October NME User Fee Lineup Includes Solifenacin, Darifenacin

FDA has at least 28 pending applications with user fee deadlines in October, including seven NMEs and one new biologic.

The large October grouping reflects last year's end-of-year rush in submissions and should help the agency top the 17 NMEs cleared in 2002, the lowest number approved since 1983 (¹ Pharmaceutical Approvals Monthly Jan. 1, 2003, p. 14). FDA already has a good start on 2003 NME approvals: as of Sept. 1, the tally is 13, the most recent being AstraZeneca's statin Crestor , on Aug. 12, and Bayer/GlaxoSmithKline's erectile dysfunction therapy Levitra , on Aug. 19.

FDA attributed the low number of approvals in 2002 to a slowdown in submissions, a trend that appears to have at least moderated. The seven NMEs and 28 applications with user goals in October are more than double the respective number of disclosed applications that were due last October.

Several of the pending NMEs, however, face obstacles to a timely approval. Only four of the seven - Yamanouchi's solifenacin, Novartis' Enablex (darifenacin), Novartis' Certican (everolimus), and GlaxoSmithKline's fosamprenavir - have not been subject to announcements suggestive of delayed approval (see chart for list of applications with ² August-October user fee goals ).

Yamanouchi's solifenacin (YM-905) NDA for relief of symptoms of urinary frequency, incontinence and urgency has a user goal of Oct. 19. Novartis' overactive bladder treatment, darifenacin, could see action a few days earlier; the NDA was submitted to FDA in early December 2002. Solifenacin and darifenacin are both selective M3 muscarinic antagonists.

Novartis' acquisition of darifenacin from Pfizer was the most significant divestiture required by the Federal Trade Commission for the Pfizer/Pharmacia merger. Novartis purchased the agent for $225 mil. and expects launch in 2004; peak sales are projected at $500 mil. (³ Pharmaceutical Approvals Monthly Feb. 1, 2003, p. 8). Novartis and Yamanouchi are the only two firms well positioned to enter the OAB market in the next two years, according to the FTC's consent decree.

GSK/Vertex' protease inhibitor fosamprenavir has an action date of Oct. 20 for treatment of HIV infection in combination with other antiretrovirals. While the firms have not suggested any anticipated delay in FDA action, Vertex recently announced failure of the amprenavir (GSK's Agenerase ) prodrug to show non-inferiority to a lopinavir/ritonavir regimen in treatment-experienced patients. Despite the study results, Vertex expects approval in both treatment-naïve and -experienced patients (see ⁴ ).

Novartis' proliferation inhibitor Certican has an upcoming user fee date on Oct. 20 for prevention of rejection episodes following heart and kidney transplantation.

A 634-patient, randomized, double-blind study comparing Certican 1.5 mg and 3 mg to azathioprine in initial cardiac transplant patients appears in the Aug. 28 New England Journal of Medicine. The study employed a composite primary endpoint of death, graft loss or retransplantation, loss to follow-up, biopsy-proven acute rejection of grade 3A, or rejection with hemodynamic compromise.

At six months, investigators found the percentage of patients reaching the primary endpoint to be significantly smaller for both Certican 3 mg (27%, p<0.001) and 1.5 mg (36.4%, p=0.03) compared to azathioprine (46.7%).

Novartis announced Certican's approval in Sweden July 23. Sweden will function as the reference member state for mutual recognition in the EU.

Other pending agents with October deadlines include two major cardiovascular products: CV Therapeutics' chronic angina agent Ranexa (ranolazine), with an Oct. 30 goal, and Pfizer's Inspra (eplerenone), awaiting clearance for a congestive heart failure indication.

While the Inspra application is a supplement, it carries the weight of a new approval; Pfizer delayed launch of the aldosterone blocker pending the CHF indication. The first-in-class product was cleared Sept. 27, 2002, for treatment of hypertension. Once launched, Inspra could benefit from an endorsement for first-line use of aldosterone blockers in NIH's recently revised hypertension guidelines.

CVT's Ranexa is among the NMEs that appear unlikely to gain approval on the user fee goal. The drug had been scheduled for a September review by FDA's Cardiovascular & Renal Drugs Advisory Committee, but the meeting was cancelled, due, according to CVT, to lack of preparation time for the company and FDA.

