FDA approvals 2012


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FDA approvals 2012

  1. 1. NEWS & ANALYSIS 2012 FDA drug approvals PhotoDisc/Getty Images FDA drug approval bonanza sees cancer and orphan drugs on top again.M&A firepower shifts p91 Asher Mullard 43 NME and new BLA applications clinical-stage pipeline (Nature Rev. in 2012, roughly in line with the 41 Drug Discov. 11, 17–18; 2012) — the The US Food and Drug that it filed in 2011. Jenkins cautions particularly skewed 2012 approval Administration (FDA)’s Center against using submission volume numbers elicited concern from some Digital Vision/Punchstock for Drug Evaluation and Research to predict 2013 approvals, given the industry watchers about the potential (CDER) approved 39 new drugs last variables inherent in drug review and development of an oncology bubble. year, marking a 15‑year high. This is the lag time between filing and action “When you have a lot of cancer the most green lights since 1997, dates, but is nevertheless encouraged drugs, you have fewer other drugs,” and around 33% higher than the that submissions are at “the highest says Chris Milne, Associate Director average over the past two decades numbers we’ve seen in the past half a of the Tufts Center for the Study of (30 approvals per year; see FIG. 1). decade or so”. Drug Development, in Boston,Drugging the epi­genomep92 John Jenkins, Director of the The ongoing debate around the Massachusetts, USA. McKinsey Office of New Drugs at the CDER, United States’ deficit and government analysts reported last year that, on adds that other metrics suggest the spending might, however, throw a average, 2.6 unique compounds are approval process is in comparatively spanner in the works. FDA funding being developed for each oncology rude health. For one, the first-cycle could take a hit this year, potentially target, compared with 1.7 compounds approval rate (that is, drugs that were impacting drug reviews. “If we were per target across the entire drug approved after only their first review) to see reductions in our resources, I pipeline (Nature Rev. Drug Discov. was around 80% for products acted think we would continue to prioritize 11, 435–436; 2012). But, adds Milne, on in 2012. “That’s higher than ever on things like breakthrough therapies nearly all of the newly approved NPG before.” This rate essentially matches and priority drugs and orphan drugs,” cancer drugs received fast-track orSingle European patent the historic overall approval rate, says Jenkins. “But we’re hoping that priority review, designations that areedges closer p94 which includes drugs that go through this won’t come to pass.” reserved for therapies that offer major multiple rounds of review. advances in treatment. New cancer The factors that underlie the high Therapeutic area breakdown drugs, therefore, are still hitting unmet first-cycle approval rate, speculates As in recent years, cancer drugs are need. “I don’t think we are seeing Jenkins, could include increased heavily represented on the CDER saturation yet,” says Milne. interactions between regulators and approvals list (TABLE 1; see go.nature. “One of the things that we have companies during the development of com/xcSxQL for a full list of 2012 been seeing [in oncology] is that the drugs, better quality applications, fewer approvals by the Center for Biologics effect size or the benefit to patients Miranda Parry submissions of ‘me-too’ candidates Evaluation and Research (CBER), of these drugs is becoming larger,” (20 of the drugs approved by the FDA which are not included in the count). adds Jenkins. Ariad’s multikinase last year were first-in-class agents) and The agency approved 13 oncology inhibitor ponatinib, one of three newMike Yeadon discusses clearer benefit–risk balances. “We saw drugs in 2012 (33% of the list), drugs approved for chronic myeloidstarting a company afterpharma downsizing p96 a high rate of first-cycle approvals in up from 8 in 2011 (22%). Other leukaemia last year, induced a major 2011 as