Genentech and OSI Pharmaceuticals will be meeting with FDA early in 2005 to discuss filing plans for Tarceva (erlotinib) in pancreatic cancer.

The companies "expect to meet with FDA this first quarter to discuss our filing strategy in this indication," Product Development President Susan Desmond-Hellmann said during a year-end earnings call Jan. 10.

Genentech will present data from a Tarceva Phase III trial in pancreatic cancer at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium Jan. 27-29.

Tarceva was launched in November for the treatment of lung cancer. The potential new indication is part of Genentech's strategy to grow Tarceva and capitalize on the failure of the competing EGFR inhibitor - AstraZeneca's Iressa - to show a survival benefit in a confirmatory study (¹ Also see "AstraZeneca To Revisit Iressa Dosing Following Failed Survival Study" - Pink Sheet, 3 January, 2005., p. 12).

Tarceva generated sales of $13.3 mil. from its approval date of Nov. 18 through Dec. 31, Genentech reported.

However, Genentech noted, there was a build up in Tarceva inventory after the Iressa results were announced - which may translate into a step-up in sales in the next quarter.

"Although it's too early to predict the full impact of Iressa's negative survival data on Tarceva demand, we did increase Tarceva's channel of entry after results of the study were announced," Senior VP-BioOncology Ian Clark said.

"This resulted in $6.4 mil. in total inventory for Tarceva in year end." The increase in Tarceva inventory corresponds to market share the drug gained following the Iressa announcement, Genentech noted.

"Just three weeks into the launch and prior to the negative announcement of our competitor's...trial, Tarceva had already achieved 39% of new patients for the class. By the weekend of Dec. 24, new patient share was up to 54%," Clark said.

That share could increase much further if FDA decides to suspend the approval of Iressa under the accelerated approval regulations. The agency is expected to make a decision on the status of Iressa early this year (² 'The Pink Sheet' Jan. 10, 2005, In Brief).

Genentech's plans for Tarceva go beyond the lung cancer indication and capitalizing on the setback to Iressa. They include new indications, and potential combination use with another Genentech oncologic, Avastin (bevacizumab).

"We will continue to build on the potential for Tarceva in lung cancer, explore combinations with other targeted therapies including Avastin and potentially move Tarceva into earlier stage in adjuvant treatment settings," Desmond-Hellmann said.

A Phase II trial of Avastin plus Tarceva for renal cell carcinoma has completed enrollment, and a Phase III trial of Avastin plus Tarceva for non-small cell lung cancer is currently open for enrollment, Desmond-Hellmann said.

During the J.P. Morgan healthcare conference Jan. 12, Genentech was asked whether payors would accept a combination regimen of Avastin plus Tarceva, given the concerns expressed about the price of Avastin alone (³ Also see "Avastin, Erbitux Costs Invite Price Controls, Former NCI Deputy Says" - Pink Sheet, 21 June, 2004., p. 25).

Genentech noted that adding Tarceva to an Avastin regimen would be less expensive than adding Sanofi-Aventis' Taxotere (docetaxel).

To further grow the Avastin franchise, Genentech is studying the first-line metastatic colorectal cancer therapy for use in second-line treatment, currently a common off-label practice.

Genentech has initiated discussions with FDA regarding a filing strategy for second-line use following the Phase III ECOG 3200 trial, which studied use of Avastin and the FOLFOX-4 chemotherapy regimen in advanced colorectal cancer patients.

"Adding Avastin to the FOLFOX-4 chemotherapy regimen resulted in a 26% reduction in a risk of death compared to FOLFOX-4 alone," Desmond-Hellmann said.

"In the first-line setting, that's where Avastin adds its greatest value. That said, [with] the E 3200 we're reassuring that, in fact, Avastin could add value even in second-line."

"E 3200 answered two important questions: the timing of the use in terms of the patient's stage of colon cancer and use with the most commonly used chemotherapy," Desmond-Hellmann said.

