, senior vice president, Global Development and Medical Affairs, Bristol-Myers Squibb. “We will continue to work closely with the FDA to address their questions.”

The Biologics License Application for belatacept was accepted for filing and review by the FDA in September 2009. An FDA Advisory Committee panel met on March 1 of this year and voted 13-5 to recommend the approval of belatacept for the prophylaxis of rejection in kidney transplant recipients. The FDA is not bound by the recommendations of its Advisory Committee, but takes its advice into consideration when reviewing new drug applications.

About Belatacept

Belatacept is an investigational agent under development by Bristol-Myers Squibb for the prophylaxis of organ rejection in adult patients receiving kidney transplants.

Belatacept is a fusion protein designed to be a selective T cell co-stimulation blocker that binds to a specific site on certain cells of the immune system (i.e., antigen presenting cells) to block the second signal necessary to activate T cells, which are the predominate immune mediators of allograft rejection.‹