Year-End Submission Rate Stabilizes In 2005 As NDA Approvals Drop

The slow-down in year-end FDA submissions in recent years appears to have stabilized in 2005, with 16 filings in December - up slightly from 13 in December 2004.

The uptick in publicly disclosed submissions, including eight new molecular entity filings in December 2005 compared to four in December 2004, could bode well for approvals in 2006. The traditional year-end flood of NDA filings previously had ebbed from 25 in 2002 (eight NMEs) to 17 in 2003 (seven NMEs).

High profile, novel therapeutic submissions in December included J&J's first foray into the HIV therapy field with its TMC-114 protease inhibitor, filed Dec. 23 ( ¹ see chart of recent submissions ).

J&J aims to launch TMC-114 this year, pending accelerated approval. Developed by the firm's European subsidiary Tibotec, TMC-114's unique mechanism of action results in a high genetic barrier to resistance, according to J&J. The drug is therefore potent against wild-type strains and viruses resistant to other protease inhibitors, J&J maintained.

Novartis and Idenix also submitted an antiviral NME in December - the oral nucleoside analog telbivudine for once-daily, chronic hepatitis B treatment. The companies are highlighting improved response rates, better long-term efficacy and convenient dosing regimens as unmet needs associated with existing treatments. Merck's antiviral biologic vaccine Gardasil also was submitted Dec. 1 for human papilloma virus.

Bristol-Myers Squibb completed a rolling NDA for its multi-targeted kinase inhibitor NME dasatinib Dec. 28 for leukemia indications. Genta also is pursuing leukemia claims with Genasense (oblimersen), for which a rolling NDA was completed Dec. 29; an earlier NDA filing for malignant melanoma was withdrawn in 2004 ( ² (Also see "Genta Plans Confirmatory Trial To Extend Genasense To First Line CLL Use" - Pink Sheet, 15 Jan, 2006.) ).

Wyeth filed an NDA Dec. 22 for its NME desvenlafaxine extended-release, the follow-on to its antidepressant Effexor XR , more than four years before Effexor XR will be subject to generic competition. The company has forged an agreement with Teva that will allow the generic firm to launch generic Effexor XR July 1, 2010, which should provide Wyeth ample time to bring its follow-on to market.

Shire and New River are seeking a pediatric indication for children ages six to 12 for the attention deficit/hyperactivity disorder therapy NRP104. The firms are emphasizing the potential for lower abuse liability with the amphetamine prodrug compared to stimulant ADHD agents. The NME was submitted Dec. 6.

Shire, one of two firms to make more than one submission in December (along with Genentech), also submitted Mesavance for ulcerative colitis Dec. 21.

While not an NME, Mesavance would be the first once-daily mesalamine treatment available for patients with active, mild-to-moderate UC, if approved. Shire currently markets Pentasa , a different mesalamine formulation for UC.

Replidyne's antibiotic Orapem (faropenem medoxomil), an ester prodrug derivative of faropenem, would be the first oral antibiotic of the penem class marketed in the U.S., the firm said. Replidyne submitted the NME Dec. 20 for treatment of acute bacterial sinusitis, community acquired pneumonia, acute exacerbations of chronic bronchitis and uncomplicated skin and skin structure infections.

The eighth NME submission in December was Sepracor's long-acting beta agonist arformoterol, a single enantiomer of Schering-Plough's Foradil (formoterol) for chronic obstructive pulmonary disease, announced Dec. 13.

Only half of the December NME submissions are traditional novel molecules. The other four, while NMEs, are derived from existing products: the chiral compounds desvenlafaxine and arformoterol, prodrug NRP104 and prodrug derivative faropenem medoxomil.

December filings also included eight submissions related to biologics, new uses for marketed agents and new formulations.

Genentech submitted a BLA for Lucentis (ranibizumab) for neovascular "wet" age-related macular degeneration on Dec. 29, including a head-to-head trial with Novartis/QLT's photodynamic therapy Visudyne (verteporfin). Genentech has called Lucentis the first potential wet AMD therapy to "demonstrate a clinical benefit over PDT in a head-to-head study" (³ Pharmaceutical Approvals Monthly June 2005, p. 12).

Genentech hopes to follow up the BLA with a supplement giving Lucentis a dosing advantage over Pfizer and Eyetech's Macugen (pegaptanib). Preliminary results from Genentech's Phase IIIb PIER study are expected in the first half of 2006. If successful, the study would support Lucentis administration once a month for the first three months and once every three months thereafter for 24 months. Macugen is dosed every six weeks.

A BLA supplement for Genentech's Avastin (bevacizumab), submitted Dec. 19, would extend use of the oncologic to relapsed metastatic colorectal cancer in combination with 5-fluorouracil-based chemotherapy. Avastin was approved in February 2004 for first-line treatment of metastatic colorectal cancer with 5-FU-based chemotherapy.

A new claim for Enzon's Oncaspar (pegaspargase) oncologic also was accepted for review by FDA for first-line treatment of acute lymphoblastic leukemia, the firm announced Dec. 1.

AstraZeneca submitted a supplement for Seroquel (quetiapine) treatment of depressive episodes associated with bipolar disorder, the firm announced Dec. 30. The agent currently is approved for acute manic episodes associated with bipolar disorder, as well as for schizophrenia.

A submission for Astellas' tacrolimus, a once-daily, modified-release formulation of the firm's Prograf immunosuppressant for prevention of organ transplant rejection, was announced Dec. 26.

Eisai resubmitted Aricept (donepezil) for severe Alzheimer's disease after reformatting the sNDA in electronic format, the firm announced Dec. 19. FDA had refused to accept an original Aug. 31 sNDA paper application due to formatting deficiencies.

Despite the encouraging advance in end-of-year submission totals in 2005, year-end approvals were down sharply, reflecting in part the slow-down in submissions in prior years.

The NDA approval total of seven in December 2005 (including five NMEs), compares to 15 NDA approvals for the same month in 2004. The agency cleared six NDAs in the final month of 2003 ( ⁴ (Also see "FDA’s 2005 New Molecular Entity Total: 18, Including Five In December" - Pink Sheet, 15 Jan, 2006.) ).

FDA also cleared a single biologic in the final month of both 2005 and 2004; Bristol-Myers Squibb's Orencia (abatacept) BLA was approved on Dec. 23 ( ⁵ ).