Replies to post #45768 on Biotech Values

[DewDiligence]

Apixaban Non-Inferior to Warfarin Control Group in Phase-2 Study

[Apixaban is the potential blockbuster for which BMY recently solicited help from PFE (#msg-19134406). It is one of the candidates vying to supersede warfarin as the SoC oral anticoagulant for chronic use (#msg-18759853).]

http://www.reuters.com/article/topNews/idUKN0339144420070708?rpc=44

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Sun Jul 8, 2007 4:26AM EDT
By Lewis Krauskopf

NEW YORK, July 8 (Reuters) - An experimental anti-clotting medicine from Bristol-Myers Squibb Co. (BMY) and Pfizer Inc. (PFE) met its main effectiveness and safety goals in a mid-stage study, researchers said on Sunday, positioning it as a future option over current popular but problematic drugs.

Patients treated with apixaban, a pill, had comparable rates in two main measures to those on the standard of care -- an injected therapy plus one drug from the class that includes the widely used warfarin. The measures included rates of blood clots and dangerous bleedings.

Though effective at alleviating clotting, many anticoagulant therapies come with serious drawbacks. Heparin drugs must be injected or given intravenously, and warfarin is notoriously difficult to regulate properly because of its interactions with food and other medicines.

Apixaban, meanwhile, is an oral drug that does not need regular monitoring or dose adjustments, making it a "great alternative," said Dr. Harry Buller, lead investigator on the study and chairman of the department of vascular medicine at the Academic Medical Center in Amsterdam.

"The search for new anticoagulants is not so much to beat them in terms of efficacy," Buller said. The reason for "the whole explosion of anti-thrombotic agents (is) to make life easier for these patients," he said.

Buller was presenting the study's results on Sunday at the International Society on Thrombosis and Haemostasis meeting in Geneva.

Late-stage trials are already underway for apixaban, and the companies plan to file for U.S. approval in the second half of 2009. Apixaban is one of several pills being developed by drug makers that block the Factor Xa protein, which plays an early role in the chemical process leading to blood clots. Researchers hope they also can be used by patients with atrial fibrillation, or irregular heartbeat, to prevent stroke.

'DISASTER WITH EXANTA'

Excitement over Factor Xa drugs follows the downfall of Exanta, a once-promising anticoagulant from AstraZeneca Plc (AZN) that had been associated with liver toxicity. Exanta blocked another clotting protein called thrombin.

"After the disaster with Exanta, people are really looking for new anticoagulants to fill that gap and to replace warfarin, and I think this step ... is very pleasant to see," Buller said of the apixaban clinical trial.

The 12-week Phase 2 study involved 520 patients who suffered a deep vein thrombosis, which is a clot that forms most frequently deep inside the leg.

There were three apixaban treatment groups: patients on 5 milligrams of the experimental drug twice a day; 10 mg twice a day; or 20 mg once a day. A fourth control group received an injectable anticoagulant plus warfarin or a similar drug.

The main efficacy measure involved the combined rate of incidents, including a new deep vein thrombosis or lack of improvement in the original DVT, and blood clots that progress to the lungs known as pulmonary emboli.

Rates of the incidents were 6 percent for patients on 5 mg of apixaban, 5.6 percent for the 10 mg, and 2.6 percent for the 20 mg. The rate was 4.2 percent for the control group. Buller said differences among treatment groups were not clinically relevant.

The main safety measure examined bleedings, the rates of which were 8.6 percent for the 5 mg apixaban group, 4.5 percent for the 10 mg, 7.3 percent for the 20 mg, and 7.9 percent for the control group. These differences were not clinically relevant either, Buller said.

There were no adverse events, including no sign of liver toxicity, he said.

Bristol-Myers and Pfizer agreed in April to develop and sell apixaban together. They are currently running two Phase 3 apixaban trials: one to prevent blood clots among surgical patients or those whose illness puts them at risk; a second to prevent stroke for patients with atrial fibrillation [#msg-19134406].
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[DewDiligence]

BMY, PFE Begin Phase-3 Trials of Apixaban to Treat VTE

[Apixaban is one of a select group of drug candidates vying to replace the much-maligned warfarin as the standard anticoagulant in a wide range of indications (#msg-18759853). Its main competitors are rivaroxaban from Bayer/JNJ and LY517717 from LLY. All three drugs are FXa inhibitors and thus have a fundamentally different MoA from heparin (and MNTA’s M118), which inhibits both FXa and FIIa (see diagrams in #msg-26897966 and #msg-26898084).

