2010 FDA drug approvalsThe US Food and Drug Administration approved slightly fewer new drugs than in recent years, and the industry’s focus on specialty-care products continued to shine through.

Asher Mullard

The US Food and Drug Administration’s (FDA’s) Center for Drug Evaluation and Research (CDER) approved 15 new molecular entities and 6 new biologics in 2010. The total of 21 new products falls below the 25 approved in 2009 and the 24 in 2008.

“I can’t say that this number of approvals is terribly surprising one way or the other — it’s pretty much what we expected it to be,” says Christopher Milne, Associate Director of The Tufts Center for the Study of Drug Development in Boston, USA. “It’s not what it used to be, but it’s never going to go back to the days when 35 was the norm,” (see FIG. 1).

While it may be difficult to draw conclusions about research and development (R&D) productivity from a

1-year snapshot of FDA approvals, Cowen and Cowen analyst Eric Schmidt highlights one more heartening trend: “The FDA generally got through its workload — something that was in question if you look back 2–3 years ago.” In 2007 and 2008, he argues, there was a stagnant environment at the FDA, underpinned by understaffing, in which the agency did not do anything. “At a minimum, you’d say the FDA is more functional than it used to be,” he says. “But they not only got through their workload, I think in general the FDA made good decisions.”

Specializing in specialty care“One of the biggest trends in approvals in 2010 was the continued shift from primary care to specialty care,” says Andrew Jones,

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an analyst at Ernst & Young. In the past, he explains, pharmaceutical companies sought blockbusters among primary-care drugs for mass-market indications — such as Pfizer’s cholesterol-lowering atorvastatin or AstraZeneca’s proton pump inhibitor esomeprazole.

Increasingly, however, firms are moving towards specialty-care and orphan-disease markets. The roster of newcomers in 2010, for instance, includes five orphan drug products (Table 1; 2009 saw six new orphan products) and several ‘specialty care’ products (such as Shire’s velaglucerase alfa for Gaucher’s disease, Theratechnologies’ tesamorelin for HIV lipodystrophy and Merz’s IncobotulinumtoxinA for cervical dystonia and blepharospasm).

“What we’re seeing is a result of prior investment into areas where companies believe they can deliver meaningful improvements to patient outcomes and provide a good evidence base to satisfy payers,” says Jones. “This trend is really about payer dissatisfaction with high prices for what might have in the past been incremental innovation and ‘me too’ products, as well as saturation in some disease areas by innovative products and generic versions that already do the job pretty well.”

Milne agrees that the need to serve payers is increasingly shaping drug discovery and development programmes, but highlights “disease management” approvals of 2010 as the outcome. Chief among these approvals he lists Novartis’s fingolimod, the first oral multiple sclerosis drug, and Novo Nordisk’s liraglutide for type 2 diabetes. As payers question what they are getting for

their money, he says, drug firms are increasingly taking reimbursement issues into account and seeing scope to deliver improvements to expensive treatment paradigms for chronic diseases.

Apart from oncology indications, for which four new products were approved in 2010, the approvals were spread thinly across the therapeutic areas. “Given the investment that is going into oncology, I don’t think it’s surprising that there were several oncology product approvals last year,” says Jones. “I think we’re going to continue to see oncology being a dominant area for approvals.” But given the shift to specialty markets, he adds, we may also keep seeing a similarly fragmented approval pattern across the rest of the therapeutic areas in coming years.

From a biotechnology sector perspective, Schmidt notes that 2010 was not a bad year: “Biotech companies are certainly fairly represented on the approval list.” Last year, by contrast, he noted that the sector only contributed six products.

Biologics, more specifically, accounted for over 25% of the CDER approvals, a proportion

that seems likely to increase. “Companies are still pretty gung-ho for biologics as far as I can tell,” says Milne. Jones adds that last year’s US legislation mandating 12 years of data exclusivity for novel biologics and a new biosimilars pathway will prevent stagnation of the field. “Putting in place the approval pathway for biosimilars really creates an incentive for innovator companies to re-invest. A period of exclusivity followed by an open market drives the market.”

