After 2015's bumper crop, 2016's new drug approvals don't measure up

The FDA received 36 applications for new molecular entities in 2016, of which only 22 were approved.

After two of the most bountiful years in nearly two decades, new drug approvals slowed this year, with 2016 notching a disappointing 22 approvals compared to the 45 approved in 2015 and the 41 in 2014.

The drop-off doesn’t stem from a lack of applications, though. The FDA received 36 applications for new molecular entities in 2016, on par with the average of 35 per year in the past decade. So what gives?

The key culprit looks to be timing: multiple drugs slated for 2016 approval—including AstraZeneca’s Tagrisso, Genentech’s Alecensa and Pfizer’s Ibrance—bagged accelerated approvals in 2015, boosting that year’s crop to 45, a high topped only by the 53 approved in 1996. And while Clovis Oncology and Pfizer sneaked into 2016 with mid-December approvals, they still weren't enough to tip the scale.

Another major factor is the spike in applications that met with a complete response letter. The FDA reported on Dec. 9 that 12 BLA/NME applications received a CRL in 2016, compared to just two the previous year.

A CRL effectively hamstrung AstraZeneca’s hopes of getting its $2.7 billion hyperkalemia drug through. Many thought that safety concerns might earn the drug, ZS9, a limited approval or even a rejection, but its downfall turned out to be manufacturing issues found in a preapproval inspection. AstraZeneca has since resubmitted the drug, but despite bagging four approvals in 2014 and two in 2015, the British pharma had to go without in 2016.

The low approval rate doesn’t reflect the FDA’s efforts to ramp up the path to market for some drugs: Five drugs scored breakthrough designation, while 13 were approved under priority review. Lilly’s soft tissue sarcoma drug Lartruvo picked up breakthrough, orphan drug and priority review status, and so did AbbVie and Roche’s chronic lymphocytic leukemia med Venclexta, which actually earned three separate breakthrough designations.

While these speedier approval pathways worked in some companies’ favor, the increased use of accelerated routes to approval could be raising the risk of failure earlier in development.

But whatever caused 2016’s drop-off, some analysts we contacted, including Leerink’s Geoffrey Porges and Evercore’s Umer Raffat, agreed that the downturn can’t be read into too much. However, EvaluatePharma predicted in its 2017 Preview that the failure of Eli Lilly’s Alzheimer’s drug solanezumab did not bode well for clinical milestones coming up this year, and that new drug approvals were also heading for a dip in 2017.

Without a doubt, the biggest story this year was that of Sarepta’s Exondys 51, which Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, all but strong-armed to approval. The drug is cleared for Duchenne muscular dystrophy patients that have a particular mutation of the dystrophin gene.

The condition is characterized by progressive muscle deterioration and typically confines patients to wheelchairs by their early teens. Trial participants who received the drug showed an increase in the production of the protein dystrophin—the absence of which causes muscles to degenerate—but did not prove the drug conferred any clinical benefit, including improved motor function. The agency is requiring Sarepta to conduct a follow-up trial to demonstrate tangible gain.

Hepatitis C seems to be the indication that keeps on giving, notching two approvals in 2016. A relative latecomer to the hep C arena, Merck’s Zepatier was the first drug to earn approval in January 2016, and by May, was already asserting itself. Merck is undercutting its competitors by offering Zepatier at $54,600, a virtual steal compared to the $94,500 that Gilead charges for Harvoni and the $83,319 prediscount price tag for AbbVie’s Viekira Pak. The peak sales estimate for Zepatier is pegged at $2 billion.

Gilead’s latest, Epclusa, is the first drug to treat all six genotypes of hep C. It goes for roughly $20,000 less than Harvoni and looks to reel in more than $10 billion in sales. But the company may chalk up 2016 as a loss; in December, a federal jury ordered Gilead to hand over $2.54 billion to Merck in a patent infringement verdict, the equivalent of 10% royalties on Harvoni and Sovaldi.

Other honorable mentions include Jazz Pharma’s Defitelio, the first drug for severe hepatic veno-occlusive disease to hit the U.S. market, and Sanofi’s delayed GLP-1 med Adlyxin, which has to compete with the likes of Novo’s Victoza, Lilly’s Trulicity and AstraZeneca’s Bydureon. But Sanofi could turn things around by taking advantage of payer pressure to exchange discounts for favorable coverage and gaining ground in ex-U.S. markets. It’s also anticipating an approval for a combo of Adlyxin and its background insulin Lantus.

Biogen and AbbVie scored a nod for Zinbryta, a multiple sclerosis med delivered via once-monthly self-injection as opposed to more frequent injections given by a healthcare professional. However, Zinbryta’s approval comes with a boxed warning on safety risks and should “generally” be used in patients who have failed on two or more MS drugs.

While several major players scored approvals in 2016, Merck, AbbVie and Eli Lilly take the joint crown with two approvals each, though AbbVie’s OKs were both in tandem with other drugmakers. But the weak showing also means a number of the usual suspects were absent, including AstraZeneca, Amgen, and Novartis, which topped the chart in 2015 with four approvals. Despite being denied in 2016, Novartis, at least, should be on track for a 2017 approval—its CDK 4/6 breast cancer drug ribociclib picked up priority review status in November. And it may be the first to get a CAR-T med to market as it races with Kite Pharma, which has already kicked off a rolling submission with the FDA.

For its part, EvaluatePharma has tagged therapies at the forefront of innovation—such as CAR-T and CRISPR—as prospects “among the most highly valued in drug development.” But it cautions that any mishaps along the way could “easily undermine confidence” in R&D. In the meantime, EvaluatePharma highlighted some major cardiovascular trials as well as candidates in the immuno-oncology space as ones to keep an eye on in 2017. -- Amirah Al Idrus