well,” adds Jenkins. “It is an therapeutic areas with multiple new cytogenetic response in 54% of all interesting phenomenon: we haven’t entries included gastroenterology, patients and in 70% of patients with changed the standards of approval, so respiratory and antimicrobials, but the T315I mutation, which confers I would have to think the process is with nowhere near the same success resistance to earlier-generation PhotoDisc/Getty Images efficient and running well.” as oncology (FIG. 2). drugs, for example. The increasingly If the first-cycle approval rate stays Although the focus on oncology dramatic response rates, which make high, preliminary data on the new is well-entrenched within industry for easier benefit–risk assessments, molecular entity (NME) and biologics — and cancer drugs are likely to in part reflect the targeted nature of license application (BLA) submissions continue to take the lion’s share of the therapies and developers’ abilities toMarket for smoking in 2012 suggest that 2013 could be yet approvals for years to come, given select the patients who are most likelycessation therapies p97 another good year. The FDA received their heavy representation in the to respond, he adds.NATURE REVIEWS | DRUG DISCOVERY VOLUME 12 | FEBRUARY 2013 | 87 © 2013 Macmillan Publishers Limited. All rights reserved
  2. 2. N E W S & A N A LY S I S 60 53 NMEs BLAs 50Number of drugs approved 40 39 35 33 30 31 30 29 27 25 24 24 21 21 21 19 20 17 18 18 16 15 10 6 7 7 6 7 6 6 6 5 5 3 3 3 2 4 3 2 2 2 0 0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Figure 1 | Annual FDA approvals since 1993. New molecular entities a Prescription Drug User Fee Act (PDUFA) agreement. Authority over (NMEs) and biologics license applications (BLAs) approved by the Center many, but not all, biologics was transferred NatureCDER in|2002.Discovery to the Reviews Drug for Drug Evaluation and Research (CDER) since 1993, the first full year Products under the authority of the Center for Biologics Evaluation during which the US Food and Drug Administration (FDA) worked under and Research (CBER) are not included in this drug count. Novel mechanisms of action among last pharmaceutical players, up from four nothing particularly novel or remarkable about year’s cancer drugs included Genentech/Curis’s emerging sponsors in 2011. The importance this drug,” notes Schmidt, “but HIV is just vismodegib for the treatment of metastatic of small companies for drug development is such a massive market place that I think they or locally advanced basal cell carcinoma. not new, adds Jenkins, but “the phenomenon are going to make quite a bit of progress with Vismodegib is the first approved Hedgehog of those companies carrying the application all Stribild from a commercial standpoint.” pathway inhibitor (Nature Rev. Drug Discov. the way through the application process is”. Rounding out the potential big hitters 11, 257–258; 2012). Jenkins credits in part the FDA’s efforts are Pfizer’s Janus kinase (JAK) inhibitor Another perennial theme on the approval to meet with drug sponsors throughout tofacitinib, the first oral disease-modifying list is orphan drugs for the treatment of rare drug development to ensure applications are drug for rheumatoid arthritis to be approved diseases. The agency approved 13 orphan drugs in order, whereas Eric Schmidt, an analyst for more than a decade, and Pfizer/ in 2012 (33% of the list), and such products at Cowen and Cowen, points to biotech’s Bristol-Myers Squibb’s factor Xa inhibitor have now accounted for 33–37% of approvals increasingly efficient use of research and apixaban, the latest anticoagulant competing in each of the past 6 years. As with last year, a development (R&D) dollars and its focus to become a replacement for warfarin considerable proportion of the orphan drugs on orphan indications. in indications such as stroke prevention in were also cancer drugs (6 out of 13, compared patients with atrial fibrillation. with 7 out of 11 in 2011), reflecting better The big five But