“You might expect the number of biologic approvals to be higher already given the investment that’s been going into this area,” he notes, “but this is where I’d remind people about the Center for Biologics Evaluation and Research [CBER].” CBER approvals are often overlooked in estimates of R&D productivity and FDA efficiency, but key biologics — including sipuleucel-T for prostate cancer — are approved through this alternative channel (Table 2).

Big winnersA handful of the new approvals jumped out at analysts as being particularly mechanistically interesting, commercially exciting or otherwise noteworthy.

“The one that ticks all the boxes is denosumab,” says Jones. Amgen’s denosumab, a first-in-class monoclonal antibody that is specific for receptor activator of nuclear factor-κB ligand (RANKL), was first approved in June 2010 in the United States for the treatment of postmenopausal osteoporosis (Nature Rev. Drug Discov. 9, 591–592; 2010). Later in the year, it also received approval for the prevention of skeletal-related events in patients with bone metastases from solid tumours. The product originated from a labour-intensive genomics project that Amgen initiated in the 1990s, in which scientists set out to mutate a slew of uncharacterized genes in mice and then look for abnormal physiology. Luckily, in one of their early experiments they mutated a gene that modulated bone density, leading to the identification of RANKL as a target.

Among the benefits of denosumab, says Jones, is that it is thought to act earlier to prevent bone destruction than the current standards of care for osteoporosis, the bisphosphonates. “But perhaps the most exciting thing about denosumab is the potential for more approvals to come,” he adds. These include not only prevention of osteoporosis, but also prevention of bone metastasis in patients with cancer. Many analysts anticipate sales of over US$1 billion for denosumab.

Figure 1 | FDA drug approvals since 1996. New molecular entities and biologics license applications approved by the US Food and Drug Administration’s (FDA’s) Center for Drug Evaluation and Research, by year.

One of the biggest trends in approvals in 2010 was the continued shift from primary care to specialty care.

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Another potential blockbuster that got the green light in 2010 was Dendreon’s therapeutic prostate cancer vaccine sipuleucel-T (Nature Rev. Drug Discov. 9, 513–514; 2010). A first of its kind, the vaccine is made by extracting a patient’s white blood cells, priming them with the prostate cancer antigen prostatic acid phosphatase (PAP) and then re-introducing the cells into the patient.

Because of the priming process, the autologous antigen-presenting cells are able to activate a T cell immune response to PAP-expressing tissue.

Dendreon had previously submitted the drug to the FDA for approval in 2007, but regulators did not approve it at the time and requested further data to demonstrate efficacy. Based on new data showing the

vaccine increases survival by ~4 months compared with placebo, the company resubmitted sipuleucel-T in 2009. “From a technology point of view, there is a lot of talk about how industry does not innovate. This year we’ve got a completely brand new type of product, which is very exciting,” says Jones. The personalized vaccine still has to prove itself in the market, however. “Certainly

Table 1 | FDA Center for Drug Evaluation and Research (CDER) approvals in 2010

generic name (trade name)

Lead company indication Properties Date (review type)

New molecular entities

Dalfampridine (Ampyra) Acorda Therapeutics Improving walking in patients with multiple sclerosis

Potassium channel blocker 22 Jan (P,O)

Liraglutide (Victoza) Novo Nordisk Type 2 diabetes Glucagon-like peptide 1 receptor agonist 25 Jan (P)

Velaglucerase alfa (Vpriv) Shire Gaucher’s disease Recombinant human β-glucocerebrosidase

26 Feb (P)

Carglumic acid (Carbaglu) Orphan Europe Acute hyperammonaemia Carbamoyl phosphate synthetase 1 activator

18 Mar (P,O)

Polidocanol (Asclera) Chemisch FBRK KRSSLR

Uncomplicated spider veins and uncomplicated reticular veins

Sclerosing agent 30 Mar (S)

