The year 2007 holds the potential to fatten Wyeth's new drug lineup: after a lean 2006, when no Wyeth new molecular entities were approved, the company leads the industry in potential NME approvals for the coming year.

Wyeth currently has four NMEs with user fee goal dates in 2007, just ahead of Novartis (three NME action dates in 2007). GlaxoSmithKline and Sanofi-Aventis each have two potential NME approvals in 2007 (see chart: ¹ NME Class of 2007? ).

Novartis was the only one of those four companies to have an NME approved in 2006 - the antiviral Tyzeka with partner Idenix. GSK partnered with ID Biomedical on the flu vaccine FluLaval .

For Wyeth, the start of 2007 is reminiscent of the same time in 2006: the next user fee for a Wyeth NME on the calendar is for Pristiq (desvenlafaxine), thanks to a user fee extension, resulting in Jan. 22, 2007, goal date.

Wyeth anticipates an "approvable" action for the Effexor XR follow-on, CEO Robert Essner told Morgan Stanley's CEOs Unplugged conference Jan. 3. Manufacturing issues at Wyeth's Guayama, Puerto Rico facility are one reason for the prediction, he suggested.

The Guayama issues are also a likely contributor to delays in the approval of Wyeth's extended-cycle contraceptive Lybrel (levonorgestrel/ethinyl estradiol). Lybrel, not an NME but a new formulation, has been approvable since July 2006. Wyeth has predicted a 2007 advisory committee review and approval (² [A#00680410003], p. 8).

April then brings two NME user fee goals for the Madison, New Jersey based company. Wyeth's priority review NDA for the oncologic Torisel (temsirolimus), the first mTOR inhibitor to reach FDA, has an April 5 goal date. The user fee goal for Wyeth's osteoporosis prevention agent Viviant (bazedoxifene) falls a few weeks later, on April 23.

April 23 is also the action date for Wyeth's second Pristiq NDA, for vasomotor symptoms of menopause.

The fourth Wyeth NME already under FDA review is bifeprunox, the firm's second NME for the psychiatric market. The Solvay/Wyeth antipsychotic carries a user fee goal date of Aug. 11.

Novartis has three NMEs with 2007 user fee goal dates: the DPP-4 inhibitor antidiabetic Galvus on Feb. 28, the renin inhibitor antihypertensive Tekturna in March, and the targeted kinase inhibitor oncologic Tasigna in September.

More Activity In The DPP-4 Inhibitor Class

Galvus is in position to become the second DPP-4 inhibitor on the market for diabetes, after Merck's Januvia was cleared in October. The segment is likely to continue to heat up, as illustrated by the first major licensing agreement of 2007, a deal worth up to $1 billion between AstraZeneca and Bristol-Myers Squibb for Bristol's Phase III DPP-4 inhibitor saxagliptin and Phase II SGLT2 inhibitor dapagliflozin.

The past year also provided some cautionary notes for the enthusiasm for the DPP-4 class. GlaxoSmithKline halted Phase III trials of its DPP-4 inhibitor Redona (denagliptin) following unfavorable preliminary data from preclinical long-term toxicity trials.

After requesting dermatologic data from all DPP-4 developers in November 2005 because of concerns raised by primate toxicity data, FDA's heightened attention to skin safety has persisted. The February Galvus action date represents a three-month extension to give FDA time to evaluate new primate dermatological data submitted by Novartis (³ Also see "Novartis Touts Galvus Efficacy Vs. Januvia After Metformin Comparison Fails" - Pink Sheet, 4 December, 2006., p. 9).

FDA's review of Tekturna (aliskiren, formerly Rasilez ) has also been extended to address safety concerns, in this case related to the colon. Novartis submitted clinical data from a 30-patient study of Tekturna's potential to cause changes to the colonic mucosa in early December, advancing the user fee goal to March.

GSK's two NMEs with 2007 user fee goals both have spring action dates. GSK's candidate for the growing targeted kinase inhibitor oncologic field, Tykerb (lapatinib), is a priority review candidate for second-line breast cancer treatment with a user fee goal on March 15. Another kinase inhibitor, Novartis' Tasigna, is pending for chronic myeloid leukemia with action expected in September.

