KISUNLA Solution for injection Ref.[110679] Active ingredients: Donanemab

Donanemab-azbt is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against insoluble N-truncated pyroglutamate amyloid beta. The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease. Donanemab-azbt reduces amyloid beta plaques, as evaluated in Study 1 [see Clinical Studies (14)].

Effect of KISUNLA on Amyloid Beta Pathology

The effect of KISUNLA on amyloid beta plaque levels in the brain was evaluated using amyloid Positron Emission Tomography (PET) imaging (18F-florbetapir tracer). The PET signal was quantified using the Standard Uptake Value Ratio (SUVR) method to estimate brain levels of amyloid beta plaque in composites of brain areas expected to be widely affected by Alzheimer’s disease pathology (precuneus, frontal, anterior cingulate, posterior cingulate, parietal, and temporal cortices), compared to a brain region expected to be spared of such pathology (cerebellum). Results of amyloid PET were also expressed on the Centiloid scale.

In Study 1 [see Clinical Studies (14)], KISUNLA reduced amyloid beta plaque levels in the brain in a time-dependent manner, starting at Week 24, and continuing through Week 76 (p<0.0001), compared to placebo (see Figure 1 and Table 7). In clinical pharmacology studies, KISUNLA demonstrated a dose- and time-dependent reduction in amyloid beta plaque, with the decrease observed starting at Week 12.

Figure 1. Reduction in Brain Amyloid Beta Plaque (Change from Baseline) on Amyloid Beta PET Imaging Composite (SUVR and Centiloids) in Study 1^a:

^a ****p<0.0001.

During an off-treatment period, amyloid PET values began to increase with a median rate of 2.80 Centiloids/year.

Effect of KISUNLA on Tau Pathophysiology

A reduction in plasma p-tau217 was observed with KISUNLA compared to placebo in Study 1 (see Table 7).

Table 7. Biomarker Results of KISUNLA in Study 1 (AACI):

N is the number of patients with baseline value.

^a Results should be interpreted with caution due to the uncertainties in bioanalysis.

Exposure-Response Relationships

Model based exposure-response analyses for Study 1 demonstrated that exposures to donanemab-azbt were associated with a reduction in clinical decline on iADRS and CDR-SB. An association between reduction in amyloid beta plaque from baseline and clinical decline on iADRS and CDR-SB was also observed.

The pharmacokinetics (PK) of KISUNLA were characterized using a population PK analysis with concentration data collected from 2131 patients with Alzheimer’s disease who received KISUNLA in single or multiple doses. Accumulation of <1.3-fold occurs with every-4-week dosing; steady-state exposures are achieved after a single dose. In single doses from 10 to 40 mg/kg (~2 times the approved recommended dosage of 1400 mg for 70 kg of body weight), and multiple 10 and 20 mg/kg doses, exposures (C_max and AUC) increased proportionally.

Distribution

The central volume of distribution is 3.36 L.

Elimination

KISUNLA is expected to be degraded by proteolytic enzymes in the same manner as endogenous IgG. The mean terminal half-life of donanemab-azbt is approximately 12.1 days. Donanemab-azbt clearance is 0.0255 L/h.

Specific Populations

Age, sex, or race were not found to affect the pharmacokinetics of donanemab-azbt. While body weight was found to influence both clearance and volume of distribution, the resulting changes were not clinically significant.

Patients with Renal or Hepatic Impairment

No clinical studies were conducted to evaluate the pharmacokinetics of donanemab-azbt in patients with renal or hepatic impairment. Donanemab-azbt is degraded by proteolytic enzymes and is not expected to undergo renal elimination or metabolism by hepatic enzymes.

Carcinogenesis

Carcinogenicity studies have not been conducted.

Mutagenesis

Genotoxicity studies have not been conducted.

Impairment of Fertility

No studies in animals have been conducted to assess the effects of donanemab-azbt on male or female fertility.

