Full positive results from the HELIOS-A phase 3 study of Vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated ( ATTR ) amyloidosis, which met its primary and both secondary endpoints at nine months in patients with hereditary ATTR ( hATTR ) amyloidosis with polyneuropathy, were presented.
The 9-month results achieved the study’s primary endpoint, with Vutrisiran showing improvement in the mean change from baseline in the modified Neuropathy Impairment Score ( mNIS+7 ) as compared to external placebo data from the APOLLO phase 3 study of Patisiran. At 9 months vutrisiran also met all secondary endpoints, demonstrating improvement in quality of life as assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy ( Norfolk QoL-DN ) instrument and improvement in gait speed as assessed by the timed 10-meter walk test ( 10-MWT ), both compared to the external placebo group.
The majority of patients has experienced improvement in neuropathy and in quality of life, both relative to baseline, showing the potential for Vutrisiran to reverse polyneuropathy manifestations of hATTR amyloidosis.
Vutrisiran has also demonstrated an encouraging safety profile with no drug-related discontinuations or deaths.
HELIOS-A study results
At 9 months, Vutrisiran met the primary and all secondary endpoints in HELIOS-A, specifically:
a) Vutrisiran has achieved a rapid and sustained reduction in serum TTR levels with an 83% mean steady-state serum TTR reduction from baseline. Consistent results in serum TTR level reduction were observed between the vutrisiran and patisiran arms of HELIOS-A, aligned with the therapeutic hypothesis;
Vutrisiran treatment ( n=122 ) resulted in a 2.24 point mean decrease ( improvement ) in mNIS+7 score from baseline at 9 months as compared to a 14.76 point mean increase ( worsening ) reported for the external placebo group ( n=77 ), resulting in a 17.0 point mean difference relative to placebo ( p equal to 3.54x10-12 ).
Improvement in mNIS+7 from Vutrisiran treatment was also consistently observed across all pre-specified patient subgroups, including age, sex, race, geographic region, baseline neuropathy impairment, genotype, prior TTR stabilizer use, baseline familial smyloid polyneuropathy ( FAP ) stage, and inclusion in the pre-specified cardiac subpopulation.
Patients randomized to the Patisiran reference arm in HELIOS-A showed results consistent with the Vutrisiran arm.
Vutrisiran treatment resulted in a 3.3 point mean decrease ( improvement ) in Norfolk QoL-DN score from baseline at 9 months as compared to a 12.9 point mean increase ( worsening ) reported for the external placebo group, resulting in a mean 16.2 point difference relative to placebo ( p equal to 5.43x10-9 ).
Patients treated with Vutrisiran remained stable in gait speed ( mean decrease of 0.001 meters/second in 10-MWT ), while patients in the external placebo group demonstrated worsening ( mean decrease of 0.133 meters/second in 10-MWT ) ( p equal to 3.10x10-5 ).
Improvement in the exploratory cardiac endpoint, NT-proBNP, a measure of cardiac stress, was observed in the Vutrisiran arm in both the pre-specified cardiac sub-population and the modified intent-to-treat ( mITT ) population, relative to the external placebo group.
The cardiac subpopulation was defined as patients who had pre-existing evidence of cardiac amyloid involvement ( baseline left ventricular wall thickness greater than or equal to 1.3 cm and no aortic valve disease or hypertension in medical history ). NT-proBNP adjusted geometric fold change from baseline was 0.95 for the Vutrisiran cardiac subpopulation group ( n=35 ) and 1.60 for the external placebo cardiac subpopulation ( n=34 ) group, with an adjusted geometric fold change ratio of 0.60 ( p equal to 0.0016 ) in favor of Vutrisiran.
Similar results from baseline were seen in the mITT population in favor of Vutrisiran relative to the external placebo group ( p equal to 9.20x10-7 ).
In addition, Vutrisiran has demonstrated improvements in other exploratory endpoints measured at 9 months, including change from baseline in modified body mass index ( mBMI ) and the Rasch-built overall disability scale ( R-ODS ), relative to external placebo.
In the study and as previously reported with topline results from the HELIOS-A study, Vutrisiran has demonstrated an encouraging safety and tolerability profile relative to placebo with 9 months of dosing and there were no drug-related discontinuations or deaths.
There were two study discontinuations ( 1.6% ) due to adverse events in the Vutrisiran arm by month 9, both due to death, neither of which was considered related to study drug.
There were two serious adverse events considered related to Vutrisiran by the study investigator, consisting of dyslipidemia and urinary tract infection.
Treatment emergent adverse events occurring in 10% or more patients included diarrhea, pain in extremity, fall, and urinary tract infections, with each of these events occurring at a similar or lower rate as compared with external placebo arm.
Injection site reactions ( ISRs ) were reported in 5 patients ( 4.1% ) and were all mild and transient.
There were no safety signals regarding hematology, renal function or liver function tests ( LFTs ).
Hereditary transthyretin-mediated amyloidosis ( hATTR ) is an inherited, progressively debilitating, and fatal disease caused by mutations in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. ( Xagena )
Source: Alnylam Pharmaceuticals, 2021