On Friday, Novartis announced that its anti-IL17A antibody secukinumab (Cosentyx™) demonstrated clear superiority over its rival, Stelara™ ustekinumab from Johnson & Johnson, an antibody against IL-12 and IL-23, in the treatment of psoriasis.
What marks this out as significant is not the potential commercial impact for $NVS, nor the step-change in efficacy this delivers for patients suffering from psoriasis – though quite clearly both are true.
Instead, it’s the commitment prior to approval to test the drug head-to-head against arguably its stiffest competitor. This kind of direct comparison is exactly what the medical profession needs – without it, doctors are left with two comparable sets of data from different trial designs and little hope of determining which agent is most suited to the patient in front of them. But the industry has, in the past, been very wary of providing such unequivocal comparative evidence.
Changes, though, are being forced on drug companies. Whereas once upon a time, regulatory approval alone was sufficient to secure meaningful sales, increasingly that is no longer true. Even after the stiff battle with regulators has been won, new product launches today face an arguably even stiffer test: to win over doctors and payers.
While the options for treatment for a particular disease were limited, knowing a drug was safe and effective (the hurdles for regulatory approval) is sufficient to justify use. But almost every large indication today already boasts a slew of approved therapeutics options, all of which are “safe and effective”. Against such a landscape, it is increasingly obvious that driving significant use requires direct comparison trials such as the CLEAR trial in psoriasis that Novartis reported last week.
Such trial designs are double-edged swords however – success will surely drive sales of the new agent, but failure to demonstrate superiority would equally certainly consign the expensively-approved newcomer to the trash can. How many people want to play “double or quits” with their newly-approved (or, worse still, perhaps, not-yet-approved) blockbuster candidate?
In an industry renowned for its conservative decision-making, its not surprising that owners of newly-launched drugs have tended to test the water first, and only resort to comparative trials if sales are low and slow. With Crestor™ rosuvastatin, for example, where AstraZeneca were already selling more than $5billion a year of product, head-to-head comparison with its competitor Lipitor™ atorvastatin were only contemplated more than five years after approval – when the impending loss of patent protection for atorvastatin threatened Crestor™ sales. Even when those trials failed to demonstrate any material superiority, the established sales were unaffected. That hardly counts as risk-taking.
But $NVS adopted an entirely different strategy with Cosentyx™. Comparitor trials were the mainstay of the late-stage development program, rather than an afterthought.
First, in 2013, in the FIXTURE study, they demonstrated superiority over an anti-TNF product, Enbrel™ etanercept from Amgen in a head-to-head study. With that scalp under their belt, they set their sights on the then newly-approved Stelara™ ustekinumab. The CLEAR study is the product of that strategy, and with the demonstrated superiority completely vindicates it.
Let’s be in no doubt: this brave new world is very much to the advantage of patients and payers. Better comparator data will, in itself, lead to better outcomes and saved dollars.
It may not, however, be universally such good news for the pharmaceutical industry. The biggest drag on capital efficiency in R&D is “late” risk – that is, risk that can only be discharged at the end of the development cycle, when the vast majority of the costs have already been expended. Failure at the end of development, or worse still, in the marketplace, erodes capital returns very quickly. If the industry is forced (by the commercial landscape, rather than by regulators) to do more comparator studies of this type, then more late-stage failures will be the order of the day.
After all, the circumstances Novartis faced with Cosentyx™ were sadly not typical: the impact of anti-IL17A on moderate-to-severe plaque psoriasis is little short of a modern-day miracle. Both the number of patients seeing a 75% reduction in symptoms (on the standardized PASI scale) within a month, and the number who see at least a 90% reduction sustained for a year suggests that Cosentryx™ is, if not a cure, then the next best thing.
Armed with such impressive clinical efficacy, finding the courage to take on all-comers in transparent head-to-head trials is not so challenging. But for most drugs currently entering the late-stage pipeline, confidence of superiority across such a broad patient population is mostly absent. In many cases, companies are rushing to win a race with almost identical competitors: antibodies against PCSK9 or PD-1 for example. Where the competitive advantage (in terms of clinical profile) may be small – or even non-existent – the desire to conduct transparent head-to-head comparator trials will be notably absent.
The solution here is simple. And it is not to shy away from direct head-to-head comparator trials. Instead, the industry needs to learn to kill drugs much earlier in clinical development, before the costs mount too high, as soon as it becomes clear that the clinical profile doesn’t offer that step-change that marks out Cosentyx™ as ‘special’. Such drugs may get approved, but they will not win any prizes in comparator studies, or for that matter sales in the marketplace.
But perhaps the most worrying lesson from the psoriasis trials is the further evidence of the shortening half-lives of the market leader products. Assuming Cosentyx™ is approved in the US, after the recent FDA panel recommendation to that effect, and quickly grabs the lion’s share of the psoriasis market, Stelara™ will join the growing band of supernovae: drugs that shined brightly very quickly, but were soon overtaken by the next innovation. Incivek™ telaprevir from Vertex Pharmaceuticals is the clearest example of a supernova drug to date. But comparator trials threaten to make it the norm rather than the exception in the future.
It is hard enough to win economic payback for investment in drug discovery and development. The worst nightmare for those of us investing in that space is shortening product life-cycles.
But for all the challenges the changing face of late-stage development present to the industry, the benefits to the patients and to society (through reduced healthcare costs) are so great that it is clearly a future we must embrace. And the only way to survive, and even thrive, in this future-world is to keep a tight lid on R&D costs – and above all only to progress into late-stage development those product candidates, like Cosentyx™, where the clinical advantage is crystal clear.
This article by DrugBaron was original published by Forbes, and can be found here
RxCelerate Ltd is an outsourced drug development platform based near Cambridge, UK. We specialize in delivering an entire road map of drug development services from discovery and medicinal chemistry through to formal preclinical development and clinical up to Phase IIa. In the last five years, we have witnessed dramatic changes in the drug development …