Top 10 pipeline blowups, setbacks and snafus in H2 2016
2016 has to rank as one of the worst years in recent drug R&D history. We’ve been treated to everything from a repeat Phase III debacle for Eli Lilly in Alzheimer’s to back-to-back clinical holds on a CAR-T drug that kills some patients from Juno. We’ve seen stellar organizations like Bristol-Myers’ R&D team overstep while Gilead went from doing no wrong to doing no right. And that was just what we saw in the last few months.
These weren’t just the normal failures you can expect in any business as high risk as biopharma R&D. There’s bad judgment and sometimes evasiveness in the face of embarrassing disasters.
Add in my look at the top 10 snafus for H1 along with a series of biotech disasters for companies like Seres, Ophthotech and many others, and the completed picture looks like a worst-case scenario for any investigator in the business. It’s no coincidence that we also saw ROIs in R&D continue to slide while new approvals plunged this year.
Lets hope next year, with blockbuster hopefuls in gene therapy, cancer, MS and more, can help overcome the picture of ineptitude that has dominated 2016. It can’t get much worse.
Juno Therapeutics — JCAR015’s lethal legacy
CEO: Hans Bishop
The problem: JCAR015 was handed one of the shortest clinical holds due to patient deaths in the FDA’s history. Within days regulators bought into Juno’s solution: Drop fludarabine — chemo used to condition patients for cell therapy — and you’ll see the incidences of neurotoxicity disappear. It didn’t work, as witnessed by two more patient deaths that forced the company to put it on a voluntary hold. And experts in the field warned from the get-go that Juno was following a dubious path to get back into the clinic, putting patients — albeit very sick patients — at unnecessary risk. The setback is likely to end development of Juno’s lead CAR-T, putting them far behind Kite and Novartis. And it raises serious doubts about the executive team’s credibility, as well as new questions about the FDA’s willingness to abandon its risk/benefit standards in favor of developers. Lessons learned? There’s no sign of any.
Bristol-Myers Squibb – A checkpoint frontrunner’s pratfall
New York, NY
CEO: Giovanni Caforio
The problem: Of all the epic miscalculations that occurred in 2016, few can rival Bristol-Myers Squibb’s blunder with Opdivo. Shooting for an FDA OK to use their pioneering checkpoint in frontline lung cancer cases, investigators overshot their mark, rather greedily going after a broad patient population and failing badly, on several scores. Merck, running in right behind Bristol-Myers, played it just right, and the FDA rewarded their savvy with a near instant expansion of their market. It’s no coincidence that the company soon after began a major reorg in the R&D group.
Eli Lilly – Another home run swing whiffs
CEO: John Lechleiter
The problem: Let’s leave aside for a moment the changing of the guard at Eli Lilly. John Lechleiter stayed on long enough to either claim credit or accept responsibility for solanezumab, its twice failed Alzheimer’s drug that was put back in a large Phase III program. And that’s where the buck should stop. Lilly, of course, was chasing a clinical signal — straight into a ditch. By revising its trial design and relying on better diagnostics, Lilly believed it could avoid a repeat of its 2012 flop. Perhaps one of Lechleiter’s biggest achievements was to convince many analysts and news organizations that the data from the last failure indicated a clear promise for its future use. That gave Lilly four more years to execute a turnaround in its pipeline. But the big home run swings like this continue to underscore the company’s inability to get the next megablockbuster through Phase III. And it capped yet another year in which late-stage Alzheimer’s R&D has known nothing but catastrophe.
Novartis — CAR-T
CEO: Joe Jimenez
The problem: There are still quite a few unanswered questions about what prompted Novartis to shutter its cell and gene therapy unit and disperse its 400 staffers, laying off 120 and seeing off its chief, Usman “Oz” Azam. You may not have heard, but Azam landed not long after at Tmunity, a startup launched by Penn’s Carl June, who’s working on the next wave of CAR-T tech. Novartis’ explanation — it was streamlining the work and eliminating costs — only served to mystify outside observers, who were likely to see this as a setback that would play out after Novartis made its first play for a pioneering approval in 2017. Why lose your top talent in a field you plan to dominate?
Gilead — The domino theory
Foster City, CA
CEO: John Milligan
The problem: By the time Gilead’s Phase III for momelotinib staggered in with unimpressive results in mid November, analysts had just about had it with the one time biotech darling. GS-4997 was already raising doubts, and Gilead had to write off simtuzumab along with GS-5745 for ulcerative colitis and Crohn’s. Eleclazine (GS-6615) also failed a late-stage study. And that all happened in a matter of months. Gilead has gone a long way to destroying confidence in its pipeline, though there are some big programs still in the mix. Add in a $2.54 billion jury verdict for violating Merck’s hep C patents, as its hep C franchise is on the wane, and you have a recipe for one of the worst reversals in the industry this year.
