Almost one-third fewer novel product applications are on FDA's user fee calendar for the second half of 2010 as compared to the docket at the same point in 2009, a dearth that could imperil the slow but steady improvement in annual new molecular entity and novel biologic approvals after the nadirs reached earlier in the decade.

At the mid-point of 2010, FDA can look back on a healthy six-month tally of NME and novel BLA approvals: a total of 17, more than in the first half of any of the preceding five years (see chart: "¹ Fast Off The Starting Blocks In 2010"). Approvals, of course, are rarely evenly spread throughout the year, but the trend-line certainly looks positive.

Less positive, however, is the outlook for new product approvals in the second half of the year. While over thirty potentially significant applications had second-half user fee goal dates for the second half of 2009, only 22 publicly disclosed pending novel products are slated for action for the rest of 2010 (see chart: " ² Awaiting FDA Action: Novel NDAs And BLAs With User Fee Goal Dates In The Second Half 0f 2010"). The number drops to 17 when potentially significant products that do not qualify as NMEs or novel biologics are excluded.

Underlining the gloomy forecast for second-half approvals, at least six new products appear unlikely to garner approval when their goal dates come up - almost a third of the new drug and biologic products remaining on the 2010 PDUFA calendar.

Extrapolating from advisory committee votes to FDA actions may be a fool's game - FDA can and will deviate from the recommendations of its advisory panels if it sees fit - but a lopsided committee vote either for or against approval is nonetheless suggestive of a drug's prospects.

Advisory committees posted overwhelming votes against approval of three 2010 candidates: NicOx's nitric oxide-modified naproxen for osteoarthritis, naproxcinod; MedImmune's Synagis successor for respiratory syncytial virus, Rezield (motavizumab); and, most recently, Boehringer Ingelheim's sexual dysfunction drug for women, Girosa (flibanserin) (see ³ advisory committee chart).

On the other hand, Theratechnologies' Egrifta (tesamorelin), the first drug for HIV-associated lipodystrophy, Novartis' oral multiple sclerosis therapy Gilenia (fingolimod), and HRA/Watson's Ella (ulipristal) emergency contraceptive received unanimous advisory committee votes in favor of approval - certainly no guarantee of an official approval letter, but a positive sign nonetheless.

A cancelled advisory committee date for Lux/Isotechnika's Luveniq (voclosporin) so FDA can resolve what it called "several outstanding issues" does not bode well for a first-cycle approval of the uveitis drug, which has priority review status (⁴ Also see "Last-Minute Cancellation Of Advisory Panel Meeting Throws Future of Luveniq Into Doubt" - Pink Sheet, 23 June, 2010.).

Human Genome Sciences and Novartis are already laying the groundwork for a protracted review of their albumin-modified interferon, Zalbin (albinterferon alfa 2b), for hepatitis C. In June, HGS announced that FDA had communicated concerns that made approval of the submitted biweekly dosing regimen unlikely; the sponsors are considering moving forward with a monthly dosing regimen (⁵ Also see "Monthly Or Bust: Zalbin's Chances For Approval Likely Rest On Monthly Use Data" - Pink Sheet, 15 June, 2010.).

HGS' prospects are likely better for its recently-submitted monoclonal antibody Benlysta (belimumab), partnered with GlaxoSmithKline. If Benlysta, a highly anticipated product for lupus, receives the priority review the sponsors have requested, it could see action in December. The historical difficulty of developing therapies for the disease, however, could complicate the review and dampen the prospects for a 2010 approval (see ⁶ Also see "Late-Stage Lupus Therapies Glow In Halo Of Benlysta Spotlight" - Pink Sheet, 1 July, 2010. ).

An upcoming advisory committee on July 28 should give a good indication of AstraZeneca's chances of injecting new blood into what has been an anemic lineup of launches in the past several years. Given the problems with the Rezield BLA from its MedImmune subsidiary, which had been expected to be a significant commercial prospect for the company, AstraZeneca's hopes to make the NME/BLA approvals list this year, and have a blockbuster entry, are centered on Brilinta (ticagrelor) for acute coronary syndromes.

Novartis is positioned to reprise its 2009 position at the top of the novel approvals count in 2010. With two novel approvals under its belt already ( Zortress to prevent kidney transplant rejection and the meningococcal vaccine Menveo ), Novartis is awaiting FDA action on Gilenia and the more troubled Zalbin.

