Bayer Nexavar Safety Profile Fuels Research In Multiple Cancer Indications

A dual mode of action and favorable safety profile will be the chief selling points for Bayer/Onyx' kidney cancer agent Nexavar (sorafenib), company officials said during Bayer's R&D investor conference in London Dec. 8.

"We fully expect Nexavar to establish Bayer as an emerging player in targeted cancer therapy," Global Clinical Development-Therapeutic Oncology Area Head Susan Kelley said. "We believe we have in Nexavar a very unique approach" by targeting "both the anti-angiogenic and anti-proliferative effects."

Phase III data have shown sorafenib to be "very well tolerated," Kelley noted. "The bulk of the adverse events that occurred [did so] at low grade, and therefore make it very feasible to use this drug both as a single agent and in potential combination regimens with minimal risk of needing to interrupt or discontinue the drug in patients due to side effects."

Nexavar Launch Eyed For Early 2006

Bayer expects to launch the first-in-class specialty oncology product for advanced renal cell carcinoma soon in the U.S.

FDA agreed to undertake a priority review of the Nexavar NDA in July, meaning a decision should be forthcoming by mid-January. Bayer and partner Onyx submitted the application under the agency's continuous marketing application pilot 1 program, which allows sponsors of fast-track agents to submit NDAs in separate reviewable units with six-month review periods. The last unit was submitted on July 11.

"We are well prepared in the United States to launch tomorrow. Everybody's involved, we hired all professionals with oncology experience, we have product in inventory," Bayer Pharmaceuticals President Wolfgang Plischke said. "I don't want to speculate when it [will be] approved, [but] the only thing we have to do is print the final labeling."

Bayer/Onyx are fielding 100 oncology professionals and are working with the Kidney Cancer Association and a network of advocacy groups to promote Nexavar, Kelley said.

The oral multi-kinase inhibitor blocks both tumor proliferation and angiogenesis by targeting serine/threosine and receptor tyrosine kinases, Bayer explained.

Conversely, Genentech's Avastin (bevacizumab), Pfizer's Sutent (sunitinib) and AG-013736 only target angiogenesis, while Genentech's Tarceva and Wyeth's CCI-779 only target proliferation, according to Kelley's slide presentation. Genentech is conducting trials of Avastin and Tarceva in combination for renal cell carcinoma and non-small cell lung cancer (¹ (Also see "Genentech Plans Avastin/Tarceva Combo Filing; Avastin Warning Hurts Growth" - Pink Sheet, 17 Jan, 2005.), p. 19).

Bayer expects results in the second half of 2006 from a Phase III trial of Nexavar in more than 900 patients with advanced kidney cancer who had previously failed systemic therapy. The study began in late 2003.

Preliminary results indicate that advanced renal cell carcinoma patients tolerate Nexavar well, Kelley said. "It's pretty clear that there were not very many differences in the incidence of particular side effects between the Nexavar arm and the placebo arm and also, very importantly, that there was a very low rate of drug discontinuation for adverse events with only 10% of the Nexavar patients and 8% of the placebo patients discontinuing drug due to toxicity."

Adjuvant Therapy, Lung Cancer Trials On Horizon

Encouraged by the favorable safety profile, Bayer is pursuing an indication for long-term use of Nexavar as an adjuvant therapy to prevent recurrence after surgical removal of kidney tumors, Kelley said.

Bayer and its partners, the Eastern Cooperative Oncology Group, the National Cancer Institute and two cooperative groups in Europe, plan to begin six- to seven-year Phase III adjuvant therapy trials in 2006, Kelley said. The U.S. study will have three arms - Nexavar, placebo and Pfizer's Sutent.

In the first half of the year, Bayer also will begin a Phase III study in the U.S. and Europe of Nexavar in combination with standard chemotherapy agents for advanced non-small cell lung cancer.

In early studies, Bayer has not seen the bleeding in the squamous cell lung cancer population that occurred with Avastin - an adverse event that led to a restriction of Avastin's Phase III studies to non-squamous histologies, Kelley noted.

In response to an analyst question regarding the increased off-label use of Avastin for non-squamous cell lung cancer in advance of FDA approval, Kelley maintained that it does not necessarily follow that Nexavar's market will be restricted to the squamous-cell patients who cannot take Avastin.

