Last year, a total of 49 New Molecular Entities (NMEs) were approved for marketing around the world, according to PME research, a record haul that has not been surpassed since the mid-1990s, before the often-reported R&D productivity drought took hold.
2014 was remarkable for not only the number of NMEs that made it through the regulatory process but also for the broad spread of indications and novel mechanisms of action on display. This year’s list includes a handful of ‘me too’ drugs but the proportion is much lower than was typically seen in the 1990s and – conversely – the number of first-in-class drugs seems higher.
Optimists might interpret that as evidence of an underlying shift in the drug development activities of the pharma industry, and perhaps the start of a pay-off for the investment in new research approaches and more specialised, targeted treatments. It remains to be seen however whether the trend – which follows a similar but more pronounced pattern as emerged in 2013 – is anything more than the usual ebb and flow of R&D output.
One factor behind the hike in NMEs could feasibly be the FDA’s ‘breakthrough’ designation, which was introduced in 2013 to refine and improve the agency’s accelerated review programme and try to bring novel therapies to patients more quickly. No fewer than eight of the NMEs approved in the US as their first market had been granted breakthrough status, while another four antibiotics were reviewed under Qualified Infectious Disease Product (QIDP) status, which also expedites the process.
In fact, the US was far and away the leading country for NME approvals, accounting for 31 (63%) of the total, followed by the EU with nine (20%) and Japan – a distant third in recent years – only a little behind with seven (14%).
Meanwhile, the EMA has also taken steps to accelerate new drug assessments, focusing on providing more scientific support in the early stages of medicine development, which was given in around 70% of applications last year, up from around 50% in 2013.
As in previous years there has been a continuing shift away from traditional new chemical entities (NCEs) and towards biologic agents, with around a third of the candidates in the latter category.
2014 is remarkable as the year in which antibacterials staged a comeback with seven new antibiotics registered
First-in-class therapies
Among the new drug classes that debuted for the first time in 2014, the standout example is arguably the programmed death-1 (PD-1) or immune checkpoint inhibitors, which block a pathway employed by cancer cells to evade immune responses and are predicted to become multibillion-dollar products with applications in several cancer types.
Bristol-Myers Squibb won the race to market, debuting its Opdivo (nivolumab) for melanoma in Japan shortly before Merck & Co got FDA approval for its Keytruda (pembrolizumab) for the same indication in the US.
Other first-in-class agents include: Merck & Co’s PAR-1 antagonist Zontivity (vorapaxar), a novel antiplatelet agent; AstraZeneca’s PARP inhibitor Lynparza (olaparib) for cancer; Otsuka’s Deltyba (delamanid), a nitro-dihydro-imidazooxazole drug for multidrug-resistant tuberculosis (MDR-TB); Gilead Sciences’ Zydelig (idelalisib) for certain types of leukaemia and lymphoma, which inhibits a protein that plays a role in the activation, proliferation and viability of B cells; and Novartis’ Cosentyx (secukinumab), the first interleukin-17 (IL-17) inhibitor for inflammatory conditions.
2014 also saw the first NS5A inhibitor for hepatitis C virus (HCV), namely BMS’ Daklinza (daclatasvir). This was swiftly followed Gilead’s ledipasvir – used alongside the company’s massively successful sofosbuvir in the first HCV combination pill – as well as AbbVie’s ombitasvir, which formed part of a much-anticipated, four-drug HCV regimen – Viekira Pak – that was approved in the US as the year drew to a close.
Crunching the numbers
A look at the table reveals where pharma has been investing its R&D dollars in recent years, with 12 of the 49 NMEs in the anti-infectives category, 11 in cancer and six in diabetes, with central nervous system (CNS) and rare diseases accounting for five new drugs apiece. It also shows areas where activity is on the wane, with 2014 a lean year for cardiovascular and respiratory disease therapies.
Digging down into the anti-infectives category, 2014 is also remarkable as the year in which antibacterials staged something of a comeback, with seven new antibiotics registered as society becomes increasingly concerned about the emergence of multidrug-resistant bacteria.
Cancer was once again a very fertile area with 11 NMEs across nine separate mechanistic categories and two new therapies each for malignant melanoma and non-small cell lung cancer (NCLC). There was also a crop of drugs for rare tumours – including AZ’s Lynparza and Eli Lilly’s Cyramza (ramucirumab) – as well as four therapies for rare diseases outside the oncology sphere, reflecting pharma’s increasing interest in developing specialty drugs for niche conditions, which typically come with longer patent terms, accelerated review times and higher price tags.
Among these, notable examples include PTC Therapeutics’ Translarna (ataluren) – the first medicine approved for the treatment of Duchenne muscular dystrophy (DMD) – and Sanofi/Genzyme’s Cerdelga (eliglustat) for Gaucher disease, a small-molecule glucosylceramide synthase inhibitor which provides an oral alternative to the injectable enzyme replacement therapies currently used to treat the condition.
Diabetes was remarkable mainly for its preponderance of me-too drugs, with all the new NMEs approved in the year either GLP-1 agonists or SGLT2 inhibitors, two classes that already have a number of established products on the market.
Pharma’s focus on developing drugs for specialist populations is leading to questions about whether healthcare can continue to be funded in the traditional manner
Big pharma still dominating
The marketing authorisations for the NMEs were held by 38 different companies, with all but a handful bringing just one new medicine to market during the year.
Among those with multiple approvals were AstraZeneca (AZ), Novartis (including Alcon), Eli Lilly, Merck & Co and Biogen Idec – with three apiece – and Bristol-Myers Squibb (BMS), Sanofi/Genzyme, Boehringer Ingelheim, Gilead Sciences, Cubist Pharma, Takeda and Kowa with a pair each.
Of course, what the NME numbers do not reveal are the additional challenges faced post-registration, such as the need to demonstrate that new therapies must demonstrate value to healthcare payers as well as clinical efficacy and safety in order to succeed in the marketplace.
Moreover, pharma’s increasing focus on developing premium-priced drugs for more specialist populations, such as rare disease and specific cancer genotypes, is leading to questions about whether healthcare can continue to be funded in the traditional manner. For example, Amgen’s Blincyto (blinatumomab) for a rare form of leukaemia has been priced at $178,000 a year, while AZ’s Myalept (metreleptin) for the ultra-rare metabolic disorder lipodystrophy – now divested to Aegerion Pharmaceuticals – has been set at an eye-watering $325,000 a year.
As this article was being finished the Cancer Drugs Fund in the UK had de-listed 25 drugs in a bid to limit a hefty overspend. The debate has included accusations that some drugmakers have set the price of some medicines that have failed NICE evaluations deliberately high.
Escalating prices have prompted renewed calls for a different model of healthcare funding as healthcare systems struggle to look after patients with orphan diseases, particularly in cancer which has seen a slew of new immunotherapies for highly-targeted patient populations reach the market in recent years with price tags upwards of $100,000 a year.
Meanwhile, the herd mentality of the industry that was apparent in the 1990s has not gone away, despite the increased number of potential drug targets. Companies are still clustering around the same targets and therapeutic areas and may well be setting up in years to come the same competitive pressures that affected ‘me-too’ NCEs ahead of the biologics revolution.
For instance, Opdivo and Keytruda, Cosentyx and other pioneering drugs in the table and due to emerge in 2015 are being followed by rivals that will increase competition and may peg back their commercial prospects.
