Oncology, CNS Agents May Dominate 2006 NME Approvals; 2005 Total Is 18

The first half of 2006 could bring at least five novel oncologic approvals, including three for hematologic cancers.

Bristol-Myers Squibb's multi-targeted kinase inhibitor dasatinib and Genta's Bcl-2 inhibitor Genasense (oblimersen) could be approved for leukemia indications before the end of the first half of 2006, if granted priority reviews. Both agents were submitted in late December.

The preponderance of targeted therapies among the pending oncologic applications illustrates the growing maturation of the field. In addition to dasatinib and Genasense, Pfizer's targeted renal cell carcinoma (RCC) agent Sutent (sunitinib) is possibly the highest profile cancer drug currently under review at FDA.

Further Transition To Targeted Therapies

If approved on its Feb. 10 user fee date, Sutent would face direct competition from Bayer/Onyx' targeted agent Nexavar (sorafenib), which cleared FDA Dec. 20 with a broad indication for advanced RCC (¹ (Also see "Bayer/Onyx Nexavar Approved For Broad Advanced Kidney Cancer Indication" - Pink Sheet, 2 Jan, 2006.), p. 8).

Pfizer is seeking a metastatic RCC indication as well as a claim for malignant gastrointestinal stromal tumors, although CEO Hank McKinnell recently said labeling for the product could be better than expected.

In the hematologic category, Genta is seeking a priority review for use of Genasense in relapsed or refractory chronic lymphocytic leukemia in combination with fludarabine and cyclophosphamide. A six month review would give the agent a June 29 PDUFA date.

The CLL application is Genta's second try at bringing Genasense to market. The firm initially sought a melanoma indication, but withdrew the NDA in May 2004 following a negative advisory committee review (² (Also see "Aventis, Genta To Meet With FDA After Genasense NDA Withdrawal" - Pink Sheet, 24 May, 2004.), p. 12).

Bristol hopes to gain two initial indications for dasatinib: treatment of chronic myelogenous leukemia in chronic, accelerated or blast phases, as well as Philadelphia chromosome positive acute lymphoblastic leukemia. A priority review designation would give dasatinib a June 28 action date (see chart: " ³ NME Class of 2006? ").

If approved by its May 15 action date, MGI/SuperGen's hypomethylating agent Dacogen (decitabine) would be the third entrant into the myelodysplastic syndromes market. The sponsors submitted a complete response to a Sept. 1 "approvable" letter in November.

CNS Is Largest Category Of Pending NMEs...

Central nervous system drugs appear to be the dominant category of pending new molecular entities, with nine publicly disclosed novel agents currently under review at FDA.

The group includes three important follow-on compounds: Cephalon's Provigil follow-on Nuvigil (armodafinil) has a Jan. 31 deadline for excessive sleepiness; Johnson & Johnson's paliperidone, an active metabolite of Risperdal , has a Sept. 29 PDUFA date for treatment of schizophrenia; and Wyeth's Effexor antidepressant follow-on desvenlafaxine was submitted Dec. 22, giving it an Oct. 22 deadline.

The CNS tally also includes two novel smoking cessation aids: Pfizer's selective nicotinic acetylcholine receptor partial agonist Champix (varenicline) and Sanofi-Aventis' cannabinoid-1 receptor blocker Acomplia (rimonabant). Pfizer's product is receiving a priority review and has a review deadline in May.

In addition to smoking cessation, Sanofi is seeking Acomplia indications for treatment of obesity and metabolic disorders. Rimonabant was submitted in April 2005, giving it a February user fee deadline. Sanofi said it expects a decision in the first quarter.

One of the most anticipated CNS agents is Pfizer/Neurocrine's insomnia treatment indiplon, which has been delayed by technical difficulties with the sponsors' NDA. Immediate-release indiplon has a Feb. 15 review deadline; a decision on the controlled-release formulation is expected March 27.

The other pending CNS agents include Eisai's anti-epileptic rufinamide; Shire/New River's amphetamine derivative NRP104; and Schwarz' early-stage Parkinson's patch Neupro (rotigotine). Both rufinamide and Neupro are resubmissions.

...Cardiovascular & Infectious Disease Follow

The cardiovascular and infectious disease sectors both have three novel agents pending. If approved, CV Therapeutics' partial fatty acid oxidation inhibitor Ranexa (ranolazine) could make the biggest splash in the cardiovascular space. Ranexa's Jan. 27 PDUFA date comes almost three years after the original NDA submission in December 2002. CVT is seeking a narrower indication for the angina agent than it had previously sought.

Encysive's endothelin A receptor antagonist Thelin (sitaxsentan) could add to the rapidly populating pulmonary arterial hypertension market.

