Two Phase III studies of ALN AT3 show significant improvements in hemophilia A or B.

The Phase III studies compared once monthly fitusiran prophylaxis (80mg) with on-demand use of factor concentrates in the ATLAS-A/B study, and on-demand use of bypassing agents in the ATLAS-INH study. Across both clinical studies, prophylactic treatment with fitusiran reduced annualized bleeding rates by >89% compared to the control arms, showing a statistically significant and clinically meaningful improvement in bleeds when compared to on-demand treatments, and also showing significant improvement in quality of life. The fitusiran Phase III clinical program is ongoing. Sanofi is currently investigating the efficacy and safety of fitusiran under an amended protocol which includes lower doses and an extended dosing regimen in all ongoing adult and adolescent studies. Fitusiran has the potential to provide prophylactic treatment for all people with hemophilia A or B, with as few as six injections per year.

ATLAS-A/B Phase III Study (NCT03417245): ATLAS-A/B is a Phase III randomized, open-label study investigating the efficacy and safety of fitusiran in males at least 12 years with severe hemophilia A or B without inhibitors who had previously been treated with on-demand factor therapy. Study participants (n=120) were randomized 2:1 to receive either once-monthly 80mg subcutaneous fitusiran prophylaxis or on-demand factor therapy for bleeding episodes. The primary endpoint is annualized bleeding rate (ABR). The key findings in this study include the following: A statistically significant and clinically meaningful reduction in treated annualized bleeding rate of 89.9% in the fitusiran prophylaxis arm (95% CI 84.1%; 93.6%], P <0.0001) compared to the factor on-demand arm. median (interquartile range) annual bleeding rate for treated bleeds is 0.0 (0.0; 3.4,) in the fitusiran arm compared to 21.8 (8.4; 41.0) in the factor on-demand arm. 50.6% (n="40)" of study participants in the fitusiran prophylaxis arm had zero treated bleeds compared to 5.0% (n="2)" of participants in the factor on-demand arm. the most common adverse events reported in at least five (6.3%) participants in the fitusiran prophylaxis arm were increased alanine aminotransferase (alt), upper respiratory tract infection, nasopharyngitis, abdominal pain, increased aspartate aminotransferase (ast), cough, arthralgia, asthma, gastritis, and headache. treatment emergent adverse events of special interest (teaesis) of any alt or ast elevation>3 x upper limit of normal were reported in the fitusiran prophylaxis arm in 15 (19.0%) participants. There were no TEAESIs of suspected or confirmed thromboembolism reported.

Phase III ATLAS-INH Study (NCT03417102): The ATLAS-INH study is a randomized, open-label Phase III study designed to evaluate the safety and efficacy of fitusiran in males at least 12 years with severe hemophilia A or B with inhibitors to factor VIII or IX. Study participants (n=57) receiving on-demand treatment with bypassing agents (BPA) were randomized in a 2:1 ratio to receive once-monthly 80mg subcutaneous fitusiran prophylaxis or continue with on-demand BPA. The primary endpoint is annualized bleeding rate. The key findings in this study include the following: Fitusiran prophylaxis resulted in a statistically significant reduction in treated annualized bleeding rate of 90.8% (95% CI 80.8%; 95.6%), P<0.0001) in comparison to treatment with bpas. the median (interquartile range) treated annualized bleeding rate is 0.0 (0.0; 1.7,) in the fitusiran prophylaxis arm compared to 16.8 (6.7; 23.5) in the on-demand bpa on-demand arm. 65.8% (n="25)" participants in the fitusiran prophylaxis arm had zero treated bleeds compared to 5.3% (n="1))" in the bpa on-demand arm. the most common adverse events reported in at least five (12.2%) participants in the fitusiran prophylaxis arm were increased alt, increased ast, upper abdominal pain, increased gamma-glutamyl transferase, headache, upper respiratory tract infection, arthralgia, increased blood alkaline phosphatase, and increased transaminases. teaesis of alt or ast elevation>3 x upper limit of normal and suspected or confirmed thromboembolism were reported in the fitusiran prophylaxis arm in 10 (24.4%) and 2 (4.9%) participants, respectively. Fitusiran significantly reduced annualized bleeding with a meaningful improvement in health-related quality of life. Reported TEAEs in the fitusiran prophylaxis arm of ATLAS-A/B and ATLAS-INH were generally consistent with previously identified risks of fitusiran, or risks associated with the underlying disease of severe hemophilia A or B. Results from the ATLAS-A/B study, investigating fitusiran in people without inhibitors, are being presented in the Late-Breaking Abstract Session and findings from the ATLAS-INH study, which evaluated fitusiran in people with inhibitors to factor VIII or IX, were shared in the Plenary Scientific Session on December 12, 2021.