Replies to post #98840 on Biotech Values

[DewDiligence]

FDA briefing docs are out for AZN’s Brilinta:

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ucm220190.htm

[DewDiligence]

Advisory Panel Endorses AZN’s Brilinta in 7-1 Votes

[The vote was 7-1 in favor of Brilinta for both the PCI and non-PCI subgroups of the ACS indication, so FDA approval seems likely. Brilinta is an antiplatelet drug that will compete with SNY/BMY’s Plavix and LLY’s Effient. Although the lay press often refers to both drug classes both as “blood thinners,” antiplatelets belong to a different class than such products as Lovenox, Angiomax, Xarelto, Pradaxa, unfractionated heparin, and MNTA’s M118, which are anticoagulants.

Antiplatelets and anticoagulants do have one thing in common, however: both address enormous medical needs. This affords new entrants the chance to become very big-selling drugs if they are differentiated from the competition and have no major safety issues. To date, Effient has been a commercial bust, which opens the door for Brilinta to become the chief competitor to Plavix, which has worldwide annual sales of more than $8B.]

http://finance.yahoo.com/news/FDA-Advisory-Committee-prnews-2121477169.html?x=0&.v=1

›FDA Advisory Committee Recommends US FDA Approval of Brilinta (Ticagrelor) for Acute Coronary Syndromes

Wednesday July 28, 2010, 6:50 pm

WILMINGTON, Del., July 28 /PRNewswire-FirstCall/ -- AstraZeneca (NYSE:AZN) today announced that the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee recommended the FDA approve AstraZeneca's investigational drug ticagrelor for the reduction of thrombotic events in patients with Acute Coronary Syndromes (ACS).

The Advisory Committee voted as follows:

1. Should ticagrelor be approved for reduction of thrombotic events in patients with nonST-elevation (NSTEMI) and ST-elevation (STEMI) ACS intended to be managed by PCI?

Yes 7
No 1

2. Should ticagrelor be approved for reduction of thrombotic events in patients with nonST-elevation (NSTEMI) and ST-elevation (STEMI) ACS intended to be managed medically?

Yes 7
No 1

The review by the Advisory Committee, part of the FDA's evaluation of the New Drug Application (NDA) submitted for ticagrelor, is based on the results of the large, head-to-head patient outcomes study PLATO (A Study of PLATelet Inhibition and Patient Outcomes). PLATO was designed to establish whether ticagrelor could improve cardiovascular (CV) outcomes in ACS patients, compared to clopidogrel. The study design reflected current clinical practice and included all major ACS patient types (STEMI and UA/NSTEMI), whether they underwent invasive procedures (PCI, coronary artery bypass graft surgery) or were medically managed.

"We are pleased with the Advisory Committee's recommendation to support the approval of ticagrelor. We look forward to continued discussions with the FDA as it evaluates the panel's recommendation and completes its review of the NDA," said Howard Hutchinson, M.D., Chief Medical Officer, AstraZeneca.

AstraZeneca filed the regulatory submission for ticagrelor, in the second half of 2009. The proposed trade name for ticagrelor in the US is BRILINTA™ (ticagrelor), pending approval from the FDA. Ticagrelor is also currently under regulatory review in nine territories around the world, including the European Union (EU), Canada, and Brazil.

The FDA frequently convenes advisory committee meetings to obtain independent expert guidance and recommendations on clinical matters. While the FDA is not required to follow this guidance, the agency takes the advice into consideration when rendering its final decisions on pending applications and other public health matters.

About ACS

ACS is an umbrella term for conditions that result from a reduction in blood flow to the heart muscle. These conditions range from UA (chest pain) to myocardial infarction (MI) (heart attack):

• STEMI is a type of heart attack in which the coronary artery is generally blocked off by a blood clot, and as a result virtually all the heart muscle being supplied by the affected artery starts to die.

• UA/NSTEMI is a type of heart attack in which a blood clot partly occludes an artery and as a result only a portion of the heart muscle being supplied by the affected artery dies. UA is one of the types of ACS, a series of conditions most commonly produced by the rupture of a plaque in a coronary artery. UA is "unstable" not only because a plaque has potentially ruptured (a situation which threatens to progress to a myocardial infarction), but also because the symptoms it produces -- the angina -- generally occurs more frequently, often at rest, and lasts longer.