consensus estimates have “huge error stratification of cancer patient populations. Despite much ado about the death of the bars”, cautions Schmidt. “Expectations are too “I would predict that we’re going to see a blockbuster model, consensus estimates by optimistic for most drugs. My guess is that growing percentage of approvals in orphan analysts forecast multibillion-dollar global the drugs from this list that succeed will blow indications,” says Jenkins. annual sales for five of the new drugs within through US$2 billion, and the ones that fall 5 years (FIG. 3). short will fall way short.” Emerging sponsors on the rise Two of these, again, are cancer drugs. One big winner in 2012 was Pfizer, which The top earner could be Astellas/Medivation’s Other highlights received green lights for five drugs (four enzalutamide, an androgen receptor agonist With 33 NMEs and 6 biologics making of which it owns fully, and one of which approved for prostate cancer. Enzalutamide up the CDER’s class of 2012, other it is partnered on). But this success by the is the fourth metastatic prostate cancer drug scientifically exciting and clinically biggest of big pharma belies the increasing to enter the market in the past 3 years, but “is important candidates abound. importance of emerging sponsors — viewed as possibly the best ever”, notes Schmidt. From a scientific perspective, perhaps companies that are receiving their first Genentech’s HER2‑targeting pertuzumab, one the most exciting newcomer of 2012 was approval. Emerging sponsors were granted of only two monoclonal antibodies (mAbs) to Vertex’s ivacaftor, the first disease-modifying 16 drug approvals in 2012 (41% of the make the cut in 2012, could potentially take drug to be approved for a subset of patients cohort), up from 11 (37%) in 2011. a lucrative slice of the breast cancer market. with cystic fibrosis. After its approval, the “Our general sense is that we are seeing Gilead extends its HIV dominance cystic fibrosis transmembrane conductance more drug development being done by small with Stribild, a combination of a new regulator (CFTR) stabilizer received the first emerging companies,” says Jenkins. cytochrome P450 inhibitor called cobicistat, ‘breakthrough drug’ designations for further Further analysis shows that six of a new HIV integrase inhibitor called development into additional cystic fibrosis 2012’s emerging sponsors received their elvitegravir and two established anti-HIV patient populations. The breakthrough drug approvals without support from established drugs, emtricitabine and tenofovir. “There’s programme, introduced in the FDA Safety 88 | FEBRUARY 2013 | VOLUME 12 www.nature.com/reviews/drugdisc © 2013 Macmillan Publishers Limited. All rights reserved
  3. 3. N E W S & A N A LY S I S Table 1 | New drugs approved by the Center for Drug Evaluation and Research in 2012Active ingredients Sponsor Indications Properties Review type*Glucarpidase (Voraxaze)‡ BTG Toxic plasma methotrexate concentrations Recombinant bacterial enzyme that P, O International in patients with delayed methotrexate hydrolyses methotrexate clearanceIngenol mebutate (Picato) Leo Pharma Actinic keratosis MOA unknown SAxitinib (Inlyta) Pfizer Advanced renal cell carcinoma VEGFR1, -2 and -3 inhibitor SVismodegib (Erivedge) Genentech Metastatic or locally advanced basal cell Smoothened (Hedgehog pathway) P carcinoma inhibitorIvacaftor (Kalydeco) Vertex Cystic fibrosis in patients with the G551D CFTR potentiator P, O mutation in the CFTR geneTafluprost (Zioptan) Merck Sharp Elevated intraocular pressure in patients Selective prostaglandin F prostanoid S Dohme with open-angle glaucoma or ocular receptor agonist hypertensionLucinactant (Surfaxin) Discovery Prevention of respiratory distress syndrome Pulmonary surfactant S LaboratoriesPeginesatide acetate Affymax Anaemia due to chronic kidney disease Synthetic, pegylated erythropoiesis- S(Omontys) stimulating agentFlorbetapir F-18 (Amyvid) Avid Radio­ Diagnostic agent to estimate amyloid-β Radioactive diagnostic