GRADUATE I AND II: Revisiting the key findings from two Phase III studies evaluating the efficacy and safety of subcutaneous gantenerumab in early Alzheimer’s disease (AD)

Abstract

AbstractBackgroundGantenerumab is a fully human monoclonal antibody administered subcutaneously. It binds to aggregated forms of amyloid‐beta protein. GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two 27‐month, global, Phase III, randomized, placebo‐controlled trials designed to investigate the efficacy and safety of gantenerumab in participants with early AD (mild cognitive impairment due to AD or mild AD dementia).MethodEligible participants with early AD were randomized 1:1 to receive gantenerumab or placebo. A universal titration scheme was used for all participants receiving gantenerumab, irrespective of APOEε4 genotype, in order to reach target dose of 510 mg every 2 weeks. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes (CDR‐SB). Secondary efficacy endpoints, imaging and fluid biomarkers were also assessed.ResultGRADUATE I and II enrolled 985 and 980 participants, respectively. The studies did not meet their primary endpoints. Change from baseline in CDR‐SB at Week 116 for the gantenerumab and placebo groups respectively was 3.35 and 3.65 in GRADUATE I (difference –0.31; 95% confidence interval [CI] –0.66 to 0.05; p = 0.095; 8% relative reduction [RR]) and 2.82 and 3.01 in GRADUATE II (difference –0.19; 95% CI –0.55 to 0.17; p = 0.2998; 6% RR). Secondary measures including ADAS‐Cog13, ADCS‐ADL, FAQ had non‐significant point estimates in favor of gantenerumab, as did the majority of exploratory measures, including NPI‐Q (Table 1). In the gantenerumab arm, change in amyloid PET from baseline to Week 116 was –57.4 (SE 2.84) centiloids for GRADUATE I and –48.0 (SE 2.85) centiloids for GRADUATE II. ARIA‐E occurred with gantenerumab and were manageable and mostly asymptomatic. Plasma exposure using Q2W dosing was comparable to previous data and similar between the GRADUATE studies (At steady state: mean Cmax and Cmin: GRADUATE I 88.1 µg/mL and 54.1 µg/mL; GRADUATE II 88.5 µg/mL and 56.8 µg/mL).ConclusionThe GRADUATE studies did not meet their primary endpoints, although non‐statistically significant effects favoring gantenerumab were observed across the majority of clinical outcome measures. Clinical benefit may require amyloid plaque removal to a threshold level; however, the parameters remain to be defined.