Replies to post #78581 on Biotech Values

[DewDiligence]

Re: FDA wants more data on Xarelto

Hardly any FDA applications get outright approval by the PDUFA date these days, so a CR Letter with no demand for new trials is a good outcome for JNJ and Bayer, IMO.

Given the less than completely clean safety profile (#msg-36360107), the questioning of the efficacy endpoints by some panelists (#msg-36415556), and the way the advisory panel spent 45 minutes worrying about potential off-label use (#msg-36474892), the FDA might have requested additional safety data that would have delayed approval by a year or more.

[DewDiligence]

Xarelto addendum: This drug has the potential to move the needle materially even for a company as large as JNJ:

• 800,000 hip- and knee-replacement surgeries each year in the US alone.

• Above number will more than double during next two decades. (Boomers aren’t getting any younger!)

• VTE prevention following hip/knee replacement is only the tip of the iceberg of indications where Xarelto could be utilized.

• No oral anticoagulant has been approved by the FDA since warfarin in 1954!

[DewDiligence]

More bad news for Xarelto, the FXa inhibitor from Bayer/JNJ,
is buried within this seemingly innocent PR from ASH about an
extension study in prevention of VTE recurrence. The bad news
is twofold: i) Xarelto caused clinically-relevant bleeding at five
times the rate of the placebo arm; and ii) Bayer and JNJ revoked
their prior guidance of replying to the FDA’s CRL by the end of
2009 and have not given guidance as to when they will reply.

Although Xarelto is already approved for VTE prevention in the
EU, its overall commercial prospects are looking dimmer every
day, and it’s becoming increasingly unlikely, IMO, that Xarelto
will be the mega-blockbuster JNJ has been seeking to arrest the
decline in its pharma business.

http://finance.yahoo.com/news/Phase-III-Study-of-bw-2942705368.html?x=0&.v=1

›Phase III Study of Rivaroxaban Shows That Extending Anticoagulant Treatment by Six or 12 Months Significantly Reduced Risk of Second Symptomatic VTE

Late-Breaker Data Presented at Annual Meeting of the American Society of Hematology

9:00 am EST, Sunday December 6, 2009

NEW ORLEANS--(BUSINESS WIRE)--Johnson & Johnson Pharmaceutical Research and Development, L.L.C. (J&JPRD), announced today that results from the Phase III EINSTEIN-Extension (EXT) clinical trial of the novel oral anticoagulant rivaroxaban showed a significant reduction in the risk of recurrent symptomatic venous thromboembolism (VTE), compared to placebo, in patients who have been treated for a previous deep vein thrombosis (DVT) or pulmonary embolism (PE). The rate of major bleeding was low. The findings were reviewed at today’s press briefing during the 51st Annual Meeting of the American Society of Hematology (ASH), and will be fully presented as part of the late-breaker session of the general meeting at 7:30 AM CST, Tuesday, December 8th.

To be eligible for enrollment in EINSTEIN-EXT, patients had to have previously completed six to 12 months of treatment with a vitamin K antagonist (VKA) [i.e. warfarin] for an acute episode of VTE or have participated in the ongoing Phase III EINSTEIN-DVT or EINSTEIN-PE trials, in which they were treated with either rivaroxaban or a VKA, for the same time duration. Upon enrolling in EINSTEIN-EXT, patients were randomized to receive either 20 mg of rivaroxaban dosed once-daily or placebo and were evaluated for an additional six or 12 months.

Rivaroxaban was well tolerated. Patients treated with rivaroxaban showed a highly statistically significant relative risk reduction (RRR) of 82% in the recurrence of a symptomatic VTE1 versus those treated with placebo [1.3% vs. 7.1%, (p<0.0001), respectively].

“The results from EINSTEIN-EXT highlight the potential clinical benefit of extending prophylaxis for an additional six or 12 months beyond the currently recommended treatment duration,” said Harry R. Büller, M.D., Academic Medical Center in Amsterdam. “This study could help transform the way physicians treat patients who have previously suffered a DVT or PE. Currently, up to 10% of patients who are treated adequately, according to today’s recommended guidelines, still experience a recurrence within 12 months of the initial event.”

Rates of major bleeding, the primary safety endpoint, were low and not statistically significantly different between the two groups [so far, so good, but keep reading] [0.7% vs. 0.0%, (p=0.11) for the rivaroxaban and placebo arms, respectively].