The phase-3 program for Apixaban is one of the largest ever conducted for any drug in any class. (That’s why even a company as big as BMY could not afford to run the program on its own and enlisted PFE to share the burden.) All told, the phase-3 Apixaban program includes eight trials and 45,000 (!) patients: four trials in VTE prevention for patients who are either undergoing orthopedic surgery or hospitalized with limited movement; two trials in VTE prevention for patients with atrial fib; and the two trials described below for the treatment of patients with VTE. Control arms in the various trials consist of warfarin, aspirin, Lovenox, or placebo.

As a FXa inhibitor with no activity against FIIa, Apixaban is well-suited to indications pertaining to venous thromboembolism (such as the ones described above) and is less suited to indications pertaining to arterial thromboembolism such as ACS. Nonetheless, BMY/PFE have run a phase-2 trial in ACS for which data will be reported at a medical conference in September. (Please see #msg-29698599 for a discussion of how MNTA’s proprietary anticoagulant, M118, fits into this competitive landscape.)]

http://biz.yahoo.com/bw/080610/20080610006500.html

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First patient dosed in 12-month study examining the effects of the investigational drug apixaban in patients with blood clots in the leg veins or lungs

Tuesday June 10, 4:00 pm ET

PRINCETON, N.J. & NEW YORK--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY ) and Pfizer (NYSE: PFE ) announced today the start of a new Phase 3 clinical trial to assess the effect of apixaban in patients with venous thromboembolism (VTE), a potentially fatal disease process that begins with blood clots in the leg veins or lungs. Apixaban, which is currently being developed by the two companies, is an investigational oral, highly selective factor Xa inhibitor, a new class of agents with therapeutic potential to prevent and treat blood clots.

The AMPLIFY (Apixaban after the initial Management of Pulmonary embolism and deep vein thrombosis with First-line therapy) trials are part of the EXPANSE program - the global Phase 3 clinical development trial program for apixaban. AMPLIFY and AMPLIFY-EXT are two major clinical trials involving approximately 7,300 patients with deep vein thrombosis (DVT), a blood clot in the vein, or pulmonary embolism (PE), a potentially fatal condition caused by a blood clot blocking a vessel in the lung.

“The initiation of this apixaban Phase 3 trial represents Bristol-Myers Squibb’s and Pfizer’s commitment to furthering research in the treatment of VTE, a serious disease that affects 1.3 million people annually in the US and Europe,” said Jack Lawrence, Vice President, Research and Development, Bristol-Myers Squibb. “Current oral drug treatment options for the treatment of patients with VTE are primarily vitamin K antagonists (VKA), such as warfarin. Limitations of VKAs include a slow onset of action, a narrow therapeutic window necessitating regular coagulation monitoring and dose adjustment, and multiple food and drug interactions.”

New Apixaban Phase 3 Clinical Trials

The AMPLIFY-EXT (Apixaban after the initial Management of PuLmonary embolism and deep vein thrombosis with First-line therapY- EXTended treatment) trial has initiated enrollment and will include approximately 2,430 patients who will receive, for an extended 12-month period, apixaban 2.5 mg dose or 5 mg twice daily compared to patients taking placebo to determine the effects of apixaban on recurrent VTE. Prior to entering the trial, patients will have completed 6 to 12 months of treatment for DVT or PE.

The AMPLIFY trial is expected to begin in the next few months, and will enroll approximately 4,800 patients with acute DVT or PE and will investigate the safety and efficacy of apixaban 10 mg twice daily for 1 week followed by 5 mg twice daily for 6 months compared to enoxaparin plus warfarin, the two drugs used as the current standard of care.

About Venous Thromboembolism (VTE)

Venous thromboembolism can take two forms: either as a deep vein thrombosis (DVT), a blood clot in a vein, usually in the leg that partially or totally blocks the flow of blood, or as a pulmonary embolism (PE), a blood clot blocking a vessel in the lungs. PE can be associated with significant hemodynamic deterioration or death.

VTE continues to be a major cause of morbidity and mortality in the western world, with an incidence of one to two per 1000 people, and represents one in 10 hospital deaths. In addition, post-thrombotic syndrome and pulmonary hypertension occur in 10 percent of DVT and five percent of PE patients, respectively.

The first year incidence of recurrent VTE is approximately 7.7 percent, and the risk of recurrence continues after anticoagulant treatment ends at an average of 3% per year over the next ten years.

About the Apixaban Phase 3 Program: EXPANSE

The EXPANSE apixaban clinical trial program has seven [eight if one counts AMPLIFY-EXT as a separate trial] ongoing Phase 3 clinical studies involving approximately 45,000 patients worldwide. In addition to the recently initiated VTE treatment program, the EXPANSE program also includes trials studying potential use for prevention of venous thromboembolism in patients undergoing orthopedic surgery and in hospitalized medically ill patients at high risk of VTE, and trials studying prevention of stroke and other thromboembolic events in patients with atrial fibrillation (AF). The VTE prevention program consists of:

• ADVANCE-1, 2, and 3 trials are investigating the safety and efficacy of apixaban 2.5 mg twice daily compared to enoxaparin in patients undergoing major orthopedic surgery. Results from the first trial are targeted for presentation at the American Society of Hematology in December 2008.