GSK's Flonase follow-on Allermist (fluticasone furoate), has a user fee goal date of April 28. The corticosteroid - a nasal spray for seasonal and perennial allergic rhinitis - is the only allergy therapy currently pending at FDA with a 2007 user fee goal. Unlike the one anti-allergy NME approved in 2006, Altana's corticosteroid Omnaris (ciclesonide), Allermist is not a prodrug; Allermist differs from Flonase in the nature of the 17-alpha ester group.

The Drug Chemistry Of Follow-Ons

The coming year shows how entrenched the chemical manipulation of molecules to form more commercially acceptable prodrugs, metabolites, and single-isomer drugs has become.

The class of potential 2007 NMEs represents something of a resurgence of chiral switches. Three pending NMEs are chiral switches, that is, they are single enantiomers of marketed parent racemic compounds (compounds comprised of mirror-image isomers, or enantiomers, that may have different pharmacologic properties).

FDA formally encouraged the development of purified enantiomers over racemates in a 1992 guidance on development of stereoisomeric drugs. Technological advances in chiral chemistry made possible the development, FDA noted: "Whether separated enantiomers should be developed was largely an academic question because commercial separation of racemates was difficult. Now ... technical advances (large scale chiral separation procedures or asymmetric syntheses) permit production of many single enantiomers on a commercial scale."

Wyeth's Pristiq (dexvenlafaxine) is a single enantiomer of Effexor XR (venlafaxine); Cephalon's Nuvigil (armodifinil) is a single isomer version of Provigil (modafinil); and UCB/Sanofi-Aventis' Xyzal (levocetirizine) is a single enantiomer of Zyrtec (cetirizine).

Shire's Vyvanse (lisdexamfetamine) is also a chiral separation compound, but the significance of the product lies not in its use of the amphetamine enantiomer dextroamphetamine (which is not new) but in the linkage of the enantiomer to the amino acid l-lysine to form lisdexamfetamine. Shire predicts a second quarter 2007 launch for Vyvanse, which has been approvable twice.

Following FDA's 1992 stereoisomer guidance, chiral separation has produced numerous products. Ironically, however, chiral chemistry was not the most highly heralded technology for generating new drugs in that time period. Genomics captured many more headlines in 1990s, while chiral separation was chiefly the province of specialty firms like Sepracor.

Genomics, however, has yet to produce a significant crop of new compounds. Recently, GSK attributed lean antibiotic pipelines industry-wide to bacterial genomics programs that were expected to increase the number of leads yet yielded significantly fewer candidates than expected (⁴ Also see "GSK Trades In Anti-Infective R&D Model, Starts CEDD For Infectious Disease" - Pink Sheet, 6 November, 2006., p. 22).

Four New Antibiotics In Line For FDA Action

The appearance of two new antibiotics on the list of 2007 user fee goal dates appears nonetheless to be a sign that novel antibiotics are still making their way through the pipelines, especially when combined with the likelihood of FDA action on two pending approvable antibiotic NDAs as well.

Theravance's telavancin represents a new class, the lipoglycopeptide antibiotic. Action by June 7 is possible if FDA grants the company's request for priority review. The NDA for telavancin, an injectable, seeks approval for complicated Gram-positive skin and skin structure infections. Johnson & Johnson's doripenem, an injectable carbapenem antibiotic, has an Oct. 13, 2007 user fee goal for complicated intra-abdominal and urinary tract infections.

Pfizer predicts approval and launch of its antibiotic Zeven (dalbavancin), also in the lipoglycopeptide class, for Gram-positive bacterial infections in 2007 after receiving an "approvable" letter in June 2006.

GSK also has a novel antibiotic that could see action in 2007. Altabax (retapamulin) received an approvable letter in December for secondarily infected traumatic lesions; an indication for secondarily infected dermatoses was deemed not approvable at the same time. FDA did request additional information for the traumatic lesions indication; additional studies are needed for the other indication.

GSK has not announced a new timeframe for the secondary infections applications, although the firm is expecting a second quarter 2007 decision on an impetigo NDA for Altabax, which could get the NME status de facto.

