FDA’s healthy tally of novel drug approvals in the first half of 2012, combined with a crowded second-half user fee calendar, suggests the agency is well on track to post another solid year of NME approvals – and that its recovery from the NME approval doldrums of the mid-2000s has solidified.

So far, 2012 has seen two of the fastest approvals in modern FDA history with Kalydeco and Erivedge, as well as the end of one of the longest and most convoluted reviews in Surfaxin’s five-cycle, almost eight-year approval odyssey.

While the 14 new molecular entities and novel therapeutic biologics approved between January and June 2012 are slightly less than the first half 2011 tally (18), a robust slate of applications for new agents with user fee goal dates for action in the second half of this year means the agency could easily match, if not exceed, last year’s mark of 30 CDER new molecular and new biologic entity approvals. Approvals almost never split 50/50 between the two halves of the year (see graph).

Source: FDA

Perhaps the most important factor laying the groundwork for a strong second half of 2012 is the wealth of NDAs and BLAs awaiting action (see chart, [A#06120701006]). The user fee calendar for the second half of 2012 has more than twice as many novel or significant drug candidates as the slate of NDAs and BLAs pending action in the last six months of 2011 Also see "FDA Sets A Fast Pace Of Novel Approvals In First Half, But That's Likely To Slow" - Pink Sheet, 1 July, 2011..

Review metrics so far are consistent with the past few years. CDER cleared 64%, or nine, of the 2012 NMEs/NBEs on the first review cycle, well within the range of the PDUFA IV era and very close to the 63.3% full-year 2011 average share of first-cycle reviews Also see "Innovation Pays: Priority Drugs Drove Novel 2011 Approvals To New Heights" - Pink Sheet, 1 January, 2012.. FDA continued to meet most Prescription Drug User Fee Act timeframes for action.

But the outliers are particularly notable.

CDER turned in two of the fastest approvals of the decade in quick succession in January – Vertex Pharmaceuticals Inc.’s cystic fibrosis therapy Kalydeco (ivacaftor), at 3.4 months the fastest approval for a therapeutic NME outside of oncology in the modern era, and the first Hedgehog pathway inhibitor, Genentech Inc./Curis Inc.’s Erivedge, which cleared FDA in 4.7 months for advanced basal cell carcinoma Also see "CDER Approvals In January Came Early And Often" - Pink Sheet, 1 February, 2012..

But the year also saw the conclusion of the epic review of Windtree Therapeutics Inc.’s synthetic pulmonary surfactant Surfaxin (lucinactant) after five review cycles and almost eight years since its 2004 submission Also see "Discovery Labs Admits Pricing For Long-Awaited Surfaxin Will Be Tricky" - Pink Sheet, 12 March, 2012..

Proportionally Fewer Priority Approvals

One of the major drug approval storylines in 2011 was the high level of innovation, with FDA touting the 12 first-in-class agents in the approval class – 40% of calendar year approvals. Almost half of CDER approvals in 2011 had priority review status.

So far, 2012 is looking more standard in terms of innovation. Only four of the 14 CDER approvals, or 28%, had priority review: two drugs (Kalydeco and Erivedge) and two therapeutic biologics, BTG International Inc.’s Voraxaze (glucarpidase) and Genentech’s Perjeta (pertuzumab). Voraxaze is approved for an orphan oncology supportive care indication, treatment of toxic methotrexate concentrations in patients with impaired renal function, while Perjeta targets a much larger market of HER2-positive breast cancer patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

FDA appears to be holding a strict line in awarding priority review status. At least four NDAs with 2012 PDUFA goals that sought priority review failed to receive it, including Onyx Pharmaceuticals Inc.’s Kyprolis (carfilzomib) for refractory multiple myeloma, Gilead Sciences Inc.’s “Quad” HIV therapy (elvitegravir, cobicistat, emtricitabine, and tenofovir), NPS Pharmaceuticals Inc.’s Gattex (teduglutide) for short bowel syndrome, and Aegerion Pharmaceuticals Inc.’s lomitapide for homozygous familial hypercholesterolemia.

In CBER, the level of innovation among 2012 BLA candidates is relatively lackluster, although the center is still likely to surpass its low total of three novel biologics approved in 2011.

[Sidebar#06120701032]

Oncology Pipeline Continues To Produce

Oncology is looking to be the most productive sector in terms of new drug approvals in 2012, as it was in 2011 and in most years. A Tufts Center for the Study of Drug Development study of review division performance held the oncology office up as the “exemplary” review division for its productivity Also see "Oncology Review Division At The Head Of The Pack – But Can The Others Keep Up?" - Pink Sheet, 1 April, 2012.. Of course, oncology NDAs also have some advantages over other disease applications, requiring smaller and shorter trials and carrying a risk/benefit ratio that allows for more serious adverse events.

Almost 30% of CDER’s first half approvals were for oncology drugs, including three of the four priority approvals (Pfizer Inc.’s kinase inhibitor Inlyta, for advanced renal cell carcinoma, had a standard review).

