Kisunla Mechanism of Action

Pharmacology: Pharmacodynamics: Reductions in cerebral amyloid plaques, as measured by amyloid positron emission tomography (PET), were observed among patients receiving donanemab. Donanemab reduced tau pathophysiology, as measured by plasma P-tau217.
Mechanism of action: Donanemab is an immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against an insoluble, pyroglutamate N terminal truncated form of amyloid beta (N3pE Aβ) present only in brain amyloid plaques. Donanemab binds to N3pE Aβ and aids plaque removal through microglial-mediated phagocytosis.
Biomarkers: The percentage of donanemab treated patients with amyloid clearance (that is, less than 24.1 Centiloids or visually negative on an amyloid PET scan) in Study TRAILBLAZER-ALZ 2 is represented in Figure 1. (See Figure 1.)
A reduction in plasma P-tau217 (log 10) was observed with donanemab compared to placebo. In a study population with low to medium levels of brain tau (baseline SUVr ≤1.46), LS mean change difference ± SE was -0.19 ± 0.011 and -0.25 ± 0.014 at Weeks 24 and 76, respectively, compared to placebo (p < 0.0001 at both time points). Consistent with this, in a study population with low to medium and high levels of brain tau, LS mean change difference ± SE was -0.16 ± 0.010 and -0.22 ± 0.012 at Weeks 24 and 76, respectively, compared to placebo (p < 0.0001 at both time points).

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Clinical trials: Clinical efficacy and safety: The efficacy and safety of donanemab were evaluated in a Phase 3 (TRAILBLAZER-ALZ 2) and a Phase 2 (TRAILBLAZER-ALZ) study, both double-blind placebo controlled, parallel group, in patients with early symptomatic AD (Mild Cognitive Impairment (MCI) or mild dementia due to AD) and evidence of amyloid beta pathology confirmed by amyloid PET scan. The participants also had evidence of pathologic tau deposition on a flortaucipir PET scan. The Phase 3 study confirmed the efficacy and safety results observed in the Phase 2 Study. For the safety analysis, patients were followed for up to 76 weeks or last dose plus 57 days.
Phase 3 Study TRAILBLAZER-ALZ 2: In this study, 1736 patients were randomised 1:1 to receive 700 mg of donanemab every 4 weeks for the first 3 doses, and then 1400 mg every 4 weeks via intravenous infusion (N=860) or placebo (N=876) for a total of up to 72 weeks. The study enrolled men or women, aged 60 - 85 years with gradual and progressive change in memory function for 6 months or more, a MMSE score of 20 to 28 at screening, who met the florbetapir F18 or florbetaben F18 scan criteria and flortaucipir F18 scan criteria. Patients were included in the study based on visual assessment of tau PET imaging with flortaucipir and quantitation by standardised uptake value ratio (SUVR). The low-medium tau level population included patients with tau SUVR ratios of 1.10 to 1.46, inclusive, with a topographic deposition pattern consistent with moderate AD or ≤1.46 with a topographic deposition pattern consistent with advanced AD. The high tau level population included patients with tau SUVR ratio >1.46 with a topographic deposition pattern consistent with either moderate or advanced AD. The study includes a double-blind extension period of 78 weeks duration. Dosing was continued until study completion or amyloid plaque was cleared, defined as demonstrating a plaque level of less than 25 Centiloids for two consecutive amyloid PET scans or a single PET scan demonstrating a plaque level of less than 11 Centiloids. Additionally, dose suspension was allowed for treatment-emergent ARIA. If patients were already on symptomatic treatment (acetylcholinesterase inhibitors (AChEI) and/or the N Methyl D aspartate inhibitor, memantine) at study entry, these treatments could continue. Symptomatic treatments could be added or changed during the study, at the investigator's discretion. The study excluded patients with pre-existing ARIA-E, greater than 4 microhaemorrhages, more than 1 area of superficial siderosis, any intracerebral haemorrhage >1 cm or severe white matter disease. Patients with significant neurological disease affecting the central nervous system other than AD that may affect cognition, including other dementias, were excluded. Patients with no or very low tau pathology were excluded from the randomised placebo-controlled portion of the study.
At baseline, 266 participants had MCI and 1040 had mild AD. Of the total number of patients randomised, 29% (510/1736) were ApoE ε4 non-carriers, 54% (930/1736) were heterozygotes, and 17% (289/1736) were homozygotes. Mean age was 73 years, with a range of 59 to 86 years, with a mean (SD) baseline weight of 71.7 kg (15.7), with a gradual and progressive change in memory function for at least 6 months and a Mini-Mental State Examination (MMSE) score of 20 to 28 (inclusive). 57.4% were female, 91.5% were White, 5.7% were of Hispanic or Latino ethnicity, 6.0% were Asian, and 2.3% were Black. 55.6% of patients were on AChEI, and 20.3% on memantine. 61% of patients were on either AChEI or memantine use.
There were two primary analysis populations based on tau PET imaging at screening with flortaucipir: low medium tau level population; and combined population (low medium plus high tau level population).
The primary efficacy endpoint was change in cognition and function as measured by the integrated Alzheimer's Disease Rating Scale (iADRS) score from baseline to 76 weeks. The iADRS is an integrated assessment of cognition and daily function comprised of items from the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS Cog₁₃) and the Alzheimer's Disease Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL) scale, measuring the core domains across the AD clinical continuum. The total score ranges from 0 to 144, with lower scores reflecting worse cognitive and functional performance. Other efficacy endpoints included Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB), ADAS-Cog₁₃, ADCS-iADL.
Treatment with donanemab statistically significantly slowed clinical decline compared to placebo at week 76, with consistency across measures of cognition and function (see Figure 2 and Table 1).

