Kisunla Adverse Reactions

Summary of the safety profile: In two placebo-controlled studies in patients with AD, a total of 984 adults received at least one dose of donanemab. Of these, 816 participants were in the indicated population. Study participants were administered three doses of 700 mg donanemab at four weekly intervals, followed by 1400 mg of donanemab at four weekly intervals for a maximum of 18 months (standard titration).
Based on ApoE ε4 carrier status, of the patients treated with donanemab, 30% (291/984) were non-carriers, 53% (522/984) were heterozygotes and 17% (168/984) were homozygotes. With the exception of events of ARIA, the safety profile was the same across genotypes.
The most frequently reported adverse reactions were ARIA-E (24.4%), ARIA-H (31.3%) and headache (13.1%). The most important serious adverse reactions were: Serious ARIA-E (1.5%), serious ARIA-H (0.4%), and serious hypersensitivity including infusion-related reactions (0.6%). Anaphylaxis was uncommonly reported (0.3%). All patients reporting infusion-related reactions had ADA. Increased incidence of infusion-related reactions/immediate hypersensitivity events were associated with high ADA titre (see Precautions). (See Table 6.)

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Less Common Adverse Reactions: Injury, poisoning and procedural complications - anaphylactic reaction (uncommon).
Description of selected adverse reactions: Amyloid-related Imaging abnormalities in the indicated population (Standard titration): ARIA (ARIA-E or ARIA-H) was observed in 32.6% (266/816) of patients treated with donanemab, compared to 12.7% (105/825) of patients on placebo in the placebo-controlled studies. Symptomatic ARIA occurred in 5.8% (47/816) of patients on donanemab. Serious ARIA events were reported for 1.3% (11/816) of patients treated with donanemab. Clinical symptoms associated with ARIA-E resolved in approximately 75% (33/44) of patients.
ARIA-E was observed in 20.8% (170/816) of patients treated with donanemab compared with 1.6% (13/825) of patients on placebo. The maximum radiographic severity for ARIA-E was mild in 6.5% of patients, moderate in 12.3% of patients, and severe in 1.7% of patients. Symptomatic ARIA-E was reported for 5.4% of patients treated with donanemab in placebo controlled clinical trials. The median time to resolution of ARIA-E was approximately 9 weeks.
ARIA-H can occur spontaneously in patients with AD independent of treatment. ARIA-H was observed in 26.7% (218/816) of patients treated with donanemab compared with 11.6% (96/825) of patients on placebo. The maximum radiographic severity for ARIA-H was mild in 14.1% of patients, moderate in 5.0% of patients, and severe in 7.5% of patients. Symptomatic ARIA-H was reported for 1.0% (8/816) of patients treated with donanemab compared with 0.2% (2/825) of patients on placebo. Isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) was observed in 11.8% (96/816) of donanemab treated patients compared to 11.0% (91/825) on placebo.
The majority of first ARIA radiographic events in the placebo-controlled studies occurred early in treatment (within 24 weeks of initiation of treatment), although ARIA can occur at any time and patients can have more than one episode.
Phase 3 Study TRAILBLAZER-ALZ-6: The donanemab dosing regimen of 350/700/1050 mg, followed by 1400 mg every 4 weeks was evaluated in a phase 3b multicentre, randomised, double-blind, study in adults with early symptomatic AD (MCI due to AD or mild AD dementia, MMSE score 20 to 28 inclusive) and evidence of amyloid beta pathology confirmed by amyloid PET scan.
843 patients were randomised at a 1:1:1:1 ratio into four donanemab dosing regimens for a total of 72 weeks, 700 mg for the first three infusions, then 1400 mg every 4 weeks thereafter (n=207; standard titration), or one of the three alternative dosing regimens (including the dosing regimen: 350/700/1050 mg, followed by 1400 mg every 4 weeks; n=212; modified titration).
The primary endpoint of the study was the proportion of participants with any occurrence of ARIA-E by week 24. The results showed that 14% of patients receiving 350/700/1050 mg (modified titration), compared with 24% receiving 700/700/700 mg (standard titration), experienced any occurrence of ARIA-E by week 24, a 41% relative risk (see Table 7) reduction. Similar amyloid plaque reductions were seen at 24 weeks in all dosing regimens.

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The secondary endpoint of the study was the proportion of participants with any occurrence of ARIA-H by week 24. The results showed that 20% of patients receiving modified titration, compared with 25% receiving standard titration, experienced any occurrence of ARIA-H by week 24, a 18% relative risk reduction.
ApoE ε4 Carrier Status and Risk of ARIA: In placebo-controlled studies, the incidence of ARIA was lower in non-carriers (24.1% donanemab vs 11.3% placebo) and heterozygotes (37.4% donanemab vs 13.4% placebo) than in homozygotes (58.3% donanemab vs 21.3% placebo). Among patients treated with donanemab, symptomatic ARIA-E occurred in 4.1% of non-carriers and 6.1% of heterozygotes compared with 7.7% of homozygotes. Serious events of ARIA occurred in approximately 0.7% of non-carriers, 1.7% heterozygotes and 3% of homozygotes. Among patients treated with donanemab, the rate of severe radiographic ARIA-E was lower in non-carriers 1.0% (3/291) and heterozygotes 2.1% (11/522) compared to homozygotes 4.2% (7/168). The rate of severe radiographic ARIA-H was lower in non-carriers 4.5% (13/291) and heterozygotes 9.2% (48/522) compared to homozygotes 24.4% (41/168).
Among the patients who experienced an event of ARIA-E and continued on donanemab with or without dose interruption, the rates of recurrence were 32.4% (11/34) in non-carriers, 26.7% (27/101) in heterozygotes and 28.6% (14/49) in homozygotes.
Among the patients who experienced an event of ARIA-H and continued on donanemab with or without dose interruption, the rates of recurrence were 35.1% (13/37) in non-carriers (compared with 31.8% [7/22] on placebo), 39.1% (45/115) in heterozygotes (compared with 38.6% [17/44] on placebo), and 51.7% (31/60) in homozygotes (compared with 30.8% [8/26] on placebo).
Intracerebral Haemorrhage: In placebo-controlled studies, intracerebral haemorrhage greater than 1 cm has been observed after treatment with donanemab in 0.3% compared to 0.2% for placebo. Additionally, in the pivotal study, a concurrent intracerebral haemorrhage with fatal ARIA-H has been observed in a patient treated with donanemab (see Precautions).
In Study TRAILBLAZER-ALZ 6, intracerebral haemorrhage greater than 1 cm was reported in 1% (2/212) of patients treated with donanemab for 24 weeks at the dosing regimen of 350/700/1050 mg, followed by 1400 mg every 4 weeks.
Infusion-related reactions: Infusion reactions were observed in 8.5% of patients treated with donanemab compared to 0.4% on placebo. Anaphylaxis was uncommonly reported (0.3%). Serious infusion reactions or hypersensitivity occurred in 0.6% of patients treated with donanemab compared to 0.2% on placebo.
The majority of infusion reactions and hypersensitivity reactions have occurred within the first 4 doses of donanemab, although they can occur at any time.
Reporting suspected adverse effects: Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to the Drug Office, Department of Health.