The pharmaceutical industry's strategy of looking to biologics as a source of innovation is clearly demonstrated in FDA's novel approvals in 2009.

Caught between looming patent cliffs and small molecule development disappointments, Big Pharma companies have increasingly diversified into large molecules (¹ Also see "Big Pharma's Leap into Biologics: Bridging both Scientific and Cultural Gaps" - In Vivo, 1 October, 2007.).

The share of biologics in the Center for Drug Evaluation and Research's annual approval tally reached 24 percent in 2009, by far the highest share of ² CDER approvals since the drug center took responsibility for therapeutic biologic applications in October 2003.

The most successful sponsors in 2009 were heavily weighted towards BLAs. Novartis and GlaxoSmithKline both posted four novel approvals in the year - and for both companies, three of the four approvals were for biologics. Johnson & Johnson followed with two approvals, both biologics, and biologics manufacturer CSL also posted two original BLA approvals, both for orphan blood products.

That many of the biologic approvals came from Big Pharma sponsors, instead of biotech firms, shows that the large molecule diversification approach is paying off (³ Also see "Big Pharma’s March Into Biotech Could Make Big Biologics A Big ’09 Theme" - Pink Sheet, 23 March, 2009.).

Without the Big Pharma biologics, the novel product count for 2009 would have taken a hit. But, as it stands, CDER's final tally of novel products (both new molecular entities and original therapeutic biologics) was 25 in 2009, an uptick from 24 in 2008 and a welcome further step out of the depths of 2005 to 2007 when CDER cleared, respectively, 20, 22 and 18 novel applications.

FDA's Center for Biologics Evaluation and Research retains responsibility for vaccines and blood products, which contributed nine original BLA approvals, up from seven in 2008 (see ⁴ 2009 CBER approval chart).

Biologics Made Up For Dip In NME Count

Therapeutic BLA approvals drove CDER's gain in total novel approvals over the previous year. In 2009, CDER approved 19 NMEs and six BLAs (see ⁵ 2009 CDER approval chart). In 2008, CDER approved 21 NMEs but only three BLAs (⁶ Also see "CDER Closes Out 2008 With 24 Novel Approvals, But Few Are First In Class" - Pink Sheet, 26 January, 2009.).

Compared with NMEs, the approved therapeutic biologics had a higher rate of priority reviews, a regulatory status that serves as a surrogate marker of innovation. One half of the approved BLAs held priority status, compared with 30 percent of NMEs.

Biotechnology continues to widen the horizons for rare diseases. All three priority BLA approvals - GlaxoSmithKline/Genmab's Arzerra , Novartis' Ilaris and Dyax' Kalbitor - were for orphan populations. One-third of CDER's priority review status approvals were for BLAs, but three of its six orphan drug approvals were for biologics.

While biotech has thrived in niche settings that can support high price tags, the future landscape is likely to see an increasing commoditization of biotech products. With a regulatory pathway for biosimilars on the legislative horizon, larger firms are gearing up for a new market. Teva predicts that follow-on biologics will emerge as a force in the U.S. around 2015 (⁷ Also see "Follow-on Biologic's Day Will Come - Post 2015, Teva Says" - Pink Sheet, 12 January, 2010.). CDER approved one biosimilar product in 2009, Novartis' Extavia , a branded version of Bayer-Schering's beta interferon Betaferon .

With all the ferment in biotech, the major biotechnology companies are oddly absent from the 2009 biologics approvals list. Amgen was close, but the "complete response" for Prolia (denosumab) put it off track.

NMEs Take Longer

The therapeutic biologics reviews were also substantially quicker than the NME reviews. Those six CDER-reviewed BLAs had an average time from submission to approval of 12.9 months - close to half the average time to approval for all NMEs.

The average time to approval for all 19 NMEs in 2009 is 27.3 months. That is a shockingly high figure thanks to the over-15-year review of the antiepileptic Sabril , which started out with Hoechst Marion Roussel's troubled NDA for adult use, and ended up with the specialty firm Ovation, which resuscitated the NDA and concurrently submitted another for infantile spasms, an area of high unmet need. The NDAs were simultaneously approved, and although FDA coded each as an NME, the final tally only counts the molecule once. The approval of a troubled application was facilitated by the use of a Risk Evaluation and Mitigation Strategy (see sidebar: "⁸ REMS Helped Push Final Tally Ahead").