• The ADOPT study is investigating apixaban 2.5 mg twice daily for one month compared to standard of care (enoxaparin for at least 6 days followed by placebo) for the prevention of VTE in hospitalized patients who are medically ill and at risk of VTE.

Apixaban is also in Phase 3 trials studying the prevention of thrombotic events, such as stroke in patients with atrial fibrillation (AF). The AF program consists of:

• The ARISTOTLE trial, which is investigating apixaban 5 mg twice daily compared to warfarin in approximately 15,000 patients with atrial fibrillation.

• The AVERROES trial, which is investigating apixaban 5 mg twice daily compared to aspirin in approximately 5,600 patients with atrial fibrillation who are ineligible for VKA treatment or haven’t tolerated previous VKA treatment.

Apixaban has also recently completed enrollment in a Phase 2 trial in patients with acute coronary syndrome (the APPRAISE trial). The results of this trial will be presented at the European Society of Cardiology meeting in September 2008.
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[DewDiligence]

Apixaban Fails to Show Non-Inferiority to Lovenox in VTE Prevention

[Apixaban is an oral FXa inhibitor being developed by BMY and PFE under a very-high-profile collaboration where PFE *received* $250M up-front and stands to make as much as $1B in total milestones: #msg-19134406. (When was the last time a Big Pharma was on the receiving end of a deal of this magnitude?)

Apixaban’s most direct competition is Xarelto (Rivaroxaban) from Bayer and JNJ, which is already approved in Europe (#msg-30972846) and is under review by the FDA (#msg-31073048).

Apixaban’s failure to achieve non-inferiority to Lovenox in the trial that is the subject of this PR is a big (but non-fatal) setback inasmuch as non-inferiority to Lovenox in orthopedic indications had been considered a given by most observers. (The “tough” trials for Apixaban and other anticoagulants are generally such indications as stroke prevention in patients with AF.) Apixaban had shown non-inferiority to warfarin in phase-2 (#msg-21044973).

Although this PR asserts that the overall Apixaban program in multiple indications will continue as planned, at the very least the NDA submission in the US will be substantially delayed relative to the prior guidance of 2H09. Thus, Xarelto will have much more time to become established without any direct competition.

The phase-3 trial that is the subject of this PR employed a rigorous NI design, which is something you don’t always see. (In many NI trials, the sponsor merely has to meet a pre-specified trial size and come within a pre-specified delta relative to the comparator drug.) Apixaban yielded an event rate of 9.0% on the primary efficacy endpoint (a composite of DVT/PE and all-cause death) vs 8.9% for Lovenox, the comparator drug.

On first glance, the nearly equal event rates would seem to assure non-inferiority; however, the (one-sided) p-value of 0.064 missed by a hair. In other words, the null hypothesis that Apixaban was inferior to Lovenox could not be rejected with 95% confidence.

Apixaban did manage to show a statsig lower rate of clinically relevant bleeding (a safety rather than efficacy endpoint) relative to Lovenox, which bodes well for other Apixaban trials in VTE prevention.]

http://biz.yahoo.com/bw/080826/20080826006372.html

›Bristol-Myers Squibb and Pfizer Provide Update on Apixaban Clinical Development Program

Tuesday August 26, 4:15 pm ET

-- Apixaban Phase II Acute Coronary Syndrome Data to be Presented at European Society of Cardiology Meeting on Sept. 2

-- U.S. Regulatory Filing for the Prevention of Venous Thromboembolism will not be submitted in 2009, as previously indicated

-- Other Clinical Programs Continue as Planned

PRINCETON, N.J. & NEW YORK--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY ) and Pfizer Inc (NYSE: PFE ) provided an update on the apixaban clinical development program today. The companies announced that new Phase II data in acute coronary syndrome patients (ACS) will be presented at the upcoming meeting of the European Society of Cardiology (ESC). In addition, Bristol-Myers Squibb and Pfizer reported that an early evaluation of results from a Phase III study of apixaban for the prevention of venous thromboembolism (VTE) in patients undergoing total knee replacement indicates that the primary endpoint of this study was not met.