About the PLATO study

PLATO was a large (18,624 patients in 43 countries) head-to-head patient outcomes study of ticagrelor versus clopidogrel, designed to establish whether ticagrelor could achieve clinically meaningful CV and safety end points in ACS patients, above and beyond those afforded by clopidogrel. PLATO was designed to reflect current clinical management of ACS patients and included and represented all types of ACS patients (STEMI, NSTEMI & UA) whether they underwent invasive procedures or were medically managed. As presented to the FDA Advisory Committee, ticagrelor demonstrated a reduction of CV events (CV death, MI, stroke) over clopidogrel (Plavix®/Iscover®) (9.8% vs. 11.7% at 12 months; 16% RRR; 95% CI, 0.77 to 0.92; p<0.001), without an increase in overall major bleeding (11.6% vs. 11.2%, p=0.43). Across the overall PLATO population, there was an 11% risk of major and minor bleeding.

About BRILINTA™/BRILIQUE™

Ticagrelor (BRILINTA/BRILIQUE) is an investigational oral antiplatelet treatment for ACS. Ticagrelor is a direct-acting P2Y12 receptor antagonist in a chemical class called cyclo-pentyl-triazolo-pyrimidines (CPTPs). Ticagrelor is the first reversibly-binding oral ADP receptor antagonist.‹

[DewDiligence]

Plavix Genetic Studies Show Mixed Results

http://www.reuters.com/article/idCNLDE67R07I20100829

›Sun Aug 29, 2010 9:57am EDT
By Ben Hirschler

STOCKHOLM, Aug 29 (Reuters) - Gene testing is shaping up to be a marketing battleground for new blood thinners like AstraZeneca's (AZN) Brilinta, underscoring the power and limitations of genetics as a tool to predict medical outcomes.

The arrival of generic copies of Sanofi-Aventis and Bristol-Myers Squibb's top-seller Plavix makes the issue a hot topic scientifically and commercially, new studies at the European Society of Cardiology congress on Sunday showed.

One study found AstraZeneca's Brilinta, unlike Plavix, requires no genetic testing to check if it will work (http://finance.yahoo.com/news/Genetic-Substudy-Shows-Fewer-prnews-2302031623.html?x=0&.v=1 ), while another showed Eli Lilly and Daiichi Sankyo's Effient also worked irrespective of gene variations [#msg-52257365].

On the face of it, the results of the two company-sponsored trials give the firms valuable ammunition in a looming marketing war with cheap copies of Plavix, or clopidogrel.

"Physicians don't like complications, so if there was an alternative to clopidogrel that worked the same way that did not have these variations then most people would jump on it," said Alfred Bove of Philadelphia's Temple University School of Medicine.

But the evidence is far from clear-cut. A third study, sponsored by Sanofi and Bristol, contradicted the idea that people with a certain genetic make-up don't benefit from Plavix.

The stakes are high because Plavix is the world's second biggest drug, with sales last year of more than $9.5 billion. The drug is already off patent in parts of Europe and will lose U.S. patent protection in 2012.

BRILINTA AWAITS APPROVAL

AstraZeneca believes Brilinta is better than either Plavix or Effient, which has been linked to higher bleeding risk, and is hoping the new gene data will add another string to its bow.

Brilinta is expected to win a green light to go on sale in the United States as early as next month, after being endorsed by a U.S. advisory panel last month.

An analysis of more than 10,000 patients in the PLATO study found Brilinta cut the risk of heart attacks, strokes and cardiovascular deaths more than Plavix, whether or not they had a genetic variability that has been previously shown to affect a patient's response to clopidogrel.

The Effient study showed similar lack of impact from gene variations, based on a smaller analysis of data from the TRITON study. Both studies were published in The Lancet journal.

The link between Plavix response rates and genetics hit the headlines in March, when the U.S. Food and Drug Administration warned that some patients have a poor response to the drug because they do not break it down well.

European regulators have not yet followed suit and Gilles Montalescot of Hospital Pitie-Salpetriere in Paris said more studies were needed before conclusions could be drawn about the value of widespread genetic profiling.

That uncertainty was underlined by the third study, in the New England Journal of Medicine, showing no difference between poor metabolisers of Plavix and others among 6,000 participants from two other trials, CURE and ACTIVE.

The lead researcher of that study, Guillaume Pare, said it added "a further layer of complexity", by showing that reported genetic variants had no effect in certain patient populations.

"The whole field is in flux," said David Holmes of the U.S. Mayo Clinic in Rochester, commenting on the three studies.

"Everybody would like to think that personalised medicine is going to be perfect. We just don't have chapter and verse to make sure that's the case."

Robert Califf of Duke University School of Medicine said it appeared genetic variability was probably important for sicker patients, including those having a stent to prop open clogged arteries, but was less significant for lower-risk patients like those in the CURE and ACTIVE studies.

For AstraZeneca, the dynamic situation means the company will have to carefully balance superiority claims against the price it plans to charge for Brilinta, medical experts said.