A secondary endpoint measuring the composite of major and clinically relevant non-major bleeding showed a statistically significant difference between the two groups [6.0% vs. 1.2%, (p<0.001) in the rivaroxaban and placebo arms, respectively]. [ouch!!]

No cases of serious liver injury were reported in either group. Liver safety results included: ALT >3x ULN + T Bili >2x ULN: 0.0%5 in both groups; ALT >3x ULN: 1.9% in the rivaroxaban arm and 0.5% of patients in the placebo arm. There were no differences in cardiovascular-related events between the two treatment groups.

The abstract (LBA-2) is available at: http://ash.confex.com/ash/2009/webprogram/Paper25669.html

About EINSTEIN Clinical Trials

Approximately two million cases of DVT and nearly 600,000 cases of PE are reported each year in the United States.6 EINSTEIN is a global program of three clinical trials in approximately 8,000 patients with acute, symptomatic deep vein thrombosis (EINSTEIN-DVT, enrollment complete) or pulmonary embolism (EINSTEIN-PE, enrollment ongoing). In these two programs, patients received oral rivaroxaban 15 mg twice-daily for three weeks, followed by oral rivaroxaban 20 mg once-daily, compared with initial enoxaparin treatment followed by a VKA.

The EINSTEIN-EXT study compared the safety and efficacy of rivaroxaban to placebo in the secondary prevention of recurrent symptomatic venous blood clots by prolonging preventive treatment by six or 12 months beyond a previously completed regimen of six or 12 months of therapy. The study enrolled approximately 1,200 patients from 28 countries around the world with symptomatic DVT or PE, which is collectively referred to as VTE.

Update on Complete Response for VTE Prevention Post Total Knee and Hip Replacement Surgery

Following discussions with the U.S. Food and Drug Administration, J&JPRD is continuing to work with its partner, Bayer HealthCare, to provide additional information from the RECORD study sites, and data from ongoing studies, to adequately address issues raised in the Complete Response letter received in May 2009. Based on those discussions, J&JPRD has decided it will not submit its complete response to the FDA seeking approval of rivaroxaban for the prevention of DVT and PE in patients undergoing hip or knee replacement surgery by the end of 2009.

Postponing the complete response until these requirements are fully addressed provides the greatest opportunity for successfully bringing rivaroxaban through the regulatory process. An updated filing strategy will be communicated following completion of these ongoing discussions.

About Rivaroxaban

Rivaroxaban is a novel oral anticoagulant being evaluated for the prevention and treatment of a broad range of disorders in which blood clotting plays a major role. In clinical studies, the compound has shown a rapid onset of action with a predictable dose response and high bioavailability, no requirement for routine anticoagulation monitoring, and limited risk for food and drug interactions. The extensive program of clinical trials evaluating rivaroxaban makes rivaroxaban the most studied oral, direct Factor Xa inhibitor in the world today. More than 65,000 patients are expected to enroll in the rivaroxaban clinical development program. Rivaroxaban is being developed jointly by Johnson & Johnson Pharmaceutical Research and Development, L.L.C., which is part of the Johnson & Johnson family of companies, and Bayer HealthCare AG.‹

[DewDiligence]

Bayer says reply to FDA’s CRL for Xarelto will not come until 2H10:

http://www.reuters.com/article/idCNLDE61P0AM20100226

Bayer’s US partner, JNJ, had recently declined to offer any guidance as to when the reply to the CRL would be submitted (#msg-38200098). The FDA issued the CRL way back in May 2009, so evidently Bayer/JNJ have a lot of work to do to satisfy the FDA’s concerns.

The Xarelto delay is a break for the other companies vying for this market—see #msg-47110236.

[DewDiligence]

Bayer/JNJ announce multiple Xarelto regulatory submissions:

http://www.bayer.com/en/news-detail.aspx?newsid=14326

• Initial EU submission for stroke prevention in AF, based on ROCKET-AF study (#msg-56712414,

• Initial EU submission for treatment of acute DVT, based on EINSTEIN-DVT study (#msg-53887547).

• FDA re-submission for VTE prevention following hip/knee surgery in response to FDA CRL issued in May 2009 (#msg-38200098).

Note: Xarelto was approved in the EU in 2008 for VTE prevention following hip/knee surgery (#msg-30972846), the indication for which JNJ is seeking FDA approval.