Source: FDA CDER
The closing tally for US FDA approvals of new drugs (officially called New Molecular Entities) in 2012 is 39, and represents the highest count since 1996 when the agency approved 53 new drugs, according to a recent Reuters report. There was indeed a late December push that squeezed in 8 approvals before year-end, including the potential blockbuster anti-clotting drug Eliquis (apixaban) co-marketed by Pfizer and Bristol-Myers Squibb. The average number of new drug approvals hovered around 23 over the past decade, but recent years indicate an upward trend.
This past year’s class of new drugs indeed highlight prevailing industry trends:
- Most important new drug of 2012?: Vertex’s Kalydeco (ivacaftor) approved in Jan ’12 became the first drug targeting the defects caused by genetic abnormalities (G55D1 mutation) associated with cystic fibrosis. Only 4% of CF patients carry this genetic defect, and trials showed sustained improvement in lung function for those patients using this drug. Kalydeco was also groundbreaking in that a large part of its early development was funded through the patient advocacy group Cystic Fibrosis Foundation, a precursor to similar patient-driven engagements in the future. Matt Herper at Forbes anointed this drug as the most important in 2012, and it’s hard not to agree.
- Continued rare disease drug development: Aside from Kalydeco in G55D1-mutant cystic fibrosis, other new drugs for rare diseases include Novartis’s Signifor (pasireotide) for Cushing’s disease, NPS’s Gattex (teduglutide) for short bowel syndrome and Roche/Genentech’s Erivedge (vismodegib) for basal cell carcinoma. The remarkable success for drugs in rare diseases is also drawing competition: Gaucher disease gained an additional treatment option in Pfizer/Protalix’s Elelyso (taliglucerase alfa) which faces an uphill battle against Sanofi’s Cerezyme and Shire’s VPRIV.
- Cardiovascular drug comeback?: Lots of promise accompany the fresh approval of Eliquis (apixaban), an anticoagulant poised to compete well with Boehringer Ingelheim’s Pradaxa (dabigatran) and J&J’s Xarelto (rivoraxaban) as the supreme alternative to warfarin. Eliquis will first launch in the commercially lucrative space of stroke prevention in atrial fibrillation (~3 million patients in the US), hoping to expand and compete in other settings where venous clots threaten. 2012 also saw the approval of Amarin’s Vascepa (icosapent ethyl) for high triglycerides and Arena/Eisai’s Belviq (lorcaserin) which may (along with Vivus’s Qsymia) energize a wave of pharmacological treatment of obesity.
- Fortifying the cancer treatment cascade: While few drugs targeted new cancer mechanisms (e.g. Erivedge being the first inhibitor of the Hedgehog pathway), there were many that provide robust back-up options to existing therapies. It is most apparent in the blood cancer CML (chronic myelogenous leukemia) which is handled well by the wonder drug Gleevec but relapses do occur. In addition to Novartis’s Tasigna (nilotinib) and BMS’s Sprycel (dasatinib), there are 3 more back-up options to CML patients who fail initial therapy – Pfizer’s Bosulif (bosutinib), Teva’s Synribo (omacetaxine) and Ariad’s Iclusig (ponatinib). Other examples of new drugs in refractory settings include Pfizer’s Inlyta (axitinib) in renal cell carcinoma, Sanofi’s Zaltrap (ziv-aflibercept) in colorectal cancer and Bayer/Onyx’s Kyprolis (carfilzomib) in multiple myeloma.
The number of approvals for NMEs are often closely monitored as a proxy metric for both the pharma industry’s productive output and the FDA’s efficiency in reviewing drug applications. And indeed, there used to be a chorus of industry pundits that criticized the FDA for being too slow to approve new drugs. That may have been true in 2007 which witnessed a record low number of NME approvals (18) despite a healthy number of NME applications filed (64) in the 2005-06 timeframe. But the FDA has certainly shored up its internal processes and can boast the following review highlights for fiscal year 2012 (ref. Dec ’12 report):
- Quicker review timing: 97% of new drugs (34/35) met their review deadlines based on the PDUFA dates (set by user fee legislation) and half of new drug approvals were expedited via Fast Track, Priority Review or Accelerated Approval. Over the past 20 years (since PDUFA in 1992), review timings have dramatically decreased from 19 months to 10 months in FY2011. In fact, Kalydeco only took 3.5 months for approval.