FDA cleared United Therapeutics' I.V. therapy Remodulin in November 2004 and CoTherix' inhaled prostacyclin Ventavis (iloprost) in December 2004; another oral treatment, Pfizer's Revatio (sildenafil), was approved last June. Several other compounds are in development for PAH.

Encysive's once-daily oral treatment has a March 24 action date. The company said it has hired 51 sales reps.

Sanofi expects an April decision on the amiodarone analog dronederone for treatment of atrial fibrillation. The firm's goal is a treatment at least as effective as Wyeth's Cordarone (amiodarone), currently the gold standard, but with improved tolerability.

In infectious disease, Novartis/Idenix' nucleoside analog telbivudine is pending with a request for a priority review; the firms announced submission of the oral chronic hepatitis B agent Jan. 3.

J&J's novel protease inhibitor for HIV-1 infection, TMC-114, was submitted Dec. 23 under FDA's Subpart H pathway. The sponsor believes the agent's novel mechanism of action allows for greater efficacy against wild-type and protease inhibitor-resistant strains of HIV.

Exuberant About Exubera

Of the 23 publicly disclosed NMEs with assigned PDUFA dates this year, Pfizer and Sanofi-Aventis' inhaled insulin Exubera may be the most highly anticipated.

After receiving a positive advisory committee recommendation in September, the product's user fee date was extended 90 days, to Jan. 27, to allow FDA to review additional chemistry data.

Novel respiratory agent NMEs pending at FDA include Sepracor's long-acting beta agonist arformoterol for chronic obstructive pulmonary disease. Sanofi's asthma corticosteroid Alvesco (ciclesonide) also is "approvable" at FDA.

Alvesco has been viewed as a potentially blockbuster entrant into the asthma and COPD market; the product has been approvable since October 2004, but Sanofi has not made a projection on its launch timeframe.

Sucampo's chloride channel type-2 activator lubiprostone NME is also pending for chronic idiopathic constipation, with a Jan. 31 action date.

From Approvable To Approval?

In addition to the 23 novel agents with user fee goal dates in 2006, there are at least 12 NMEs that are approvable at the agency which could be approved this year.

Besides Alvesco, notable approvable NMEs include GSK/Adolor's postoperative ileus agent Entereg (alvimopan). GSK views Entereg as one of its key potential launches in 2006; clinical data requested by FDA in a July letter are expected in "early 2006," GSK said (⁴ (Also see "GSK’s Six Launches, Six Filings Slated For ’06: Sign Of R&D Strategy Payoff?" - Pink Sheet, 26 Sep, 2005.), p. 21).

Schering-Plough's approvable antifungal Noxafil (posaconazole) could see action in 2006 as well. Schering expects to submit a response this year to FDA's June letter requesting additional data.

Outlook For Biologics

FDA has at least seven novel biologics currently under review. Merck is expecting decisions in 2006 on three of its vaccines - with its human papilloma virus vaccine Gardasil garnering the most attention. Merck's priority review request, still pending at the agency, would give Gardasil a June 1 user fee deadline.

Merck's other two vaccines, the rotavirus vaccine RotaTeq and the shingles vaccine Zostavax , both have PDUFA dates in February.

Genentech recently submitted its VEGF-A inhibitor Lucentis (ranibizumab) for treatment of neovascular wet age-related macular degeneration. The firm is requesting a priority review based on data showing a benefit over Novartis/QLT's photodynamic therapy Visudyne (verteporfin). A priority review would give Lucentis a June 29 user fee date.

Biogen Idec/Elan expect approval in March of a resubmission for their withdrawn multiple sclerosis therapy Tysabri (natalizumab) following a priority review. An advisory committee review is also anticipated.

Final 2005 NME Tally Is 18

FDA clearance of Bayer/Onyx' oncologic Nexavar Dec. 20, ahead of its Jan. 11, 2006 user fee goal date, helped the agency achieve a total of 18 NME approvals in 2005 (see chart: " ⁵ NME Approvals In 2005 ").

The 18 NMEs approved for the year is just over half of the 31 approved in 2004.

One fewer approval would have put FDA on par with the 17 NMEs cleared in 2002 - a psychologically significant figure representing a 20-year low for the agency. FDA cleared 21 NMEs in 2003.

FDA has attributed the reduction in the number of approvals to declining research productivity, rather than to the regulatory process or the increased scrutiny of its post-marketing safety surveillance experienced since mid-2004.

Deputy Commissioner for Medical & Scientific Affairs Scott Gottlieb cited a "disconnect" between R&D resources "and what we're getting in return in the way of new and better treatments" during a Nov. 29 Pharmaceutical Research & Manufacturers of America meeting (⁶ (Also see "Drug Approvals Will Be Down “Significantly” In ’05, FDA’s Gottlieb Predicts" - Pink Sheet, 12 Dec, 2005.), p. 6).