Oestradiol valerate and dienogest (Natazia)

Bayer Contraception Oestrogen and progestin combination oral contraceptive

6 May (S)

Cabazitaxel (Jevtana) Sanofi–Aventis Prostate cancer Microtubule inhibitor 17 Jun (P)

Alcaftadine (Lastacaft) Vistakon Pharmaceuticals

Allergic conjunctivitis H1 histamine receptor antagonist 28 July (S)

Ulipristal (Ella) HRA Pharma Contraception Progesterone receptor modulator 13 Aug (S)

Fingolimod (Gilenya) Novartis Multiple sclerosis Sphingosine 1-phosphate receptor modulator

21 Sept (P)

Dabigatran (Pradaxa) Boehringer Ingelheim

Stroke prevention in atrial fibrillation

Direct thrombin inhibitor 10 Oct (P)

Lurasidone (Latuda) Sunovion Schizophrenia Atypical antipsychotic agent 28 Oct (S)

Ceftaroline fosamil (Teflaro)

Cerexa Skin and skin-structure infections; community acquired pneumonia

Broad-spectrum cephalosporin antibiotic 29 Oct (S)

Tesamorelin (Egrifta) Theratechnologies HIV lipodystrophy Growth hormone-releasing factor analogue

10 Nov (S)

Eribulin (Halaven) Eisai Breast cancer Microtubule inhibitor 15 Nov (P)

Biologics license applications

Tocilizumab (Actemra) Genentech Rheumatoid arthritis Humanized mAb specific for the interleukin-6 receptor

8 Jan

Collagenase clostridium histolyticum (Xiaflex)

Auxilium Dupuytren’s contracture Purified collagenase clostridium histolyticum

2 Feb (O)

Alglucosidase alfa* (Lumizyme)

Genzyme Pompe’s disease Recombinant human acid α-glucosidase 24 May (O)

Denosumab (Prolia) Amgen Postmenopausal osteoporosis‡ Fully human mAb specific for RANKL 1 Jun

IncobotulinumtoxinA (Xeomin)

Merz Cervical dystonia and blepharospasm

Acetylcholine release inhibitor and neuromuscular blocking agent

30 Jul

Pegloticase (Krystexxa) Savient Gout PEGylated uric acid specific enzyme 14 Sep (O)

FDA, US Food and Drug Administration; mAb, monoclonal antibody; O, FDA orphan designation; P, FDA priority review; PEG, polyethylene glycol; RANKL, receptor activator of nuclear factor-κB ligand; S, FDA standard review. *The original recombinant alglucosidase alfa product Myozyme, developed by Genzyme, was approved by the FDA for Pompe’s disease in 2006. Lumizyme is included in this list because the FDA required a new biologics license application to be submitted in view of the potential differences to Myozyme resulting from the scaling up of production from 160 litres for Myozyme to 4,000 litres for Lumizyme. ‡Denosumab was subsequently approved for the prevention of skeletal-related events in patients with bone metastases on 18 November, for which it is marketed as Xgeva.

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reflect product development phasing, notes Jones. But, he adds, “Novartis have been progressive in terms of engaging with different types of regulatory bodies,” actively involving them in their R&D decision-making processes. Such relationships, combined with the entirety of the company’s R&D process, could underlie their success.

Looking forwardSeveral decisions that had been expected in 2010 were pushed back to 2011. “The one we’re waiting for is belimumab from Human Genome Sciences [HGS]/GlaxoSmithKline [GSK],” says Jones. HGS and GSK submitted belimumab, a monoclonal antibody that targets B-lymphocyte stimulator for the treatment of systemic lupus erythematosus, to the FDA in June and were looking forward to a 9 December 2010 Prescription Drug User Fee Act (PDUFA) date. The agency pushed back its decision timeline, however, and a ruling is now expected by 10 March 2011. No new products have been approved for lupus in nearly half a century. “From a commercial perspective, an approval would be transformational for a company like HGS,” adds Jones.

