Celladon spoils the gene therapy party


Did somebody say gene therapy was undergoing a resurgence? Celladon yesterday brought the party back down to earth with the revelation that a phase II heart failure trial had shown its Mydicar project to be an unmitigated failure.

Some credit should be given to management for spelling out in no uncertain terms that Mydicar had flunked both the primary and secondary endpoints of the Cupid2 study, though analysts who had hyped the highly risky trial today looked less impressive. Attention now turns to other companies that had basked in the reflected glow of Bluebird Bio, whose success had started the gene therapy rally.

The excitement around Bluebird concerned a tiny study presented at December’s ASH conference. Though this had detailed just four patients, out of eight treated so far, it suggested that Bluebird’s LentiGlobin could revolutionise treatment of beta-thalassaemia; the US biotech’s stock has nearly tripled since then.

Then there is UniQure’s Glybera, whose 2012 EU approval for lipoprotein lipase deficiency was the world’s first ever for a gene therapy. While Glybera seems doomed economically, UniQure this month struck a major alliance with Bristol-Myers Squibb over separate assets.

Earlier this year Sanofi endorsed Voyager Therapeutics with a $100m deal, while Spark Therapeutics’ Nasdaq IPO was enthusiastically received.

No silver lining

For Celladon, however, it is hard to see a silver lining after the failure of Mydicar in Cupid2, which had enrolled 250 patients with ischaemic or dilated cardiomyopathy and compared the gene therapy against placebo.

Even on a modified intent-to-treat basis the primary endpoint – improvement in heart failure-related hospitalisations or ambulatory treatment for worsening heart failure – was a fail: risk of progression was reduced by 7% on average, but the upper bound of the confidence interval was 1.65 and the p value was a highly non-significant 0.81.

The secondary endpoint, all-case death, also failed to show a benefit for Mydicar. On a call Celladon said it would implement staff layoffs and investigate all options for the company; the group ended 2014 with $85m in cash, which it says is enough for at least a year excluding the impact of cost cutting.

The company also said it would investigate whether the problem with Cupid2 was lack of efficacy or inadequate delivery of Mydicar into cardiomyocytes. The agent uses a viral vector to deliver a gene encoding production of the enzyme SERCA2a to cardiac tissue to improve contraction in heart muscle cells.


Mydicar was a legacy project of Targeted Genetics, a group that now exists as the bacteriophage-focused business Ampliphi Biosciences; by virtue of this Ampliphi had been due a 10% royalty on Mydicar sales.

Keen biotech watchers might have spotted another link: Targeted Genetics was also the originator of UniQure’s Glybera.

While Glybera did secure EU approval, under exceptional circumstances, it is still not launched, the first commercial patient not expected to be treated until mid-2015. And its continuing review recently hit another snag.

At least UniQure bulls can point to the group’s deal with Bristol-Myers Squibb, which concerned the heart failure candidate AAV-S100A1 and three other targets, none of which is related to Glybera (UniQure deal confirms red-hot interest in advanced therapies, April 7, 2015).

What does all this mean for gene therapy in general? Mydicar is clearly a setback for the field, though if Bristol had been looking specifically at cardiovascular projects it can at least say it backed the right horse. UniQure opened up 1% this morning, while Bluebird was off 1%.

Celladon, meanwhile, was crushed, plummeting 78%. In a note in January Stiefel Niclaus analysts had spelled out their expectation of a positive Cupid2 readout, and called Mydicar a “massive commercial opportunity [which] is a single hurdle away”.

But after peaking in March the stock went into freefall, with sellers including the company’s chief executive, Krisztina Zsebo. In hindsight that provided a pretty large red flag as to the direction in which Mydicar was heading.

Study Design Trial ID
Cupid2 250 advanced heart failure patients NCT01643330

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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