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Patients treated with donanemab also had a 39% and 37% lower risk of progressing to the next stage of disease as measured by the CDR-global score (HR: 0.61, p < 0.001; and HR: 0.63, p < 0.0001) through Week 76 in the low-medium tau and in the combined population, respectively.
At Week 76, donanemab treatment delayed disease progression by 4.4 months and 7.5 months as assessed by iADRS and CDR-SB respectively in the low medium tau population, and by 1.4 months and 5.4 months as assessed by iADRS and CDR-SB respectively in the combined population.
At Week 76, patients treated with donanemab had less decline in cognition than placebo treated participants as assessed by the MMSE change from baseline values in both the low medium tau and in the combined population.
High tau population: In the high-tau population (271 patients on donanemab and 281 patients on placebo), donanemab slowed clinical decline by 6% (1.26 ± 1.54 [p=0.415]) on iADRS, and 21% (-0.69 ± 0.25 [p=0.006]) on CDR-SB, at Week 76 compared with placebo.
Phase 2 study TRAILBLAZER-ALZ: In this study, patients were randomised to receive 700 mg of donanemab every 4 weeks for the first 3 doses, and then 1,400 mg every 4 weeks or placebo for a total of up to 72 weeks. A total of 257 participants were randomised 1:1 to donanemab (n=131) or placebo (n=126). The study enrolled men or women, aged 60-85 years with gradual and progressive change in memory function for 6 months or more, a MMSE score of 20 to 28 at screening, who met the florbetapir F18 scan criteria and flortaucipir F18 scan criteria. Patients were included in the study based on visual assessment of tau PET imaging with flortaucipir and quantification by standardised uptake value ratio (SUVR). The study enrolled a low-medium tau population of patients with tau SUVR ratios of 1.10 to 1.46, inclusive, or <1.10 if topographic deposition pattern consistent with advanced AD. In participants who were treated with donanemab, if the amyloid plaque level as assessed by florbetapir PET was 11 to less than 25 Centiloids, the dose was lowered to 700 mg. If the amyloid plaque level was less than 11 Centiloids on any one scan or was 11 to less than 25 Centiloids on two consecutive scans, donanemab was switched to placebo. Additionally, dose suspension was allowed for treatment-emergent ARIA. If patients were already on symptomatic treatment (acetylcholinesterase inhibitors (AChEI) and/or the N Methyl D aspartate inhibitor, memantine) at study entry, these treatments could continue. Symptomatic treatments could be added or changed during the study, at the investigator's discretion. The study excluded patients with pre-existing ARIA-E, greater than 4 microhaemorrhages, more than 1 area of superficial siderosis, any intracerebral haemorrhage >1 cm or severe white matter disease. Patients with significant neurological disease affecting the central nervous system other than AD that may affect cognition, including other dementias, were excluded. Patients with no or very low tau pathology and high tau pathology were excluded from the study.
At baseline, 46 participants had MCI and 185 had mild AD. Of the total number of participants randomised, 26% (68/257) were ApoE ε4 non-carriers, 52% (134/257) were heterozygotes, and 21% (53/257) were homozygotes. Mean age was 75.2 years, with a range of 61 to 86 years. 48% of patients were male and 95% were white. Patients treated with donanemab demonstrated reduced clinical decline, as evidenced by a statistically significant treatment effect on change from baseline in iADRS compared to placebo at week 76 (3.20 [-32%], p=0.042).
Pharmacokinetics: Absorption: KISUNLA is for intravenous administration only.
Distribution: Following intravenous dosing, KISUNLA undergoes biphasic elimination. The central volume of distribution is 3.36 L with 18.7% inter-individual variability. Peripheral volume of distribution is 4.83 L, with 93.9% inter-individual variability.
Metabolism: Donanemab is a monoclonal antibody and is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as an endogenous IgG.
Excretion: The half-life of KISUNLA is approximately 12.1 days. KISUNLA clearance was 0.0255 L/h (24.9% inter-individual variability).
Special Populations: The PK of KISUNLA was not affected by age, sex, or race, based on a population PK analysis. While body weight was found to influence both clearance and volume of distribution, the resulting changes do not suggest a need for dose adjustment.
Toxicology: Preclinical Safety Data: Genotoxicity: No studies have been performed to test donanemab for potential of genotoxicity. As a high molecular weight protein, donanemab is not expected to interact directly with DNA or other chromosomal material.
Carcinogenicity: No animal studies have been performed to test donanemab for potential carcinogenicity. A weight-of-evidence assessment of all data showed a low potential for risk of carcinogenicity.