CVT expects Ranexa to go to a later advisory committee, CEO Louis Lange, MD/PhD, told investors Aug. 4. The Cardio-Renal committee's next tentative meeting date is Dec. 8-9. Ranexa, a partial fatty acid oxidation inhibitor, would be the first new class of anti-angina treatment in over 20 years (⁵ Pharmaceutical Approvals Monthly Jan. 1, 2003, p. 7).

Approval on the PDUFA goal also is not the likely outcome for Forest's Alzheimer's agent memantine, which has a user fee date of Oct. 19. Although the application for moderate to severe Alzheimer's is scheduled for review by FDA's Peripheral & Central Nervous System Drugs Advisory Committee Sept. 24, Forest indicated that it expects to receive an "approvable" letter. The firm is projecting approval in spring 2004.

Forest resubmitted the memantine NDA Dec. 19, 2002; the application was originally submitted July 31, 2002, and withdrawn two months later.

Memantine has had some disappointing study results in earlier Alzheimer's disease and in neuropathic pain. In June, Forest reported negative results in mild to moderate Alzheimer's patients already receiving acetylcholinesterase inhibitors. The month before, Forest announced memantine's failure to meet statistical significance vs. placebo in a neuropathic pain trial.

Memantine is one of the key products Forest is counting on for long-term growth after its anti-depressant Celexa (citalopram) loses exclusivity in late 2004/early 2005.

Another threat to Celexa market share is Lilly's pending antidepressant Cymbalta (duloxetine), which has an October user fee goal following the firm's April response to a Sept. 13, 2002 approvable letter.

Lilly had been predicting approval in the fourth quarter, but that date has become less probable with FDA's Aug. 28 approvable letter for a separate application for duloxetine use in stress urinary incontinence. In addition to raising manufacturing issues, the August letter requests acute preclinical and clinical pharmacology studies on drug-drug interactions.

Lilly's erectile dysfunction NME Cialis also is pending at the agency with a user fee deadline in the fourth quarter. Lilly and joint venture partner Icos are highlighting the PDE-5 inhibitor's duration of response and rapid onset of action compared to Pfizer's Viagra (⁶ Pharmaceutical Approvals Monthly March 1, 2003, p. 3). If approved, Cialis would be the third PDE-5 agent to market, joining Viagra and Levitra.

GSK's COPD therapy Ariflo (cilomilast), the only respiratory NME with an October deadline, hit a major snag in approval with the Pulmonary-Allergy Drugs Advisory Committee's Sept. 5 review. The committee voted 7 to 3 that the agent did not show a "magnitude and consistency of efficacy that is sufficient to support approval" and suggested long-term efficacy studies.

Genentech/Xoma's psoriasis therapy Raptiva (efalizumab) is the sole new biologic with a deadline next month (Oct. 23). The agent was recommended for approval Sept. 9 by FDA's Dermatologic & Ophthalmic Drugs Advisory Committee.

Once approved, promotions for the anti-CD11a monoclonal antibody are expected to focus on the convenience of the once-weekly subcutaneous injection formulation. Biogen's Amevive (alefacept), currently the only biologic approved for psoriasis, is administered as a once-weekly intravenous or intramuscular injection. All three marketed tumor necrosis factor inhibitors are either pending or in development for psoriasis.

Janssen and AstraZeneca are expecting action on their atypical antipsychotics, Risperdal (risperidone) and Seroquel (quetiapine), respectively, for monotherapy and adjunctive therapy in acute bipolar mania. Risperdal's PDUFA date is Oct. 13; Seroquel's falls on Oct. 30.

Approval would put the agents on par with Lilly's Zyprexa (olanzapine), which cleared FDA in 2000 for short-term treatment of acute bipolar I manic episodes (⁷ Pharmaceutical Approvals Monthly Jan. 1, 2003, p. 10). However, Zyprexa could be cleared for long-term maintenance of response in bipolar disorder in September or October.

Cephalon's narcolepsy drug Provigil (modafinil) could gain an indication for treatment of excessive sleepiness associated with disorders of sleep and wakefulness in adults. FDA's Peripheral & Central Nervous System Drugs Advisory Committee is scheduled to review the agent Sept. 25; the product's user fee date is Oct. 20. ¨¨