Other keenly awaited products that could see approval next year include two hepatitis C virus candidates: Merck & Co’s boceprevir and Vertex’s telaprevir (Nature Rev. Drug Discov. 9, 501–503; 2010). In clinical trials, both protease inhibitors had better cure rates and shorter treatment durations than the current standard of care, which is ribavarin plus peglyated interferon. “The launch of telaprevir is the most anticipated launch in the history of biotechnology,” says Schmidt. Protalix/Pfizer’s taliglucerase alfa, an enzyme replacement therapy for Gaucher’s disease, meanwhile could become the first human recombinant protein to be produced in plant cells to be approved (see story on page 81).

“Overall,” says Schmidt, “I think the FDA’s going to continue to function well, review the applications that it receives in the coming year and make the right decisions for the most part.”

people are very optimistic for sales of sipuleucel-T — most of us think that it’s going to be a $1–2 billion drug in the United States. But so far, the launch has been a little disappointing,” says Schmidt.

The FDA’s approval of Boehringer Ingelheim’s dabigatran for stroke prevention in atrial fibrillation (SPAF) marked a much needed move towards a replacement for warfarin. Although warfarin has been the gold-standard oral anticoagulant for various indications for decades, it interacts with many drugs and foods and requires careful monitoring of dosage levels. Consequently, companies have been searching for

alternatives. Dabigitran, an oral direct thrombin inhibitor, was the first such anticoagulant to be approved for SPAF in the United States, although other contenders are also vying for this appealing market opportunity (Nature Rev. Drug Discov. 9, 903–906; 2010).

Other notable approvals in 2010 include Pfizer’s Streptococcus pneumoniae vaccine Prevnar 13, a more broadly protective version of Prevnar. “Prevnar’s been a blockbuster for ~10 years now, and every time Pfizer updates it, it does well,” says Jones. And Sanofi–Aventis’s cabazitaxel, for prostate cancer, was among the fastest FDA approvals ever — the rolling submission was completed on 31 May, and the agency approved the drug just over 2 weeks later on 17 June (Nature Rev. Drug Discov. 9, 677–678; 2010).

Out of all the companies who picked up an approval last year, only Novartis got the nod for more than one product — receiving approval for both fingolimod and Menveo (Menveo was approved by the CBER). Novartis also had a stand-out year in 2009, with three new approvals: an artemether–lumefantrine combination therapy, everolimus and canakinumab. Two years worth of data is insufficient to draw firm conclusions, and Novartis’s success with the FDA could simply

Table 2 | Selected FDA Center for Biologics Evaluation and Research (CBER) approvals in 2010

generic name (trade name)

Lead company

indication Properties Date (review type)

Meningococcal groups A, C, Y and W-135 conjugate vaccine (Menveo)

Novartis Meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135

Oligosaccharides from four N. meningitidis serogroups conjugated to Corynebacterium diphtheriae CRM

197 protein

19 Feb

Pneumococcal 13-valent conjugate vaccine (Prevnar 13)

Pfizer Disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F

Capsular antigens of 13 S. pneumoniae serotypes, linked to C. diphtheriae CRM

197 protein

24 Feb

Immune globulin subcutaneous, 20% liquid (Hizentra)

CSL Primary immunodeficiencies

Polyvalent human immunoglobulin G

4 Mar

Sipuleucel-T (Provenge)

Dendreon Prostate cancer Autologous dendritic cells treated with prostatic acid phosphatase antigen

29 Apr

Alpha1-proteinase

inhibitor (Glassia)Baxter Emphysema Alpha

1-proteinase

inhibitor1 July

O, US Food and Drug Administration (FDA) orphan designation.

From a technology point of view, there is a lot of talk about how industry does not innovate. This year we’ve got a completely brand new type of product…

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