"We are fully aware of the fact that treatment practices really only get defined once the product has labeling and is in more extensive use," she said.

"But the advice that we've received from our medical advisors and advisory boards worldwide as we have designed the Phase III program is that it's appropriate to proceed under the understanding that we intend to enroll all of those histologic subtypes and then wait and see how treatment practices are affected as we move forward with various options becoming available in the clinic."

Bayer began a Phase III trial in March of Nexavar in patients with unresectable advanced hepatocellular carcinoma, for which there is no approved treatment in the U.S. and Europe. Also, two Phase III trials of sorafenib with paclitaxel/carboplatin in patients with unresectable stage III or stage IV malignant melanoma began in May. One is a company-sponsored study, while ECOG sponsored the other.

Beyond the Nexavar program, Bayer has two oncology products in Phase I development: angiogenesis inhibitor BAY 57-9352 and the dual-acting signal transduction inhibitor BAY 73-4506.

The firm also has four oncology candidates in pre-clinical: cell cycle inhibitor BAY 80-3000, apoptosis inducer BAY 77-5378, angiogenesis inhibitor BAY 72-9629 and dual-receptor kinase inhibitor BAY 81-1557.

As part of a massive restructuring, Bayer last year focused its pharmaceutical R&D pipeline on oncology and cardiovascular products (² (Also see "Bayer U.S. Focus Will Be Oncology, Blood Products And OTCs" - Pink Sheet, 20 Sep, 2004.), p. 28).

BAY 59-7939 Aims To Topple Warfarin For Stroke

On the cardiovascular side, the firm is positioning its investigational factor Xa inhibitor BAY 59-7939 as a potential successor to oral anticoagulant warfarin for stroke prevention in atrial fibrillation, Global Clinical Development-Therapeutic Cardiovascular Area Head Frank Misselwitz told analysts.

Vitamin K agonist warfarin accounted for 88% of the standard units of anticoagulants sold worldwide in 2004, but only 14% of the €4.08 bil. in global sales that year, Misselwitz said, citing IMS data.

However, the potential market is much larger because 65% of AF patients do not take warfarin and another 19% receive suboptimal treatment from it, largely due to limitations such as the need to continually monitor and adjust dosage to maintain therapeutic levels without causing hemorrhaging, he maintained.

Bayer Learns From Competitors' Setbacks

Bayer officials acknowledged recent failed attempts to find successors to warfarin for stroke in atrial fibrillation patients.

In September 2004, FDA deemed AstraZeneca's Exanta (ximelagatran) "not approvable" due to liver concerns (³ (Also see "AstraZeneca Rethinking Blockbuster Model After Exanta “Not Approvable”" - Pink Sheet, 18 Oct, 2004.), p. 27). In addition, this past September a key component of the Phase III Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-W) examining the combination of Sanofi-Aventis/Bristol-Myers Squibb's Plavix (clopidogrel) and aspirin was discontinued after the dual anti-platelet regimen was found inferior to warfarin.

Bayer said it has learned from these failures. The "event rate" is so low in this therapeutic area, Misselwitz said, "we need to either beef up sample size or alternatively address...very high-risk patients."

ACTIVE-W "did show convincingly that there is certainly a need for an anticoagulant as compared to anti-platelet agents in that field," and the Exanta experience highlighted the need to work more closely with regulators, he added.

With BAY 59-7939, "I do see a good spirit in discussing trial designs and future designs early with the regulators," the exec said.

Bayer has initiated Phase III studies of BAY 59-7939 for prevention of venous thrombotic events (VTEs) with once-daily dosing following orthopedic surgery.

The company also is "well on track" to start two Phase III trials for chronic indications in 2006 - one involving VTEs and the other for stroke prevention in atrial fibrillation, Misselwitz said. The firm is co-developing the anti-thrombotic agent with Johnson & Johnson.

Bayer Pharmaceutical Research-Europe Head Andreas Busch listed five additional cardiovascular projects with proof-of-concept in humans expected in 2006.

They are: BAY 68-4986, an adenosine A1 agonist for coronary heart disease; BAY 63-2521, a guanylate cyclase stimulator for pulmonary hypertension; BAY 58-2667, a guanylate cyclase activator for acute heart failure; BAY 60-5521, a CETP inhibitor for dyslipidemia; and BAY 73-7977, a dual-acting peptide for diabetes.