Alnylam – The revusiran shockwave
CEO: John Maraganore
The problem: The news last October that Alnylam had decided to abruptly scrap its late-stage program for revusiran sent shockwaves through its investor group as well as the whole R&D sector it leads. The RNAi groundbreaker, which has been laboring for more than a decade on building its pipeline, was forced to axe the program after tracking a higher rate of death in the drug arm of its pivotal study. It was yet another reminder that RNAi is afflicted with unknown safety issues that can claim a drug in an unsuspecting moment. And it arrived just days after Alnylam took a nasty hit on its stock price after a much earlier-stage drug, the RNAi liver disease drug ALN-AAT, was scrapped after three patients experienced spiking liver enzymes in a Phase I/II. That’s a classic sign of program-killing toxicity. One of the underlying concerns with Alnylam is that the safety issues could be eventually linked to other pipeline efforts, though not likely to its lead drug Patisiran. Alnylam CEO John Maraganore, though, is no quitter. He’s seen plenty of ups and downs along the way. And he’s vowed to see it through to commercialization. No one doubts his sincerity on that score. But Alnylam’s stock dropped by half on the Revusiran setback, and it’s never recovered.
Boehringer Ingelheim – Hidden disasters
Chairman of the board of managing directors: Hubertus von Baumbach
The problem: The industry experienced several new cases of R&D Alzheimer’s this year. That’s when the only thing some companies can remember is the good. The bad and the ugly, and what caused it, are forgotten. And no one company had a worse experience with this disease in 2016 than Boehringer Ingelheim. In May, Boehringer was happy to celebrate the approval of Hanmi’s drug in South Korea, as it looked to accelerate this therapy straight through its own late-stage development. At the end of September, the company simply walked away without explanation. Hanmi, though, has been under investigation for staging a stock manipulation and Boehringer later conceded, after I raised questions about it, that one patient had died in a study and two more experienced severe adverse events. One lawmaker in Korea turned up a letter from Boehringer dated to August saying that they were stopping the program on the recommendation of the data monitoring committee. And the same lawmaker said that three patients had died. Boehringer reps have stopped answering my questions about this drug, such as: When exactly did they find out the drug — still marketed in Korea, despite the controversy — was dangerous? And how about that DMC letter? That’s as bad a case of R&D Alzheimer’s you’ll see.
AstraZeneca – A Brilinta Waterloo
CEO: Pascal Soriot
The problem: Brilinta has to rank as one of Pascal Soriot’s greatest disappointments. And there are a number to pick from. This year the pharma giant mounted expensive studies to prove that Brilinta was (A) Not any better than generic Plavix in treating peripheral artery disease and (B) Not better than simple aspirin in preventing heart strokes. AstraZeneca is now slowly starting to walk back its sunny forecast that this drug could one day achieve $3.5 billion in annual sales. And with that retreat the odds against ever hitting $45 billion in annual revenue — promised to investors for their support is staving off a Pfizer takeover — just got considerably worse. The news on Brilinta comes during a sour year for AstraZeneca’s team. Brodalumab was sold for scrap to Valeant after its commercial profile was marred by evidence of suicidal thinking among patients. The great hope in gaining an approval for durvalumab has been delayed, putting the company in a likely 4th or 5th spot at the FDA’s initial finish line for checkpoint drugs. And one time blockbuster hope selumetinib has now flopped in two late-stage studies, most recently last summer for KRAS-positive non-small cell lung cancer.
Cempra – The problem with antibiotics
Chapel Hill, NC
Acting CEO: David Zaccardelli
The problem: We learned more than a year ago that Cempra’s new antibiotic was linked with safety issues, and the data sent the biotech’s shares into a tailspin. But the jury remained out on soli until the FDA formally rejected it in December, completing a rout for the biotech. Cempra now is in a real dilemma. It has to decide if it wants to actually mount a major new safety study or give up on a product that may be approvable, but not commercially viable. Regulators have already indicated that evidence of liver toxicity will keep this product on the sidelines, called on only after everything else has failed. And that remarkable assessment may never be overturned. Cempra’s predicament underscores just how hard it is to develop new antibiotics, even at a time of growing drug resistance. This is the kind of situation that is likely to make it even harder to get more investment cash together for new companies in the field, making this a setback for the sector.
Pfizer – Not so hot on PCSK9
CEO: Ian Read
The problem: Pfizer’s not the kind of drug developer that skimps on clinical trials. So when it decided to go after the world’s number 3 PCSK9 drug – bococizumab – the company set up two Phase III studies for 32,000 patients. This therapy already had issues going into Phase III, most notably evidence of an immune response, which was added to signs of waning efficacy. That didn’t stack up well with the two pioneer drugs in the field from Amgen and Regeneron/Sanofi, which underscores just how hard it is to play pack R&D. Pfizer’s problem here, which led to a decision in November to dump the whole thing after touting bococizumab as a leading drug in its late-stage pipeline, is The Medicines Company’s advantage. They’ve been working on a rival drug from Alnylam that promises to do the same work with only twice-yearly dosing.