I first wrote about Celladon Corporation (NASDAQ: CLDN) on March 19, 2015. I highlighted the amazing data of CUPID 1 trial and the low bar for the primary endpoint of CUPID 2. The Breakthrough Therapy designation further confirmed the blockbuster potential of Celladon’s gene therapy MYDICAR.
I recently noted several red flags in the CUPID 1 trial.
|Placebo (n=14)||Low Dose (n=8)||Mid Dose (n=8)||High Dose (n=9)|
|Risk reduction||60% (p=0.11)||54% (p=0.12)||88% (p=0.03)|
1. The patients in the high dose group were 4 years younger than the patients in the placebo group. Moreover, the high dose group enrolled more female subjects. It is known that heart failure risk increases with age and men have higher hospitalization rates for heart failure.
2. The patients in the high dose group were significantly healthier than the patients in the placebo group. Higher NT-proBNP levels in the placebo group indicated worse outcomes. The levels of NT-proBNP are elevated in patients with left ventricular dysfunction.
3. Left ventricular ejection fraction (LVEF) did not increase appreciably in any group. If MYDICAR had restored contractility of the heart muscle, we should have observed that LVEF improved significantly in the high dose group.
4. In the low dose and mid dose group, risk reduction was not statistically significant. Patients with the mid dose of Mydicar performed worse than the low dose. The absence of a dose-dependent response raises concerns about the trial.
5. In the CUPID 1 follow-up, persistent presence of the SERCA2a transgene in cardiac tissue was detected in three of four high dose patients. However, whether the amount of SERCA2a genes is sufficient to produce higher levels of SERCA2a protein and futher result in risk reduction are unclear.
I still believe in Celladon and its breakthrough gene therapy because the the primary endpoint bar is really low and the SERCA2a gene had been taken up by the heart muscle cells indeed, but we should know about the risks and rationally evaluate the risk/reward.
 Circulation. 2011, 124(3), 304-313.
 J Card Fail. 2013, 19(8), 542-549.
 Congest Heart Fail. 2004, 10(1 Suppl 1), 23-27.
 Circ Res. 2014, 114(1), 101-108.