agent S pharmaceuticals plaques in patients with suspected Alzheimer’s diseaseAvanafil (Stendra) Vivus Erectile dysfunction PDE5 inhibitor STaliglucerase alfa (Elelyso) Pfizer Gaucher’s disease Recombinant β-glucocerebrosidase; S, O produced in carrot cellsPertuzumab (Perjeta)‡ Genentech HER2‑positive metastatic breast cancer HER2‑targeting mAb PLorcaserin (Belviq) Eisai Obesity 5‑HT2C receptor agonist SMirabegron (Myrbetriq) Astellas Overactive bladder β3-adrenergic receptor agonist SCitric acid; magnesium Ferring Cleansing of the colon before colonoscopy Osmotic and stimulant laxatives Soxide; sodium picosulfate Pharmaceuticals(Prepopik)Carfilzomib (Kyprolis) Onyx Multiple myeloma 20S proteasome inhibitor S, OAclidinium bromide Forest Bronchospasms associated with COPD Long-acting antimuscarinic agent S(Tudorza Pressair) LaboratoriesZiv-aflibercept (Zaltrap)‡ Sanofi Metastatic colorectal cancer Recombinant fusion protein that binds P VEGFA, VEGFB and PIGFCobicistat; elvitegravir; Gilead Sciences HIV‑1 infection Cytochrome P450 inhibitor; HIV‑1 Semtricitabine; tenofovir integrase inhibitor; NRTI; acyclicdisoproxil fumarate nucleoside phosphonate analogue(Stribild)Tbo-Filgrastim (Neutroval)‡ Sicor Biotech Severe neutropaenia in patients with Methionyl human G-CSF S non-myeloid malignanciesLinaclotide (Linzess) Forest Irritable bowel syndrome with constipation; Guanylyl cyclase C agonist S Laboratories chronic idiopathic constipationEnzalutamide (Xtandi) Astellas Metastatic castration-resistant prostate Androgen receptor inhibitor P cancerBosutinib monohydrate Pfizer Chronic, accelerated or blast phase Ph+ BCR–ABL inhibitor; SRC family kinase S, O(Bosulif) chronic myelogenous leukaemia inhibitorTeriflunomide (Aubagio) Sanofi Relapsing forms of multiple sclerosis Dihydroorotate dehydrogenase inhibitor SCholine C-11 MCPRF Diagnostic agent for imaging of patients Radiolabelled choline analogue P with suspected prostate cancer recurrenceRegorafenib (Stivarga) Bayer Metastatic colorectal cancer Multikinase inhibitor with targets P including RET, VEGFR1, -2, -3 and KITOcriplasmin (Jetrea)‡ Thrombogenics Symptomatic vitreomacular adhesion Recombinant truncated form of human P plasminPerampanel (Fycompa) Eisai Partial-onset seizures in patients with Non-competitive ionotropic AMPA S epilepsy glutamate receptor antagonistNATURE REVIEWS | DRUG DISCOVERY VOLUME 12 | FEBRUARY 2013 | 89 © 2013 Macmillan Publishers Limited. All rights reserved
  4. 4. N E W S & A N A LY S I S Table 1 (cont.) | New drugs approved by the Center for Drug Evaluation and Research in 2012 Active ingredients Sponsor Indications Properties Review type* Omacetaxine Ivax Chronic or accelerated-phase chronic MOA unknown S, O mepesuccinate (Synribo) myeloid leukaemia Tofacitinib (Xeljanz) Pfizer Severely active rheumatoid arthritis JAK inhibitor S Cabozantinib (Cometriq) Exelixis Progressive, metastatic medullary thyroid Multikinase inhibitor with targets including P, O cancer RET, MET, VEGFR1, -2, -3, KIT and FLT3 Ponatinib (Iclusig) Ariad Chronic, accelerated or blast-phase chronic Multikinase inhibitor with targets P, O myeloid leukaemia including BCR–ABL, KIT, RET and FLT3 Pasireotide diaspartate Novartis Cushing’s disease Somatostatin analogue P, O (Signifor) Raxibacumab‡ HGS Anthrax Human mAb against Bacillus anthracis toxin P, O Teduglutide (Gattex) NPS Short bowel syndrome GLP2 analogue S, O Lomitapide (Juxtapid) Aegerion Homozygous familial hypercholesterol­ Microsomal triglyceride transfer protein S, O aemia inhibitor Apixaban (Eliquis) Bristol-Myers Stroke and systemic embolism in patients Factor Xa inhibitor P Squibb with non-valvular atrial fibrillation Bedaquiline (Sirturo) Janssen Pulmonary multidrug-resistant tuberculosis Diarylquinoline antimycobacterial P, O Crofelemer (Fulyzaq) Salix HIV-associated diarrhoea CFTR and CaCC channel inhibitors P Amarin’s triglyceride-lowering icosapent is not included on the list because the FDA has not as yet designated it as an NME, and Vivus’s obesity drug Qysmia (phentermine and topiramate) is not included because it is classed only as a new combination.