Industry has acknowledged ebbing pipeline productivity in recent years, in part due to a growing number of late-stage failures.

In contrast to FDA's argument that the dwindling number of approvals in recent years is due to a low number of submissions, Pfizer recently cited a more difficult, risk-averse regulatory environment as contributing to setbacks in its own R&D pipeline.

"It certainly is a more difficult regulatory environment," CEO Hank McKinnell said in October (⁷ (Also see "Pfizer Parecoxib, Oporia Setbacks Reflect Tougher FDA Stance, CEO Says" - Pink Sheet, 24 Oct, 2005.), p. 17).

The comments followed the September receipt of "not approvable" letters for Pfizer's COX-2 inhibitor parecoxib and osteoporosis prevention agent Oporia (lasofoxifene). Both of the agents are NMEs. McKinnell asserted that not approvable letters would not have been issued for the products two years ago.

Pfizer also received approvable letters for its lipoglycopeptide antibiotic NME dalbavancin in September and a second such letter for its NME anidulafungin in November for esophageal candidiasis; FDA did not sign off on any of the firm's novel agents in 2005.

Some NMEs More Equal Than Others

The 2005 NME total includes two agents which are similar to other recently approved NMEs. FDA determined that both growth hormone treatments iPlex (Insmed) and Increlex (Tercica) qualify as NMEs deserving separate orphan drug designations.

Increlex is mecasermin (insulin-like growth factor-1) alone, while iPlex is a fixed dose combination of IGF-1 and rinfabate (insulin-like growth factor binding protein-3) (⁸ (Also see "Insmed Growth Agent iPlex Joins Tercica’s Increlex With Orphan Exclusivity" - Pink Sheet, 19 Dec, 2005.), p. 26).

FDA is continuing its practice of categorizing all hyaluronidase products as NMEs because they are complex biological agents that cannot be fully characterized. Halozyme's Hylenex and PrimaPharm's Hydase ,both cleared as spreading agents, are the third and fourth hyaluronidases to count as NMEs, according to the agency.

December Rush Adds Five NMEs

Hylenex and iPlex, along with Nexavar, comprise three of the five NMEs cleared by FDA in December. Celgene's Revlimid (lenalidomide) for myelodysplastic syndromes and Astellas' Vaprisol (conivaptan) for euvolemic hyponatremia, approved Dec. 27 and 29, respectively, were the final NME approvals of the year.

Over half of the NME approvals in 2005 went to firms other than traditional big pharma companies - continuing a trend in recent years.

Notably, Amylin and Astellas were the only firms to achieve more than one NME during the year: Vaprisol and the antifungal Mycamine for Astellas and the anti-diabetics Symlin and Byetta for Amylin.

With three NMEs cleared for treatment of diabetes, anti-diabetics constituted one of the largest sub-sets of the 2005 NME class. The Symlin and Byetta approvals in March and April were followed by Novo Nordisk's Levemir (insulin detemir) in June.

The three oncologic NMEs approved in 2005 included Nexavar, Revlimid and GlaxoSmithKline's Arranon (nelarabine) for leukemia/lymphoma.

Average NME Approval Time Drops In 2005

The lower number of NME approvals in 2005 compared to 2004 coincided with a decrease in the average approval time for the year.

The mean time to approval from the date of first submission was 14.4 months in 2005. By comparison, FDA's average NME approval time was 18.7 months in 2004 and 17.1 months in 2003.

The 2005 class of NMEs also had a high proportion of priority reviews. Priority review NMEs constituted 72% of the 2005 approvals - 13 versus five standard reviews during the year. In 2004, 16 out of the 31 approved NMEs received priority reviews, or 52%.

The average approval time for therapeutic biologics reviewed by FDA's Center for Drug Evaluation & Research was 7.4 months in 2005 versus 20.2 months in 2004.

Average approval time for CDER-reviewed NMEs and therapeutic biologics combined was 13.7 months in 2005 versus 19.3 months in 2004. FDA transferred most therapeutic BLAs to CDER under a reorganization announced in 2003.

In 2005, FDA approved four NMEs that had been pending at the agency for more than two years. Symlin, the longest pending NME to be approved last year, was submitted Dec. 7, 2000, and underwent three review cycles before being approved March 16.

Contributed by F-D-C Reports' ⁹ Pharmaceutical Approvals Monthly .

[Editor's note: This is part of a series of articles reviewing the pharmaceutical sector's performance in 2005 and examining the outlook for the industry in 2006. Additional articles will appear in future issues of "The Pink Sheet."]