- High approval yield on first review: 77% of new drugs were approved on the first iteration of reviews, without need for additional data or trials. This has been driven by earlier input from the FDA regarding trial design and safety monitoring, and closer alignment between drug sponsors and the FDA throughout the development process. The newfound option to implement a post-marketing risk management program (called “REMS”) also cushions lingering safety concerns by the FDA.
- Faster than other countries: Of 32 novel drugs that received approval, 75% (24/32) first received approval in the US, continuing a longstanding trend (see chart below). There remains a small divergence in approval expectations between US and international regulatory agencies, as CV drugs face challenges gaining approval in the US first (e.g. Eliquis, Tredaptive) while drugs for rare diseases tend to gain US approval first (perhaps due to more favorable market access environment).
New drugs are increasingly being first approved in the US since early 1990s. Source: FDA Dec 2012 Report
At this point, the onus for fewer new drug approvals seems to fall on industry. Despite significant improvements in FDA reviewing timelines, there has been a long-run declining trend in the number of NME applications filed over the past 15 years (see chart below). And the newly approved drugs are nowhere close to replacing the lost revenue streams of 2012, headlined by BMS/Sanofi’s Plavix which at one point had $10b in global sales. The only potential blockbusters (>$1b peak sales) in the 2012 class would likely be Pfizer/BMS’s Eliquis and Gilead’s Stribild (quad daily pill for HIV). The high-priced cancer and rare disease drugs may also be in play for strong sales (>$250m peak sales) but it’s hard to say based on the evolving market access landscape and increasing competition in these areas. There simply isn’t enough output, an idea also echoed by Ryan McBride over at FierceBiotech. Gone are the days of the “multi-blockbuster model”; companies will need to build commercial value by accumulating many medium-potential drugs, not by banking on a handful of “blockbuster totems”. R&D productivity will be key.
Source: FDA CDER
To delve into the reasons for declining R&D productivity is a topic to be addressed another day, but many pharma companies are proactively tackling the issue as to how to bolster R&D output and manage resources efficiently. It certainly isn’t for lack of spend – R&D spend continues to grow at a torrid pace even as NME approvals decline (see chart below), and the coffers will run out if this continues. When Eli Lilly executives proclaimed 2 years ago a bold strategic plan to launch 2 drugs per year starting in 2013, it was given the same credence as Rex Ryan’s proclamations to lead the NY Jets to the Superbowl. It defied both science and history, unless they figured out how to revamp the drug development model (that hasn’t happened yet). We may be seeing offshoots of that transformation as key players in the industry continue to extract insights from genomics and proteomics towards rational drug design, seek faster avenues for ‘bad’ drugs to fail, develop novel and more adaptive approaches to conduct clinical trials and leverage “Big Data”, and enter into more varied partnerships and collaborations involving academic centers, start-up companies and other big pharma firms.
Source: Kaitin KI. Clin Pharmacol Ther. 2010 March; 87(3): 356–361
2012 may have been a strong year in terms of number of new drug approvals, but it will fall short in the commercial value of those new drug approvals. This may be a watershed moment for the industry – a steady stream of new drugs will likely set up better for success (and even survival) in the future than pouring resources to develop the next blockbuster. It’s kinda like the NY Yankees – over-dependence on the “longball” for runs was their ultimate undoing in their latest playoff runs.
Filed under: Drug Companies, Drug Development, Pharmaceuticals Tagged: apixaban, BMS, chronic myelogenous leukemia, CML, Eliquis, FDA approval, Kalydeco, orphan disease, PDUFA, Pfizer, rare disease, Vertex Pharmaceuticals
