Kisunla 350 mg

Pharmacotherapeutic group: Nervous system, psychoanaleptics, anti-dementia drugs, other anti-dementia drugs, ATC code: N06DX05. Mechanism of action Donanemab is an immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against insoluble, modified, N‑terminal truncated form of amyloid beta (N3pG Aβ) present only in brain amyloid plaques.‍‍‍‍‍‍​​​‍​​​​​​ Donanemab binds to N3pG Aβ and aids plaque removal through microglial-mediated phagocytosis. The accumulation of beta amyloid plaque in the brain is one of the defining pathophysiological features of Alzheimer's disease. Pharmacodynamic effects 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. Clinical efficacy and safety The safety and efficacy of donanemab were evaluated in a Phase III (TRAILBLAZER‑ALZ 2) and a Phase II (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 III study confirmed the efficacy and safety results observed in the Phase II Study. For the safety analysis, patients were followed for up to 76 weeks or last dose plus 57 days. A small proportion (9.7 %) of patients with history of transient ischemic attacks, stroke or seizures were included in placebo-controlled clinical trials. Although the type and frequency of adverse events were overall comparable to the general study population, there was a slight increased frequency of falls (21% vs 13%) in this subgroup treated with donanemab. However, due to the small number of patients in this subgroup, the association of falls with the use of donanemab cannot be established. Phase III Study TRAILBLAZER-ALZ 2 In this study, 1736 patients, of which 1447 were in the indicated population, were randomized 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 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 who had any contraindications for MRI or PET, 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. Of the total number of patients randomized, 29 % (510/1736) were ApoE ε4 non-carriers, 54 % (930/1736) were heterozygotes, and 17 % (289/1736) were homozygotes. At baseline, 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. 61.0 % of patients were on either AChEI or memantine use. The demographics of patients were similar regardless of ApoE ε4 genotype. Mean (SD) of amyloid Centiloids at baseline were 102.5 (34.5). 68.2 % and 31.8 % were in the low-medium and high tau categories, respectively. A total of 24.7 % of patients discontinued treatment in the study. Of those, 29.3 % were patients in the donanemab arm and 20.1 % of patients in the placebo arm. There were two primary analysis populations based on tau PET imaging at screening with flortaucipir: 1) combined population (low‑medium plus high tau level population), and 2) low‑medium tau level population. Early symptomatic patients with AD with no or very low tau pathology were excluded from the randomized placebo-controlled portion of the study. 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‑Cog 13 ) 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‑Cog 13 , ADCS‑iADL. Treatment with donanemab statistically significantly slowed clinical decline compared to placebo at week 76, with consistency across measures of cognition and function (Figure 1 and Tables 4 and 5). Treatment effect in subgroups (age, BMI, gender, race, APOE ε4 carrier status, disease severity [MCI or mild dementia due to AD], tau terciles and concomitant symptomatic treatment) was consistent with the results in the combined study population. Figure 1: iADRS Mean change from baseline in the indicated population and the indicated population focused on low-medium tau through 76 weeks in Study TRAILBLAZER-ALZ 2. Table 4: Clinical outcomes of donanemab study TRAILBLAZER‑ALZ 2 at week 76 in the indicated population and the studied combined population Indicated Population Combined Tau Population* Clinical endpoints Donanemab (N = 717) Placebo (N = 730) Donanemab (N = 860) Placebo (N = 876) iADRS a Mean baseline 104.66 103.83 104.55 103.82 Change from baseline -10.21 -13.59 -10.19 -13.11 Difference from placebo (95 % CI) p-value 3.38 (1.83, 4.92) p < 0.0001 - 2.92 (1.51, 4.33) p < 0.0001 - CDR-SB b Mean baseline 3.96 3.94 3.92 3.89 Change from baseline 1.67 2.43 1.72 2.42 Difference from placebo (95 % CI) p‑value -0.77 (-1.04, -0.49) p < 0.0001 - -0.70 (-0.95, -0.45) p < 0.0001 - ADAS-Cog 13 a Mean baseline 28.43 29.00 28.53 29.16 Change from baseline 5.37 7.06 5.46 6.79 Difference from placebo (95 % CI) p-value -1.69 (-2.52, -0.86) p < 0.0001 - -1.33 (-2.09, -0.57) p = 0.0006 - ADCS-iADL a Mean baseline 48.02 47.84 47.96 47.98 Change from baseline -4.55 -6.31 -4.42 -6.13 Difference from placebo (95 % CI) p‑value 1.76 (0.81, 2.72) p = 0.0003 - 1.70 (0.84, 2.57) p = 0.0001 - Abbreviations: ADAS‑Cog 13 = 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; CI = confidence interval; iADRS = integrated Alzheimer's Disease Rating Scale; NCS2 = natural cubic spline with 2 degrees of freedom; MMRM = mixed model for repeated measures. a Assessed using NCS2 analysis. b Assessed using MMRM analysis. * Statistically significant with adjustment for multiplicity in the graphical testing scheme Table 5: Clinical outcomes of donanemab study TRAILBLAZER‑ALZ 2 at week 76 in the indicated population focused on low-medium tau and in the low-medium tau population Indicated Population Focused on Low-medium Tau Low-medium Tau Population* Clinical