Hammond KH, Penny WF, Traverse JH, et al.
JAMA Cardiol 2016; published online ahead of print

Background

Heart failure is increasing in prevalence and HF hospitalisation rates and mortality remained almost constant in the past decade, suggesting that new therapies are needed [1,2]. Gene transfer has barely been evaluated in clinical trials, although there is evidence suggesting that AC6 (adenylyl cyclase type 6) gene transfer might improve cardiac function [4-9]. AC6 is a 130-kD membrane protein that is dominant in heart muscle cells and that catalyses the conversion of cAMP, which, in turn, is important for heart function [3]. Relevant AC6 data show that:

• increased cardiac AC6 content was beneficial for cardiomyocytes and the heart in preclinical studies [4]
• AC6 is reduced in failing hearts [5]
• the basal intracellular cAMP production is not altered by significant AC6 increases in preclinical models [6]
• AC6 influences heart function independently of cAMP, via calcium uptake regulation [7]
• Increased expression ofAC6 restored LV function in a genetic preclinical model of cardiomyopathy [8]
• expression of AC6 normalised prolonged action potential duration and reduced ventricular arrhythmias in cardiomyopathy [9]

In this randomised, double-blind, placebo-controlled, phase 2, dose-finding study, the effect on heart function and the safety of intracoronary delivery of an E1/E3-deletedhumanadenovirus 5 encoding human AC6 (Ad5.hAC6) was assessed, in 56 participants with stable but symptomatic HF and reduced EF.

Main results

EF:
High dose administration of Ad5.hAC6 resulted in:

• increased EF at 4 weeks: 29.7% vs. 36.3%; mean increase: +6.0 [+SE:1.7] EF units; n = 21; P< 0.004. This increase was dose-related (P < 0.04).

• not increased EF at 12 weeks: 29.7% vs. 34.2%; mean increase: +3.0 [2.4] EF units; n = 21; P=0.16

The administration of placebo did not result in a significant EF increase:

• at 4 weeks: 29.6% vs. 33.7%; mean increase: +4.1 [2.2] EF units; n= 14; P=0.08
• at 12 weeks: 29.6% vs. 31.6%: mean increase: +0.8 [1.2] EF units; n=13; P=0.42

Exercise duration:
Exercise duration showed no significant group differences in change from baseline between placebo and high dose, not at 4 weeks and not at 12 weeks.

HF symptoms and NYHA classification:
Administration of high dose Ad5.hAC6 led to a significant reduction in symptoms:

• 12 weeks after randomization: 28.8[2.4] vs. 20.5 [3.0]; n = 22; P = 0.0005)
• 4 week and 12 weeks: NYHA decrease by 1.0 unit (from 3.0 to 2.0); P < 0.11 at 4 weeks and P < 0.01 at 12weeks

Admission rates for patients with HF were lower in the AC6 group (RR: 0.33; 95%CI: 0.08-1.36; P=0.10)

• 9.5% (4 of 42) in the AC6 group
• 28.6%(4 of 14) in the placebo group

Further results:

• AC6 gene transfer increased basal left ventricular peak −dP/dt. 4-week change from baseline: placebo: +93 [51]mmHg/s; high dose Ad5.hAC6: −39 [33]mmHg/s; placebo [n = 21]; P < 0.03
• AC6 did not increase arrhythmias
• No significant adverse events occurred during AC6 administration

Conclusion

AC6 gene transfer by means of intracoronary delivery of Ad5.hAC6 in stable HF patients with reduced EF significantly increased the LV function, and was not associated with increased adverse events.

Find this article online at JAMA Cardiol

References

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