Removing the outlier 183.6-month, four-cycle review of the Sabril adult complex partial seizure NDA (but retaining the first-cycle approval for infantile spasms in a more typical 20 months), the average time to approval is 18.7 months for NMEs approved in 2009. The 18.7 month figure is still on the high end for the contemporary FDA; FDA has only topped 18 months two other times this decade.

When the swifter-reviewed BLA cohort is added in, the average time to approval for all 25 CDER novel products drops to 17.3 months with the shorter Sabril review (or 23.8 months with the longer Sabril clock).

The extraordinarily long Sabril review to the contrary, 2009 was not actually notable for outsized approval times. While 2008 saw seven approvals requiring over 24 months from submission to licensure, 2009 had only four approvals with two-year-plus reviews.

Still, when a review went long for a 2009 NME, it went really long. As is typical, the longest reviews were predominantly for standard review products: Sabril for adults (183.6 months), Takeda's Uloric for gout (50 months), and Theravance's antibiotic Vibativ (32.8 months). The exception is Sanofi-Aventis' Multaq , a priority review antiarrythmic that clocked a 48.7-month time to approval.

CBER Approval Time Rises

CBER posted an increase in average time to approval from 15.3 months in 2008 to 16 months in 2009. Two reviews taking more than two years drove the added time: GSK's HPV vaccine Cervarix at 30.6 months and Octapharma's coagulation factor Wilate at 35.7 months.

CBER's approvals were almost evenly split between vaccines (4 approvals, all involving a Big Pharma) and plasma-derived proteins (five BLAs from small specialized firms for niche plasma-derived proteins). While four of the blood product biologics were conventionally derived from human plasma, one - GTC's Atryn - is a landmark due to its production in the milk of transgenic goats.

Ironically, the CBER action with the most 2009 impact - the licensure of four H1N1 influenza vaccines - does not count toward the original BLA approval tally. In order to speed approval, FDA cleared the H1N1 vaccines as supplements to the sponsors' already approved seasonal influenza vaccine BLAs (⁹ Also see "H1N1 Vaccines Get Green Light In U.S., But Is Anything Else Needed?" - Pink Sheet, 21 September, 2009.).

The highest-profile original BLA approved by CBER in 2009 was GlaxoSmithKline's Cervarix, the second entrant to the HPV vaccine market. While the lengthy review allowed Merck's Gardasil to solidify an early lead, it's a big market.

Novartis/Intercell had a first-of-its-kind vaccine approval with Ixiaro for Japanese encephalitis, but the geography of JE limits the market to travelers.

The other two 2009 vaccine approvals went to late entrants in well-established markets where new options were needed to alleviate periodic or ongoing manufacturing limitations and shortages. The egg-based production of current flu vaccines leaves the market prone to periodic shortages. Novartis' Agriflu may not blaze new trails (as it is still produced in eggs), but a greater diversity of suppliers helps ensure an adequate supply of a product important to public health.

GSK became the third U.S. marketer of Hib vaccines with approval of the booster vaccine Hiberix , but the approval eased a shortage caused by manufacturing difficulties with Merck and Sanofi-Aventis' vaccines. The additional GSK vaccine meant CDC could reinstate its regular booster recommendation in June 2009, after suspending the requirement due to the shortage.

Willie Sutton R&D: Go Where The Money Is

One interesting feature of the 2009 class of NMEs is that it includes several novel products in familiar classes - the fruits of an R&D strategy that favored taking many shots at the same goal over gambles on new targets. After a decade of mostly lean years in terms of approvals, companies are looking for money wherever they can find it - even if that means pursuing me-too drugs and fighting for crumbs in a crowded marketplace.

That means 2009 saw the approval of two more atypical antipsychotics (Vanda's Fanapt and Schering-Plough's Saphris ), another statin (Kowa's Livalo ) and another tumor necrosis factor antagonist (Johnson & Johnson's Simponi ).

The lack of novelty was a big theme for the 2008 class of NME and BLA approvals, where comparatively few drugs were first-in-class or represented a significant therapeutic advance (¹⁰ Also see "CDER Closes Out 2008 With 24 Novel Approvals, But Few Are First In Class" - Pink Sheet, 12 January, 2009.).