GlaxoSmithKline, the other top performer in the 2009 approvals count, has two potential novel approvals with upcoming 2010 user fee goals. Both products are partnered, Benlysta with HGS and the anti-epileptic Potiga (ezogabine, formerly retigabine) with Valeant. GSK had no first half NME or novel BLA approvals.

Eisai could be a stealth top performer for 2010 NME/BLA approvals. While the Japanese firm has no such approvals to date this year, it has two pending NMEs - its refractory breast cancer treatment eribulin and, via a recent licensing deal, Arena's lorcaserin for obesity.

Novel, Just Not Through The Molecule

Reformulations and other new approaches that use existing molecules for novel uses and undertreated conditions, or novel combinations of previously approved drugs, make up an unusually high proportion (around 20 percent) of the potentially significant new applications with user fee dates during the remainder of 2010 relative to most years, when there has been more action on the NME front.

The obesity market is avidly watching three new products pending in the long dry, but enticingly lucrative, space - and only one, Arena/Eisai's lorcaserin, is an NME. Vivus' Qnexa and Orexigen's Contrave (with a January 2011 PDUFA goal) are both novel combinations of previously approved drugs (⁷ Also see "Obesity: Three New Drug Candidates Promise A New Dawn" - Pink Sheet, 1 February, 2010.).

In the consistently active diabetes space, one of the most hotly anticipated new products is not a novel molecule but an extended-release formulation: Amylin, Lilly and Alkermes' once-weekly formulation of the type 2 diabetes drug Byetta (exenatide), dubbed Bydureon . MannKind has been energetically publicizing its bid to banish memories of Pfizer's commercial failure with Exubera inhaled insulin with its ultra rapid acting inhaled insulin product Afrezza ; a recent resubmission in response to an FDA "complete response" letter gives Afrezza a shot at a 2010 approval.

Shionogi's liquid formulation of glycopyrrolate reformulates an old anticholinergic for a novel indication, chronic drooling, especially targeted at cerebral palsy. Avanir's Zenvia combines two established drugs, dextromethorphan and quinidine, for another novel indication, involuntary emotional expression disorder. FDA is currently reviewing a reformulated lower-dose formulation submitted in response to an "approvable" letter.

Biologics' Share Of Approvals Poised To Decline - Probably Temporarily

The user fee lineup for the second half of 2010 is only one-quarter biologics, raising the prospect of a very different ratio of NMEs to BLAs than is seen in the first half of the year's approvals. Between January and June 2010, FDA approved eight NMEs and nine novel BLAs (and CBER opened the second half with the July 1 approval of another BLA, for Kamada's Glassia ). At CDER, one-third - four of 12 - of the center's 2010 novel approvals were for biologics. For perspective, in 2009, the share of BLAs in CDER's novel approvals reached a record high of 24 percent (⁸ Also see "Biologics Reached Record Share Of Novel Approvals In 2009" - Pink Sheet, 1 January, 2010.).

The novel BLAs still in line for action in 2010 range from Rezield and Zalbin, both with questionable prospects, to Savient's Krystexxa (pegloticase), a gout therapy awaiting finalization of a REMS and communication plan (⁹ Also see "As Gout Market Opens Up, Experts Await Therapies To Better Lower Uric Acid" - Pink Sheet, 1 November, 2009.). The last BLA in line could have the biggest commercial potential: HGS/GSK's hotly anticipated Benlysta aims to be the first new therapy for systemic lupus in 40 years.

Regardless of what happens in the next six months, the rise of biologics appears unstoppable in the long-term. And the categories may, at times, converge: Genentech just announced a BLA submission for an antibody-drug conjugate that links the biologic trastuzumab ( Herceptin ) with a cytotoxic drug payload (see ¹⁰ Also see "Roche Files BLA For Conjugated Herceptin Follow-On Trastuzumab-DM1" - Pink Sheet, 1 July, 2010.). The company requested priority review for the BLA, which could put a goal date for FDA action in early January 2011, or earlier.

- Bridget Silverman ( ¹¹ b.silverman@elsevier.com )

FDA's NME Approval Rebound At Risk: Drought Of Novel Products In Line For Action In Remainder Of 2010 Could Depress Upward Trend From First Half

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