*Review classifications are standard (S), priority (P) and orphan (O). ‡ Biologics license application. 5‑HT, 5‑hydroxytryptamine (serotonin); AMPA, α-amino‑3‑hydroxy-5‑methyl-4‑isoxazole propionic acid; CaCC, calcium-activated chloride channel; CFTR, cystic fibrosis transmembrane conductance regulator; COPD, chronic obstructive pulmonary disease; FLT3, FMS-related tyrosine kinase 3; G-CSF, granulocyte colony-stimulating factor; GLP2, glucagon-like peptide 2; HGS, Human Genome Sciences; JAK, Janus kinase; mAb, monoclonal antibody; MCPRF, Mayo Clinic PET Radiochemistry Facility; MOA, mechanism of action; PDE5, phosphodiesterase 5; PIGF, placenta growth factor; NRTI, nucleoside reverse transcriptase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.and Innovation Act in the summer of 2012, ‘pharmers’ who hope that new production field. “These approvals may signal a changeis intended to expedite the development and systems might be safer and more efficient in the way the FDA is going to approach thereview of candidates with substantial benefit (Nature Rev. Drug Discov. 10, 81–82; 2011). review of obesity products,” says Milne.over existing therapies (see page 91). GlaxoSmithKline’s subsidiary Human Another space to watch is multiple Pfizer’s enzyme replacement therapy Genome Sciences’ raxibacumab for anthrax sclerosis. The FDA approved Sanofi’s oraltaliglucerase alfa, for Gaucher’s disease, is the first approved antibacterial mAb. immunomodulator teriflunomide forreceived the first approval for a biologic Raxibacumab was also the first product to relapsing–remitting multiple sclerosis inproduced in a plant-cell manufacturing be approved under the FDA’s animal efficacy 2012, but the approval of Biogen Idec’ssystem, providing encouragement for rule, an approval programme for products highly anticipated BG‑12 and the regulatory that for ethical reasons cannot be tested in submission of Sanofi’s alemtuzumab are humans. both expected later this year. The agency also approved Janssen’s 8 bedaquiline for pulmonary multidrug-resistant 4 tuberculosis (TB), making it the first agent in a 3.5 Annual sales (US$ billion) 13 new class of anti-TB drugs to be introduced in Enzalutamide 3 40 years. Because the drug will be used to treat Stribild 2 a neglected disease, its approval came with a 2.5 priority review voucher — the second ever 2 2 granted — entitling Janssen to a priority review 1.5 Tofacitinib of any future drug of its choice. 1 Apixaban 2 Obesity drugs were also prominent, 0.5 Pertuzumab 2 4 with two approvals bringing an end to a 0 3 decade-long drought in a potentially lucrative 2013 2014 2015 2016 2017 3 market. Only Eisai and Arena’s lorcaserin made the NME list, however. The FDA Figure 3 | Global sales forecasts for potential Oncology Imaging classified Vivus’s Qysmia (phentermine and multi-blockbusters approved Drug Discovery Nature Reviews | in 2012. Gastroenterology Ophthalmology Consensus forecast estimates are calculated Respiratory Neurological topiramate) as a new combination, because as a mean value of the estimates published by Antimicrobial Other both agents are already marketed for other financial analysts in the past months. On Cardiovascular indications, and so the drug doesn’t count average, each consensus estimate is obtainedFigure 2 | Approvals in 2012 by therapeutic among the 39 new approvals. Initial sales of from three to four individual analyst estimates.area. ‘Other’ includes urologic, sexual health, Qysmia have been seen as disappointing and Estimates provided are valid as of 3 January Nature Reviews | Drug Discoveryhaematology, rheumatology, endocrine and lorcaserin has not yet been launched, but the 2013. Data provided by Thomson Reutersdermatology drugs. obesity news flow nevertheless bolstered the Cortellis for Competitive Intelligence.90 | FEBRUARY 2013 | VOLUME 12 www.nature.com/reviews/drugdisc © 2013 Macmillan Publishers Limited. All rights reserved