HELIOS-A: 18 month Exploratory Cardiac Results from the Phase 3 Study of Vutrisiran in Patients with hATTR Amyloidosis

Presented at ESC Heart Failure 2022 by Pablo Garcia-Pavia, MD (Madrid, Spain)

Introduction and methods

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, underdiagnosed, rapidly progressive, fatal disease. It is caused by mutations in the TTR gene that result in misfolded TTR accumulating as amyloid deposits. Most patients with hATTR amyloidosis have both polyneuropathy and cardiomyopathy.

Vutisiran is an investigational RNAi therapeutic that targets the hepatic production of TTR for potential treatment of ATTR amyloidosis. It is subcutaneously administered. It is mechanism of action is similar as that of patisiran. Patisiran is an RNAi therapeutic that is administered via IV infusion, and approved for treatment of the polyneuropathy of hATTR amyloidosis based on results from the APOLLO trial.

In the phase 3 HELIOS-A trial, 164 patients with hATTR amyloidosis with polyneutopathy were randomized in a 3:1 ratio to vutisiran 25 mg SC Q3M or to patisiran 0.3 mg/kg IV Q3W. Data were compared to a placebo group from the APOLLO trial (it was not ethical to have patients on placebo in the HELIOS-A trial). The 18-month efficacy endpoints were already described; the primary endpoint of change from baseline in mNIS+7 at month 9 and all secondary endpoints were met.

The aim of this substudy was to examine the effect of vutisiran on exploratory cardiac parameters the mITT population (n=122 on vutisiran in HELIOS-A and n=77 on placebo in APOLLO) and in a prespecified cardiac subpopulation (baseline left ventricular wall thickness ≥1.3 cm and no medical history of aortic valve disease or hypertension) (n=40 on vutirisan in HELIOS-A and n=36 on placebo in APOLLO). The selected exploratory cardiac endpoints included change from baseline in NT-proBNP levels and echocardiographic parameters to month 18, scintigraphy findings at month 18.

Main results

• There was no increase in NT-proBNP from baseline to month 18 in the vutisiran group, whereas NT-proBNP levels increased in the placebo group, both in the mITT population (adjusted geometric fold change ratio at month 18: 0.480, 95%CI:0.383-0.600, P=9.61x10-10) and in the cardiac subpopulation (adjusted geometric fold change ratio at month 18: 0.491, 95%CI:0.337-0.716, P=0.0004).
• A trend toward improvement of echocardiographic parameters was observed with vutirisan in the mITT population and cardiac subpopulation at month 18 compared with the external placebo group.
• In the majority of patients receiving vutisiran, cardiac 99mTc uptake was reduced as observed by scintigraphy imaging at month 18. In patients with Perugini grade ≥2 the percentage of patients with reduced cardiac 99mTc uptake was even higher.
• 96% Of patients who received vutisiran and underwent scintigraphy were stable or improved by ≥1 Perugini grade at month 18. Of patients with ≥1 Perugini grade at baseline, 50% improved by ≥1 Perugini grade.
• Vutisiran was well tolerated and there were no difference in the cardiac safety events between those who received vutirisan in HELIOS-A and the external placebo group in APOLLO.

Conclusion

Treatment with vutisiran in patients with hATTR amyloidosis resulted in an improvement of NT-proBNP levels and a trend towards improvement of echocardiographic parameters when compared with an external placebo group of the APOLLO trial. Consistent beneficial effects were observed on cardiac measures in the mITT population and a prespecified group of patients with evidence of cardiac amyloid involvement at baseline.

In a subgroup of patients who underwent scintigraphy, reduced cardiac uptake of 99mTc was seen compared with baseline in the majority of patients treated with vutisiran, suggesting regression of cardiac amyloid.

The HELIOS-B study is ongoing and investigates cardiac efficacy and safety of vutisiran in patients with ATTR amyloidosis with cardiomyopathy.

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