Following a year of high-profile drug failures, it's not surprising that the number of 2006 FDA drug approvals has so far received a muted response. Analysts insist that research and development (R&D) productivity is 'steady' despite no significant increase in output, but lack of success with new medicines for broad disease indications seems to be leading companies to focus on expanding indications for existing drugs or on niche markets.
Only 18 new molecular entities (NMEs) — the same as in 2005 — and just 4 biologic license applications (BLAs) were approved in 2006 (Fig. 1; Table 1). The number of priority reviews and orphan designations compared with 2005 slipped slightly to ten and five, respectively (FIG. 2). The FDA has yet to confirm final numbers, but according to John Jenkins, Director of the FDA's Office of New Drugs, the decrease in approvals is a direct result of a reduced number of new drug applications (NDAs).
Figure 1 | FDA drug approvals.
New molecular entities (NMEs) and biologic license applications approved by the US FDA by year. The number of NMEs approved in 2006 stayed the same as in 2005, with a slight increase in the number of approved biologics.
Figure 2 | Priority reviews and orphan drugs.
2006 saw the FDA conducting fewer priority reviews than in 2004 and 2005 and slightly fewer drugs were given orphan designation. BLAs, biologic license application; NMEs, new molecular entities.
...the decrease in approvals is a direct result of a reduced number of new drug applications.
So, it seems industry is still struggling. Approvals originating from the top ten pharma companies accounted for less than half of the approved NMEs in 2006, although it was a good year for Pfizer and Merck who took the lion's share, including several first-in-class therapeutics.
Perhaps Merck's biggest hope is its type 2 diabetes drug Januvia (sitagliptin phosphate), the first dipeptidyl peptidase 4 (DPP4) inhibitor to be approved and one of the few drugs approved this year that is widely expected to reach the US$1 billion in annual sales required to qualify for blockbuster status.
For Pfizer, highlights include the approval of Chantix (varenicline), a nicotinic acetylcholine receptor partial agonist approved for smoking cessation, and Exubera (human insulin), the first inhaled insulin product to be approved.
Both companies have made their mark on the field of oncology too, which, as in previous years, is the indication that has hogged the approvals limelight (FIG. 3).
Figure 3 | 2006 Drug approvals by therapeutic area.
Oncology and infectious diseases were the main therapeutic areas to benefit from new drugs in 2006. CNS, central nervous system.
"It's to be expected," says Leland Gershell, a health-care analyst at Cowen and Company; "safety issues are less of a concern with cancer drugs compared with other disease classes, and our growing understanding of signal transduction pathways and oncogenic factors supports the advancement of new therapies with novel mechanisms of action."
Indeed, 2006 saw Merck enter the oncology arena with the first vaccine developed to prevent cervical cancer (Gardasil), and the approval of its histone deacetylase inhibitor, Zolinza (vorinostat) for cutaneous T-cell lymphoma. Zolinza was the second of two epigenetics-based cancer therapies that were approved in 2006; MGI Pharma's Dacogen (decitabine), a demethylating agent, was also approved to treat myelodysplastic syndromes, which can lead to leukaemia.
The approval of Pfizer's Sutent (sunitinib malate) also heralds the continued roll-out of targeted treatments for cancer that work by interfering with a well-characterized molecular event known to cause a disease. Sutent is the first in a class of multitargeted kinase inhibitors developed specifically to inhibit multiple receptor tyrosine kinases, including the receptors for platelet-derived growth factor and vascular endothelial growth factor.
Similarly, Bristol–Myers Squibb's second-generation kinase inhibitor Sprycel (dasatinib) is another targeted therapy. It was approved last year after priority review to treat imatinib-resistant chronic myeloid leukaemia. Like imatinib (Gleevec; Novartis), it targets the BCR–ABL kinase that causes chronic myeloid leukaemia but retains activity against mutant kinases that confer resistance to imatinib. Its rapid launch shows how an understanding of the molecular basis of a disease can be used to accelerate the development of the next generation of drugs.
The field of anti-infectives also fared well in 2006, accounting for nearly one-third of NME approvals (FIG. 3). However, there was little real innovation in this sector. Pylera, developed by Axcan Scandipharma, was approved to treat the cause of duodenal ulcer disease by eradicating Helicobacter pylori, but is essentially a combination of existing drugs. The remainder of the approvals in this area were mostly improvements of existing classes of antifungals and antivirals (Table 1), and antibacterial drug discovery continues to languish.
So, in the face of difficulties with developing innovative and superior drugs for many high-prevalence indications, companies seem to be turning to diseases with a clearer opportunity for therapeutic success. The approval of Myozyme (alglucosidase alfa; Genzyme) and Elaprase (idursulfase; Shire Human Genetic Therapies) in 2006 continued a string of approvals in recent years of enzyme replacement therapies for rare metabolic disorders. These drugs, as well as Dacogen, and MediGene's Veregen (kunecatechins) for genital warts, suggest that some companies are moving away from developing innovative, but risky, therapies for large, competitive markets in favour of developing drugs for smaller populations. Could this be the end of the blockbuster, in favour of the nichebuster? Analysts certainly seem to think so.