In the second half, at least seven more oncology applications are in line for FDA action. Among the most eagerly awaited is Medivation Inc./Astellas Pharma Inc.’s enzalutamide, an androgen receptor signaling inhibitor for castration-resistant prostate cancer that stopped Phase III early due to efficacy Also see "More Competition In Prostate Cancer? Medivation’s Enzalutamide Now With FDA" - Pink Sheet, 22 May, 2012.. Enzalutamide will likely have a November user fee goal if FDA accepts the sponsors’ priority review request.

Exelixis Inc. is also seeking priority review status for its medullary thyroid cancer treatment cabozantinib in the same November time frame. Cabozantinib would be the second drug approved for the rare cancer, but the company is touting its strong efficacy in more severely ill patients than were studied to support approval of the first drug, AstraZeneca PLC’s Caprelsa (vandetanib) Also see "Exelixis’ Cabozantinib Targets Particularly Sick Thyroid Cancer Patients" - Pink Sheet, 1 November, 2011..

Two pending metastatic colorectal cancer therapies have priority status. Sanofi/Regeneron Pharmaceuticals Inc.’s vascular endothelial growth factor “trap” fusion protein Zaltrap (aflibercept) has an Aug. 4 user fee goal date, and Bayer/Onyx Pharmaceuticals Inc.’s regorafenib, a multi-kinase inhibitor, has a late October goal date.

September Is Gastroenterology Month

Aside from oncology, the office that turned out the most approvals in the first half is one that does not often make waves: Office of Drug Evaluation III, home to the divisions reviewing dermatology and dental products, gastroenterology and inborn errors of metabolism (like Gaucher’s), and reproductive and urology products. Four novel products came out of ODE III, including Leo Pharma AS’ topical actinic keratosis therapy Picato (ingenol), Protalix BioTherapeutics Inc./Pfizer’s enzyme replacement therapy Elelyso (taliglucerase) for Gaucher disease and two entries into established urogenital markets, Vivus Inc.’s PDE 5 inhibitor for erectile dysfunction, Stendra (avalanafil), and Astellas Pharma Inc.’s beta-3 agonist for overactive bladder Myrbetriq (mirabegron).

Gastroenterology reviewers can expect a busy September. A decision is expected that month on Ironwood Pharmaceuticals Inc./Forest Laboratories Inc.’s linaclotide for irritable bowel syndrome, an indication strewn with withdrawn and restricted drugs. Linaclotide, a first-in-class peptide agonist of the guanylate type-C receptor, is under review for an indication for chronic constipation and IBS with constipation.

Also due in early September is Salix Pharmaceuticals Ltd./Napo Pharmaceuticals Inc. ’s priority review NDA for crofelemer, an anti-secretory agent that inhibits chloride secretion for the treatment of diarrhea associated with antiretroviral therapy in HIV/AIDS patients. And the last day of the month is the goal date for NPS Pharmaceuticals Inc.’s Gattex (teduglutide), a recombinant human glucagon-like peptide 2 analog for short bowel syndrome.

Watch For Near-Term Action From ODE II

Office of Drug Evaluation II, home to reviews for products ranging from analgesics to endocrinologic, metabolic, pulmonary and rheumatology drugs, cleared three NMEs, including two of the potentially most significant approvals of the year in Kalydeco and Arena Pharmaceuticals Inc.’s Belviq (lorcaserin), the first obesity drug approved by FDA in over a decade.

First up, in July, is Forest/Almirall SA’s aclidinium, a long-acting inhaled antimuscarinic agent for chronic obstructive pulmonary disease (see related story, Also see "Forest’s Respiratory Pipeline: Can It Open The Revenue Airway?" - Pink Sheet, 1 July, 2012.). In August, action is expected on the second candidate from the highly touted JAK inhibitor class – and the first outside oncology – Pfizer’s tofacitinib, an oral therapy for rheumatoid arthritis. Tofacitinib’s approval was endorsed by an advisory committee, but members were troubled by uncertainty over the drug’s safety profile, the limits of the indication, and the scope of risk management Also see "Will Pharmacovigilance Be Enough To Address Questions About Pfizer’s Tofacitinib?" - Pink Sheet, 14 May, 2012..

The Division of Metabolic and Endocrinologic Products can expect to continue to work long hours in the rest of 2012. Vivus’ novel combination obesity therapy Qsymia (phentermine/topiramate, formerly Qnexa) started the second half off with a bang, receiving approval on its July 17 user fee goal, and the rest of year is filled with niche lipid-lowering drugs like Amarin Pharmaceuticals Inc.’s prescription-grade omega-3 fatty acids product AMR-101, Amylin Pharmaceuticals Inc.’s leptin analog metreleptin, and Aegerion Pharmaceuticals Inc.’s microsomal triglyceride transfer protein lomitapide. One month to the day after lomitapide’s goal date comes the action date for another candidate for the same rare disease, homozygous familial hypercholesterolemia, with Genzyme Corp./Ionis Pharmaceuticals Inc.’s Kynamro (mipomersen), an apolipoprotein B synthesis inhibitor.