Genentech's fourth quarter earnings report included an unexpected slowdown in the growth rate of Avastin. Sales of the oncologic were $200.4 mil. for the three months, a modest incremental increase on the $183 mil. in third quarter sales. After 10 months on the market, Avastin generated sales of $554.5 mil., Genentech reported.

Genentech offered two reasons for the slowdown. First, "there was an inclination to use [Avastin] on a number of patients who were fairly desperate at launch and those patients may be on the drug for six or seven months, and they may have come off during the final quarter," Clark said.

Second, the company sent a "Dear Healthcare Provider" letter in August describing the increased risk of thromboembolic events (⁴ Also see "Genentech Avastin Labeling Will Reflect New Data On Thromboembolic Events" - Pink Sheet, 23 August, 2004., p. 26). Genentech followed up with a Jan. 5 letter describing a labeling change warning of the adverse events.

"I think it's also fair to say that at the time that the Dear Doctor letter went out, it caused some concern certainly in the media and that may have got through to some patients," Clark said. Nevertheless, "the underlying trends are really strong," he added.

Market penetration of Avastin's labeled indication -first-line colorectal cancer - reached 55% in the fourth quarter, "a significant increase over" the 42% seen in the third quarter, Clark said.

In the second-line metastatic colorectal cancer market (not an approved use), the drug's share rose from 34% in the third quarter to 41% in the fourth quarter, Clark said.

Colorectal cancer represents more than 95% of the current use of Avastin, Clark added. Genentech did lose market share in the third-line market, from 34% in the third quarter to 24% in the fourth quarter, the company noted.

Genentech's interest in expanding Avastin's label to the second-line setting may also be partly defensive, since off-label use may invite scrutiny by state and federal prosecutors.

In October, Genentech announced that it has been subpoenaed by the Philadelphia U.S. Attorney's Office regarding its promotions for Rituxan (rituximab), although the company did not elaborate on the focus of the subpoena (⁵ Also see "Genentech Rituxan Promotions Under Investigation By DoJ" - Pink Sheet, 11 October, 2004., p. 22).

Genentech reported that it is preparing to file for three new indications for Rituxan: frontline aggressive non-Hodgkin's lymphoma, frontline indolent NHL and indolent maintenance NHL.

"Seven years after the approval of Rituxan by FDA, Rituxan continues to demonstrate promising and clinically meaningful results in various treatment combinations and in several forms of the disease," Desmond-Hellmann said.

Rituxan was developed by Idec (now Biogen Idec) and approved for treatment of refractory or relapsed non-Hodgkin's lymphoma patients in 1997.

"In the indolent non-Hodgkin's lymphoma setting, we're currently in discussions with FDA...and anticipate this filing to occur in the first half of 2006," Desmond-Hellmann said. "One area of concern for FDA is the use of the term 'maintenance,' though we'll be working towards a nomenclature that FDA feels better describes this approach to treating patients with Rituxan."

The company also has a growing Rituxan Phase III immunology program in a number of diseases including multiple sclerosis and rheumatoid arthritis.

"Studies [are] open for enrollment for the use of Rituxan in primary progressive MS, ANCA-associated vasculitis, relapsed-remitting MS," Desmond-Hellmann said.

The first supplemental BLA filing for Rituxan for the treatment of rheumatoid arthritis is slated for the fourth quarter of this year. The initial sBLA filing will be for inadequate responders to tumor necrosis factor-alpha inhibitors (⁶ Also see "Rituxan Rheumatoid Arthritis sBLA Filing Expected In Late 2005" - Pink Sheet, 17 May, 2004., p. 32).

Genentech also filed an IND in the fourth quarter of 2004 for a Rituxan study in systemic lupus erythematosus and is planning a Phase III program, Desmond-Hellmann said.

Rituxan sales in 2004 were $1.71 bil. Net U.S. sales were $1.57 bil. and ex-U.S. sales were $137.2 mil.

Genentech Plans Avastin/Tarceva Combo Filing; Avastin Warning Hurts Growth

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