"Using blockbusters as the only way to sustain growth is short-sighted," says Mark Belsey, health-care analyst from Datamonitor. He cites threats from generics companies and the increasing reluctance of regulators to reimburse 'me-too' drugs as the reason that the blockbuster business model will not be the dominant strategy for future growth. According to Belsey, to drive strong future sales, drug companies are increasingly turning towards developing drugs for niche indications.
Gershell agrees that we are likely to continue to see a rise in approvals for niche diseases, and highlights eculizumab (Soliris), a drug developed by Alexion for treating paroxysmal nocturnal haemoglobinuria, and BioMarin's sapropterin (Phenoptin) for treating phenylketonuria as the niche drugs to watch in 2007.
Companies will also be looking externally to alliances in 2007, says Andrew Jones, Senior Analyst at Ernst & Young. In fact, Ernst & Young estimates that the top 40 pharma and biotech companies spent more than US$16 billion on acquiring more than 20 biotech and specialty pharma companies in 2006, and it's a trend that's set to continue. But companies are also looking internally at their R&D functions and are adopting new operating structures that remove the barriers to productivity, says Jones. One example of this is the Centres for Excellence in Drug Discovery at GlaxoSmithKline that have been set up to boost R&D in specific therapeutic areas.
But infrastructure changes in a large organization require a certain amount of lag time before the benefits are seen. "Take Celltech's Cimzia, for example," says Datamonitor's health-care analyst Clare Churchill. A few years ago, she explains, approval was expected for treating Crohn's disease and rheumatoid arthritis before the end of 2006. But logistical issues involved in the transfer of rights between Celltech, Pfizer and finally to UCB (following its acquisition of Celltech) have added to the time Cimzia has spent in the pipeline.
One strategy that Belsey says might avoid this lag in productivity is the 'networked pharma' model. Here, large companies capture innovation from the biotech sector through a combination of small-scale acquisitions, R&D collaborations and extensive licensing deals, rather than having to rely on in-house R&D. "Big pharma is in a transition period, and NME approvals will pick up once the impacts of specific strategies to improve R&D productivity finally kick in." So will this translate to increased approvals?
"The number of approvals in 2007 should be at least as good, if not better, than 2006," says Gershell. Many eyes will be on Sanofi–Aventis's Acomplia (rimonabant) for obesity, one of several drugs that were expected to be approved in the United States last year but have been shunted into 2007. Although approved for weight management in Europe, Acomplia only received an 'approvable' letter from the FDA, and there has been speculation as to whether the drug might be associated with depression, and if so whether this might prevent its full approval or lead to labelling restrictions.
Other approvals that were expected in 2006, but could now occur in 2007, include two Novartis drugs, vildagliptin (Galvus), another DPP4 inhibitor for diabetes, and the first-in-class renin inhibitor aliskiren (Tekturna) for hypertension. Meanwhile, Eli Lilly will be hoping for approval of its diabetic retinopathy drug, ruboxistaurin mesylate (Arxxant).
It's likely to be another good year for cancer drugs too. Following on quickly from Sprycel, Novartis is hoping to launch its own second-generation BCR–ABL kinase inhibitor, nilotinib (Tasigna), in 2007. Approval of several first-in-class cancer drugs, including Wyeth's mTOR (mammalian target of rapamycin) inhibitor, temsirolimus (Torisel), and the first small-molecule ERB1/2 inhibitor, lapatinib (Tykerb), developed by GlaxoSmithKline, is also anticipated. Another exciting prospect is Dendreon's Provenge, the first therapeutic cancer vaccine, which has been shown to benefit patients with metastatic hormone-independent prostate cancer.
For other indications, however, safety continues to be a major hurdle. According to Gershell, one of the biggest disappointments of 2006 was the FDA decision on Indiplon, an insomnia drug made by Neurocrine. The FDA gave an approvable letter for the immediate-release form but a non-approvable letter for the modified-release (MR) form.
"These decisions were somewhat surprising in light of the fact that Indiplon had demonstrated efficacy and safety in the Phase III programme conducted in over 3,000 individuals," says Gershell. For Neurocrine the non-approval of the MR product is a substantial blow as this was the product with most market potential. Gershell also cites the non-approval of Cephalon's Sparlon (modafinil) for attention deficit hyperactivity disorder in August 2006 as another example of a risk-averse approach at the FDA. Sparlon is already approved for the treatment of wakefulness in adults and has been on the market in the United States for 7 years.
But with the FDA under more permanent leadership, and safety concerns over COX2 inhibitors beginning to fade, Gershell wonders whether the situation might improve. "The rather conservative atmosphere at the FDA has had an adverse impact on drug approvals," he says, "but perhaps we will begin to see more favourable agency decisions on a higher proportion of applications in 2007 and beyond."