The division is also reviewing Novo Nordisk AS’ ultra-long acting basal insulin analog insulin degludec as a single-agent product and in combination with a bolus boost of rapid-acting insulin aspart, with an Oct. 29 user fee goal. The division reviewed another antidiabetic NME early in the year, but issued a second “complete response” letter for Takeda Pharmaceuticals USA Inc.’s DPP-4 inhibitor alogliptin and alogliptin plus pioglitazone.

ODE I’s First Half Crop Of “Complete Response” Letters

ODE I’s cardiovascular, neurology and psychiatry divisions produced “complete response” letters in lieu of novel approvals during the first half, closing out the second quarter with the action letter for Bristol-Myers Squibb Co./Pfizer’s Eliquis Also see "Eliquis Superiority Claim May Be At Stake In “Complete Response” Letter" - Pink Sheet, 26 June, 2012..

Only days before the June 25 announcement of the Eliquis “complete response” letter, the cardio-renal division issued a “complete response” letter for Johnson & Johnson/Bayer’s Xarelto (rivaroxaban) for an acute coronary syndromes claim, citing missing data in the pivotal ATLAS trial Also see "Xarelto Label Expansion Plans Slowed By FDA “Complete Response” On ACS Claim" - Pink Sheet, 22 June, 2012.. Similar issues about missing data have been raised about the Eliquis ARISTOTLE study, giving rise to speculation that the division is cracking down on the issue as it reviews this generation of NDAs based on massive global trials.

Orphan drugs have also been susceptible to “complete response” actions.

Another pair of decisions on orphan NMEs highlighted some of the inescapable tensions between FDA’s mandate to ensure that approved drugs are adequately supported by clinical data and desire to show regulatory flexibility to speed drugs to patients with undertreated rare diseases.

Chelsea Therapeutics International Ltd.’s symptomatic neurogenic orthostatic hypotension drug Northera (droxidopa) received a “complete response” letter after a favorable advisory committee review – an unusual but not unprecedented occurrence – which has been followed by a publicized round of negotiations over the terms of the letter ([A#14120703006]).

Pfizer also received a “complete response” letter for the orphan neurology product Vyndaqel (tafamidis) after an advisory committee found substantial evidence for surrogate endpoints but not clinical endpoints on the NDA ([A#00120604001]). Pfizer based the NDA for accelerated approval on one trial, but the Division of Neurology Products requested a second efficacy study to establish substantial evidence of effectiveness.

The office also issued “complete response” letters to two high profile 505(b)(2) NDAs for novel inhalation formulations of existing drugs, MAP Pharmaceuticals Inc.’s inhaled dihydroergotamine for migraine and Alexza Pharmaceuticals Inc.’s inhaled antipsychotic Adasuve (loxapine) for rapid treatment of agitation in patients with schizophrenia or bipolar disorder. Alexza recently resubmitted the NDA, which now has a Dec. 21 user fee goal.

Neurology can expect to be in the spotlight during the second half of the year, which features action dates for three new multiple sclerosis therapies. Sanofi is bidding for a leadership position in the field with two drugs expected to have roles at different ends of the relapsing MS disease spectrum. Sanofi’s oral pyrimidine synthesis inhibitor for relapsing MS, Aubagio (teriflunomide), will likely see a decision first, but the main attraction is Sanofi/Bayer’s Lemtrada (alemtuzumab) which would have a December user fee goal if FDA grants the sponsors’ priority review request.

Aubagio has shown modest efficacy but has the convenience of oral administration and a benign side effect profile; Sanofi has said it would position Aubagio for less severe patients. Lemtrada (alemtuzumab) is an I.V. CD52-targeting monoclonal antibody (previously approved in leukemia as Campath) that has generated excitement with data showing a superior benefit on relapse and disability compared with Merck KGAA’s MS mainstay Rebif, but its I.V. administration and serious adverse event profile may make it more suitable for more severe patients Also see "Sanofi Takes Another Step Forward In MS, Files Lemtrada NDA" - Pink Sheet, 1 June, 2012..

The oral segment of the MS market could get a big jolt, not only from Aubagio but also from MS market stalwart Biogen Inc.’s BG-12 (dimethyl fumarate). Currently, oral disease-modifying options are limited to Novartis AG’s Gilenya (fingolimod). The BG-12 NDA should see action this coming winter ([A#06120601027]).

The neurology division is also reviewing an NDA for a drug with what would be only the second new mechanism of action in epilepsy in a decade, Eisai Inc.’s AMPA antagonist perampanel Also see "Epilepsy NMEs: A View Of The Playing Field" - Pink Sheet, 1 June, 2012.. Perampanel has an Oct. 22 user fee goal date.

Settling In To The “New Normal”: Midway Through 2012, Another Banner Year For Drug Approvals Is Within Reach

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