Cancer, CNS Continue To Lead Drug Development

Cancer and central nervous system therapies continue to dominate the near-term NME pipeline, as they did in the prior year (⁵ Also see "Oncology, CNS Agents May Dominate 2006 NME Approvals; 2005 Total Is 18" - Pink Sheet, 9 January, 2006., p. 25).

In addition to Wyeth's two psychiatric NMEs, potential 2007 CNS approvals include Cephalon's Nuvigil for excessive sleepiness due to shift work, narcolepsy, and sleep apnea, with a March user fee deadline, and Shire's Vyvanse.

One pending approvable NME, Schwarz' Neupro patch for Parkinson's disease, is also on track for a first half 2007 approval and launch, according to the firm.

In oncology, traditionally the most active field for new drugs, the upcoming year could see action on six agents: GSK's Tykerb, Wyeth's Torisel, IDM's Junovan , Dendreon's Provenge , and Novartis' Tasigna.

Cardiovascular NMEs are well-represented, with three potential approvals, but only one is for a commercially significant market: Novartis' Tekturna, potentially the first new class of antihypertensive in a decade. Two products with the same mechanism of action (endothelin receptor antagonists) for the orphan condition pulmonary arterial hypertension could be approved - and the user fee goal dates could be mere days apart in mid-June.

Small Firms, Markets Dominate Pending Biologics

The pipeline of novel biologics with 2007 action dates is a healthy six. But while big pharma has been touting a heightened interest in biotech, only one of the pending biologics, Roche's continuous erythropoeitin receptor activator Mircera , comes from a major firm.

Mircera, a controversial (and much-litigated) candidate for the lucrative erythropoeisis stimulation market, required the resources of a major firm. The BLA has a May action deadline after Roche's mid-December filing of additional data extended the user fee goal by three months. Roche "proactively submitted" the data to make the application "as robust as possible in an evolving regulatory environment," the firm explained.

The other five biologics are sponsored by smaller firms for smaller populations. Two are recombinant human proteins: Cangene's Accretropin human growth hormone for Turner Syndrome and Zymogenetics' thrombin to achieve hemostasis during surgery.

Dendreon's Provenge (sipuleucel T) could be the first cancer vaccine approved. The BLA has a user fee goal of September 13 or earlier.

As a biodefense product, the population for Acambis' smallpox vaccine ACAM2000 is largely theoretical at this point. The vaccine has a Feb. 14 user fee goal.

Alexion's Soliris (eculizumab) is the lone monoclonal antibody with a 2007 action date. Alexion is seeking approval for the orphan condition paroxysmal nocturnal hemoglobinuria.

Reduced Expectations For Big Pharma

After two NME and three new vaccine approvals in 2006, Merck's lone 2007 NME user fee goal is for the COX-2 inhibitor Arcoxia , which has been approvable since October 2004 and embattled since the withdrawal of Vioxx weeks earlier (⁶ Also see "Merck Arcoxia MEDAL Results Will Likely Not Meet FDA Gold Standard" - Pink Sheet, 28 August, 2006., p. 5). Merck resubmitted the NDA in November 2006 for an osteoarthritis indication alone, in place of the original broad application. The resubmission has an early April 2007 user fee target, and an advisory committee has been scheduled for April 12.

Pfizer recorded three NME approvals in 2006, but is entering 2007 with only one NME user fee goal on the calendar, in addition to the firm's prediction of a Zeven approval. Pfizer acquired fesoterodine from Schwarz in April in a deal that also settled a patent dispute. The overactive bladder therapy has a January user fee date.

Sanofi-Aventis' hope for a blockbuster Acomplia could see action on an obesity indication, which carries an April 26 user fee goal, but rimonabant's smoking cessation indication remains not approvable.

Another highly anticipated potential blockbuster, GSK's HPV vaccine Cervarix , could have been a 2007 approval had GSK met its December 2006 filing target. Instead, the company announced in November that it would delay the Cervarix BLA until April 2007 (⁷ Also see "GSK Plays Up Avandia As Diabetes “Engine” After DPP-4 Program Stalls" - Pink Sheet, 6 November, 2006., p. 20). GSK attributes the delay to the event-driven nature of an ongoing clinical study.

- Bridget Silverman

2007 NME Prospects Plentiful For Wyeth, Novartis – Other Firms Fall Short

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