endpoints Donanemab (N = 498) Placebo (N = 494) Donanemab (N = 588) Placebo (N = 594) iADRS a Mean baseline 105.90 105.94 105.92 105.95 Change from baseline -6.24 -9.88 -6.02 -9.27 Difference from placebo (95 % CI) p-value 3.64 (2.11, 5.18) p < 0.0001 3.25 (1.88, 4.62) p < 0.0001 CDR-SB b Mean baseline 3.78 3.68 3.72 3.64 Change from baseline 1.19 1.97 1.20 1.88 Difference from placebo (95 % CI) p‑value -0.78 (-1.09, -0.47) p < 0.0001 - -0.67 (-0.95, -0.40) p < 0.0001 - ADAS-Cog 13 a Mean baseline 27.36 27.52 27.41 27.60 Change from baseline 3.22 4.98 3.17 4.69 Difference from placebo (95 % CI) p-value -1.76 (-2.58, -0.95) p < 0.0001 - -1.52 (-2.25, -0.79) p < 0.0001 - ADCS-iADL a Mean baseline 48.12 48.47 48.20 48.56 Change from baseline -2.96 -4.91 -2.76 -4.59 Difference from placebo (95 % CI) p‑value 1.96 (0.92, 2.99) p = 0.0002 - 1.83 (0.91, 2.75) p < 0.0001 - Abbreviations: ADAS‑Cog 13 = 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; CI = confidence interval; iADRS = integrated Alzheimer's Disease Rating Scale; NCS2 = natural cubic spline with 2 degrees of freedom; MMRM = mixed model for repeated measures. a Assessed using NCS2 analysis. b Assessed using MMRM analysis. * Statistically significant with adjustment for multiplicity in the graphical testing scheme For the primary endpoint in the combined and low-medium tau populations, additional analyses using conservative methods for the handling of missing data also favoured donanemab. The difference in mean change from placebo in the iADRS score in the combined population was 1.75 (95 % CI, 0.38 to 3.13) and in the low-medium tau population was 2.22 (95 % CI, 0.87 to 3.57). An increase in brain volume loss relative to placebo was observed with amyloid-targeting antibodies, including donanemab. The clinical relevance of this observation is currently unclear, given the results on clinical and other biomarker endpoints in Study TRAILBLAZER-ALZ 2. Biomarkers The percentage of donanemab treated patients in the indicated population and indicated population focused on low-medium tau 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 2. Amyloid plaque reduction from baseline in donanemab treated patients, as assessed by amyloid PET, in the indicated population (LS mean change ± SE) was 65.1 ± 0.9 CL at 24 weeks, 86.3 ± 1.0 CL at 52 weeks, and 90.4 ± 1.0 CL at 76 weeks. A reduction in plasma P‑tau217 (log10) was observed with donanemab compared to placebo. In the combined population, 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). Consistent with this, in the low‑medium tau population, 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 the indicated population, LS mean change difference ± SE was ‑ 0.17 ± 0.011 and ‑ 0.23 ± 0.013 at Weeks 24 and 76, respectively, compared to placebo (p < 0.0001 at both time points). In the indicated population focused on low‑medium tau LS mean change difference ± SE was ‑ 0.19 ± 0.012 and ‑ 0.26 ± 0.015 at Weeks 24 and 76, respectively, compared to placebo (p < 0.0001 at both time points). Figure 2: Percentage of donanemab treated patients in the indicated population and the indicated population focused on low‑medium tau achieving amyloid plaque clearance as monitored by amyloid PET over 76 weeks in study TRAILBLAZER‑ALZ 2 High tau population In the high-tau population (271 patients on donanemab and 281 patients on placebo), donanemab slowed clinical decline by 1.26 points on average (95 % CI: -1.77 to 4.28, p = 0.415) on iADRS, and - 0.69 points (95 % CI: -1.19 to -0.20, p = 0.006) on CDR‑SB, at Week 76 compared with placebo. In the indicated population focused on high tau (218 patients on donanemab and 235 patients on placebo), donanemab slowed clinical decline by 1.55 points (95 % CI: -1.71 to 4.80, p = 0.351) on iADRS, and - 0.60 points (95 % CI: -1.14 to -0.05, p = 0.032) on CDR‑SB, at Week 76 compared with placebo. This study was powered to demonstrate clinical efficacy in the low-medium and combined populations. The high tau population results are derived from post-hoc analyses. Phase III, direct comparative study (TRAILBLAZER‑ALZ 4) TRAILBLAZER‑ALZ 4 was a multicentre, randomised, open-label, active-comparator Phase III study investigating donanemab vs aducanumab in 148 patients with early symptomatic Alzheimer's disease. The participants were required to have evidence of amyloid beta pathology including confirmation of amyloid burden on an amyloid PET scan. Baseline flortaucipir F18 PET scan was collected but there was no tau restriction at entry. Donanemab was superior to aducanumab on the co‑primary study objectives: Percentage of patients who reached amyloid plaque clearance (less than 24.1 Centiloids) on florbetapir F18 PET scan at 6 months (donanemab 37.9 % vs aducanumab 1.6 %; p < 0.001) and percentage of patients who reached amyloid plaque clearance (less than 24.1 Centiloids) on florbetapir F18 PET scan in the low‑medium tau subpopulation at 6 months (donanemab 38.5 % vs aducanumab 3.8 %; p = 0.008). Comparable reduction in P‑Tau217 and amyloid as measured by PET was observed regardless of baseline tau presence. Paediatric population The licensing authority has waived the obligation to submit the results of studies with donanemab in all subsets of the paediatric population in the treatment of Alzheimer's disease (see section 4.2 for information on paediatric use).