While this can also be said about the level of innovation in the 2009 cohort, it does include products that show that even drugs low on the innovation scale can respond to unmet market needs, like the vaccines Agriflu and Hiberix and also some of the follow-on products, which are tailored with dosing or safety advantages to help them carve out niches in the market. However, unlike recent years, 2009's class also includes several potential blockbuster products (¹¹ Also see "A Return Of The Blockbuster, But Can 2009 Launches Live Up To Potential?" - Pink Sheet, 18 January, 2010.).

Central nervous system therapeutics, one of the most active areas for NME approvals in 2009, are notably short of novel mechanisms of action. Fanapt and Saphris are late entrants into an already extensive armamentarium of atypical antipsychotics, and the epilepsy market that Sabril entered is similarly busy (for adults; infantile spasms, Sabril's other approval, are woefully untreated). The opportunity lies in the unsatisfactory nature of existing drugs. The numerous schizophrenia and epilepsy alternatives carry significant drawbacks and a substantial proportion of patients do not benefit. The new drugs are less copycats than part of a process of refinements to cover the range of patients more completely.

One CNS approval, Forest's Savella , is one of the first therapies for fibromyalgia (and the first developed purely for fibromyalgia). But while the indication is novel, Savella's mechanism of action (inhibition of serotonin and norepinephrine reuptake) comes from the familiar psychiatric drug focus on neurotransmitter levels.

In immunology, the stable of TNF inhibitor biologics grew to five with the approval of J&J's Simponi. J&J also received approval for Stelara , an interleukin-12 and -23 blocker MAb, a plaque psoriasis treatment with a separate but similar mechanism of action to TNF inhibitors - the Stelara REMS even mirrors risk management measures FDA applied to the anti-TNF class due to the risk of serious infection. However, Stelara stands out from the plaque pack with superior efficacy in psoriasis with less frequent dosing than TNF inhibitors (¹² Also see "Stelara Clears FDA; Different Class, But REMS Looks Similar To TNF Blockers" - Pink Sheet, 28 September, 2009.).

In cardiology, hopes are high for commercial success for the two priority NMEs. Eli Lilly/Daiichi Sankyo's Effient is the vanguard of a generation of revolutionary new anticoagulants and the new antiarrythmic Multaq is expected to attain blockbuster sales. Otsuka's Samsca is the second vasopressin antagonist approved, but the first oral formulation. Kowa will be pursuing a niche marketing strategy for Livalo, the seventh statin on the market, targeting patients who are hard to treat with other statins (¹³ Also see "Seventh Statin Appoved: Kowa Will Take A Niche Strategy For Livalo" - Pink Sheet, 10 August, 2009.).

Oncology Returns To The Lead Therapeutic Area

The category with the highest level of innovation in 2009, oncology, also returned to its accustomed place atop the approvals list in 2009 after anemic anti-cancer NME approval totals in the past few years (there were only two oncologics approved in 2008) (¹⁴ Also see "CDER Closes Out 2008 With 24 Novel Approvals, But Few Are First In Class" - Pink Sheet, 26 January, 2009.).

Three of the five original oncology approvals in 2009 received priority review, indicating a high level of innovation: Novartis' Afinitor , an mTOR inhibitor in oncology, for Sutent - and Nexavar -failure kidney cancer; Allos' Folotyn , an antifolate for peripheral T-cell lymphoma; and GSK/Genmab's Arzerra , an anti-CD20 MAb for chronic lymphocytic leukemia.

In contrast, only one of the five NDA approvals for the four CNS NMEs received a priority review. Of the two NDAs for Sabril, infantile spasm was priority while adult AED application was a standard review.

Less "Padding" In The NME Count

Whereas previous years have their NME tallies somewhat inflated by products that are technically NMEs but do not really count as innovative additions, 2009 has only a few borderline products in its innovation count (¹⁵ Pharmaceutical Approvals Monthly, January 2008).

There was an over-the-counter NME approved; Sciele's Ulesfia is actually a unique treatment for lice, but its active ingredient is a commonly used excipient. The active ingredient in Novartis' Afinitor, everolimus, was already approved as part of Abbott's drug-eluting stent Xience , but qualified as an NME in that it was the first review by the drug office.

Between the big market products approved in 2009, and the relative lack of questionably innovative products on the roster, 2009's novel product approvals show signs that the biopharmaceutical industry, and FDA, are in a healthier state than just a few years ago.

- Bridget Silverman ( ¹⁶ b.silverman@elsevier.com )

Biologics Reached Record Share Of Novel Approvals In 2009

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