The efficacy of KISUNLA was evaluated in a double-blind, placebo-controlled, parallel-group study (Study 1, NCT04437511) in patients with Alzheimer’s disease (patients with confirmed presence of amyloid pathology and mild cognitive impairment or mild dementia stage of disease, consistent with Stage 3 and Stage 4 Alzheimer’s disease). Patients were enrolled with a Mini-Mental State Examination (MMSE) score of ≥20 and ≤28 and had a progressive change in memory function for at least 6 months. Patients were included in the study based on visual assessment of tau PET imaging with flortaucipir and standardized uptake value ratio (SUVR). Patients were enrolled with or without concomitant approved therapies (cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine) for Alzheimer’s disease. Patients could enroll in an optional, long-term extension.

In Study 1, 1736 patients were randomized 1:1 to receive 700 mg of KISUNLA every 4 weeks for the first 3 doses, and then 1400 mg every 4 weeks (N=860) or placebo (N=876) for a total of up to 72 weeks. The treatment was switched to placebo based on amyloid PET levels measured at Week 24, Week 52, and Week 76. If the amyloid plaque level was <11 Centiloids on a single PET scan or 11 to <25 Centiloids on 2 consecutive PET scans, the patient was eligible to be switched to placebo.

Additionally, dose adjustments were allowed for treatment-emergent ARIA or symptoms that then showed ARIA-E or ARIA-H on MRI.

At baseline, mean age was 73 years, with a range of 59 to 86 years. Of the total number of patients randomized, 68% had low/medium tau level and 32% had high tau level; 71% were ApoE ε4 carriers and 29% were ApoE ε4 noncarriers. Fiftyseven percent of patients were female, 91% were White, 6% were Asian, 4% were Hispanic or Latino, and 2% were Black or African American.

The primary efficacy endpoint was change in the integrated Alzheimer’s Disease Rating Scale (iADRS) score from baseline to 76 weeks. The iADRS is a combination of two scores: the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog₁₃) and the Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living (ADCSiADL) scale. 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, and ADCS-iADL.

There were two primary analysis populations based on tau PET imaging with flortaucipir: 1) low/medium tau level population (defined by visual assessment and SUVR of ≥1.10 and ≤1.46), and 2) combined population of low/medium plus high tau (defined by visual assessment and SUVR >1.46) population.

Patients treated with KISUNLA demonstrated a statistically significant reduction in clinical decline on iADRS compared to placebo at Week 76 in the combined population (2.92, p<0.0001) and the low/medium tau population (3.25, p<0.0001).

Patients treated with KISUNLA demonstrated a statistically significant reduction in clinical decline on CDR-SB compared to placebo at Week 76 in the combined population (-0.70, p<0.0001) (see Figure 2 and Table 8). There were also statistically significant differences (p<0.001) between treatment groups as measured by ADAS-Cog₁₃ and ADCS-iADL at Week 76 (see Table 8).

Dosing was continued or stopped in response to observed effects on amyloid imaging. The percentages of patients eligible for switch to placebo based on amyloid PET levels at Week 24, Week 52, and Week 76 timepoints were 17%, 47%, and 69%, respectively. Amyloid PET values may increase after treatment with donanemab is stopped [see Clinical Pharmacology (12.2)]. There is no data beyond the 76-week duration of Study 1 to guide whether additional dosing with KISUNLA may be needed for longer-term clinical benefit.

Figure 2. CDR-SB Change From Baseline in Combined Population Through 76 Weeks in Study 1a:

^a ****p<0.0001 versus placebo.

Table 8. Efficacy Analysis Results in Combined Population at Week 76^a:

^a Abbreviations: ADAS-Cog13 = Alzheimer’s Disease Assessment Scale – 13-item Cognitive Subscale; ADCS-iADL = Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living subscale; CDR-SB = Clinical Dementia Rating Scale – Sum of Boxes; NCS2 = natural cubic spline with 2 degrees of freedom; MMRM = mixed model for repeated measures.
^b Assessed using MMRM analysis.
^c Assessed using NCS2 analysis.
^d Percent slowing of decline relative to placebo: difference of adjusted mean change from baseline between treatment groups divided by adjusted mean change from baseline of placebo group at Week 76.