The Phase III VTE prevention study known as ADVANCE-1 compared apixaban, a novel, oral Factor Xa inhibitor given at a dose of 2.5 mg, twice daily, to the FDA-approved dose of enoxaparin, 30 mg given twice daily. The primary efficacy outcome was a composite of symptomatic or asymptomatic deep vein thrombosis, pulmonary embolism, and death by any cause. The rate of the primary efficacy endpoint on apixaban was numerically similar to that observed with enoxaparin (9.0% vs. 8.9%, p=.064), but did not meet the pre-specified statistical criteria for non-inferiority compared to enoxaparin. [See the annotations in the prologue of this post.] The actual enoxaparin VTE rate of 8.9 percent was lower than the expected VTE rate of 16 percent seen in previous similar clinical trials, resulting in an inability to demonstrate non-inferiority.

In ADVANCE-1, there were no unexpected findings in adverse events for apixaban compared to enoxaparin. The major bleeding event rate for apixaban was numerically lower, but was not significantly lower, than enoxaparin (0.7% vs. 1.4%, p=.053). The composite rate of clinically relevant non-major bleeding and major bleeding was significantly less in patients who received apixaban than those who received enoxaparin (2.9% vs. 4.3%, p =.034).

Full results of the ADVANCE-1 trial have been submitted to the American Society of Hematology Meeting (ASH) for presentation in December.

ADVANCE-1 results confirm the characteristics of apixaban as reported previously in phase II studies. The companies are considering further studies with different protocols in preventing VTE in knee surgery and will not submit the U.S. filing for VTE prevention in the 2nd half of 2009, as previously communicated. The results of ADVANCE -1 do not necessitate any changes in protocols of any other ongoing apixaban studies. Programs directed towards prevention of VTE including EMEA registrational studies, treatment of VTE, and in the prevention of stroke in atrial fibrillation continue as planned.

“Bristol-Myers Squibb and Pfizer remain enthusiastic and committed to the clinical development program for apixaban,” said Jack Lawrence, vice president, Research and Development, Bristol-Myers Squibb. “Bristol-Myers Squibb and Pfizer anticipate that the results of APPRAISE-1 being presented at ESC will provide important insight into the potential use of apixaban for the secondary prevention of cardiovascular events in patients with acute coronary syndrome, which affects an estimated 2.7 million people around the world every year.”

About the Apixaban Clinical Program

Apixaban, an oral, factor Xa inhibitor in a new class of agents that have shown therapeutic potential to prevent and treat blood clots, is currently being explored in the EXPANSE clinical trial program which includes eight Phase III clinical studies involving approximately 45,000 patients worldwide. The ADVANCE-2 and 3 trials are investigating the safety and efficacy of apixaban 2.5 mg twice daily compared to enoxaparin 40 mg once daily in patients undergoing major orthopedic surgery. The ADOPT study is investigating apixaban for one month compared to standard of care (enoxaparin 40 mg once daily for at least 6 days followed by placebo) for the prevention of VTE in hospitalized patients who are medically ill and at risk of VTE.

Apixaban is also in Phase III trials studying the prevention of stroke and other thromboembolic events in patients with atrial fibrillation (AF). The AF program consists of two trials. The ARISTOTLE trial is investigating apixaban compared to warfarin in approximately 15,000 patients with atrial fibrillation. The AVERROES trial is investigating apixaban compared to aspirin in approximately 5,600 patients with atrial fibrillation who are ineligible for vitamin K antagonists (VKA) treatment or haven’t tolerated previous VKA treatment.

The VTE treatment program consists of two trials. The AMPLIFY trial is a 6-month trial investigating apixaban compared to enoxaparin plus warfarin in approximately 4,800 patients with acute DVT or PE. The AMPLIFY-EXT trial is a 12-month trial investigating apixaban compared to placebo for extended treatment to prevent recurrent VTE in approximately 2,400 patients who have completed 6 to 12 months of treatment for DVT or PE.‹

[DewDiligence]

Eliquis observation: When PFE agreed to pay BMY $250M in up-front cash and $750M in potential milestones for half of the worldwide commercial rights (#msg-19134406), many investors thought that was excessive. However, the Eliquis partnership now looks like one of PFE’s rare manifestations of business acumen.

[DewDiligence]

PFE makes even more money from Eliquis than I thought; following is the section of the 2007 PFE/BMY press release that I highlighted in bold-face type (#msg-19134406):

The companies will jointly develop the clinical and marketing strategy of apixaban, and will share commercialization expenses and profits/losses equally on a global basis.

The word equally means a 50/50 profit split, right? Not in this instance! In the next paragraph, the PR goes on to say:

The companies will share all development and commercialization expenses along with profits/losses on a 60%-40% basis, with Pfizer assuming the larger share of both expenses and profit/losses.

Thanks to Jonathan Rockoff of the WSJ for pointing out my mistake.