"It's probably better to have more of your drug on the market at half the price you thought it was going to be than take 10 years to get it adopted," said Bove.‹

[DewDiligence]

Brilinta’s PDUFA date extended 3 months to 12/16/10:

http://finance.yahoo.com/news/US-Food-and-Drug-prnews-1647943614.html?x=0&.v=1

[DewDiligence]

AZN will conduct a 21,000-patient Brilinta trial to assess long-term MACE prevention following a heart attack:

http://www.bloomberg.com/news/2010-10-01/astrazeneca-to-start-long-term-brilinta-heart-attack-study.html

If successful, this study will strongly differentiate Brilinta from (generic) Plavix, which failed to show a benefit in a similar study a few years ago.

[DewDiligence]

FDA Issues CRL for AZN’s Brilinta

[This is yet anther case where the FDA overruled its advisory panel, which endorsed Brilinta by a 7-1 vote in Jul 2010 (#msg-52749102). This PR does not provide much detail, as is typical for CRL PR’s issued by Big Pharma; my conjecture is that the FDA wants further granularity on the North American subgroup in the PLATO study, where Brilinta did not show any benefit relative to Plavix. There’s a lot at stake here for AZN insofar as Plavix is the world’s second-largest-selling drug.]

http://finance.yahoo.com/news/AstraZeneca-Receives-Complete-prnews-1253422928.html?x=0&.v=1

›December 16, 2010, 8:59 pm EST

WILMINGTON, Del., Dec. 16, 2010 /PRNewswire/ -- AstraZeneca (NYSE:AZN) announced today that the US Food and Drug Administration (FDA) has issued a complete response letter (CRL) for the New Drug Application (NDA) for ticagrelor (BRILINTA™).

In the CRL, the FDA requested additional analyses of the PLATO data. The agency did not request that additional studies, including clinical studies, be conducted as a prerequisite for approval of the ticagrelor NDA.

AstraZeneca is evaluating the contents of the CRL and will respond to the agency's request for additional analyses of the PLATO data as soon as possible. The company remains confident in the NDA submission for ticagrelor and in its ability to respond to the agency's questions.

"Our highest priority is to provide the requested PLATO analyses to the FDA and progress to completion of the BRILINTA NDA review," said Martin Mackay, President, Research & Development, AstraZeneca.‹

[DewDiligence]

FDA approves AZN’s antiplatelet drug, Brilinta:

http://finance.yahoo.com/news/FDA-Approves-New-Medicine-bw-3163453236.html?x=0&.v=1

AZN finally manages to catch a break, and it’s been a long time coming! Despite a 7-1 vote in favor of approval by an FDA advisory panel in Jul 2010, the FDA issued a CRL in Dec 2010 (#msg-57939117) and AZN replied in Jan 2011. Today was the PDUFA date.

Brilinta is vying for the mantle of successor to the mega-blockbuster, Plavix (the second-largest-selling drug of all time), which will soon be generic in all countries. The competition includes LLY’s Effient, which has been a commercial bust to date (#msg-41731834). Thus, the more serious concern for AZN is generic Plavix, which managed-care companies and government buyers around the world can be expected to turn into a formidable foe. For AZN, the timing could not be worse for launching a new branded drug in this category.

Brilinta’s approval also forces NVS to make a no/no-go decision regarding Elinogrel (#msg-65364335).

[DewDiligence]

Effient logged 1Q12 sales of $116M (+106% YoY), of which $90M came from the US:

http://finance.yahoo.com/news/lilly-reports-solid-start-first-103000996.html

Clearly, Effient will never be a huge-selling drug, but it’s turning out to be less of a dog than some of us thought.

[DewDiligence]

Effient fails to show superiority to Plavix in low-risk ACS patients:

http://finance.yahoo.com/news/daiichi-sankyo-lilly-announce-trilogy-060000980.html

Daiichi Sankyo Company, Limited and Eli Lilly and Company today announced data from the TRILOGY ACS study, a phase III trial comparing prasugrel plus aspirin to clopidogrel plus aspirin in patients with unstable angina (UA) or non-ST elevation myocardial infarction (NSTEMI), who were managed medically without an artery-opening procedure. At 30 months, 13.9 percent of prasugrel patients vs. 16.0 percent of clopidogrel patients experienced the combined primary endpoint of heart attack, stroke or cardiovascular (CV) death in patients under 75 years of age, the primary analysis population (HR=0.91; 95% CI: 0.79-1.05). This outcome was not statistically significant (P=0.21).

Effient has been a commercial bust, logging less than $500M of annualized worldwide sales in recent quarters (i.e. only 5% of Plavix’s peak sales), and this new study certainly won’t help. More impetus for LLY to engage in some kind of financial engineering, as discussed in #msg-78887599.