LILLY RECEIVES MHRA MARKETING AUTHORISATION IN GREAT BRITAIN FOR DONANEMAB (KISUNLA ®▼) FOR THE TREATMENT OF MILD COGNITIVE IMPAIRMENT AND MILD DEMENTIA DUE TO ALZHEIMER’S DISEASE IN ADULT PATIENTS WHO ARE APOLIPOPROTEIN E ε4 HETEROZYGOTES OR NON-CARRIERS

Marketing authorisation was based on results from the TRAILBLAZER-ALZ 2 18-month phase 3 trial, which showed donanemab significantly slowed cognitive and functional decline for amyloid-positive early symptomatic Alzheimer’s disease (mild cognitive impairment or mild dementia) patients, lowering their risk of disease progression

Donanemab is the only amyloid plaque-targeting therapy with evidence to support stopping therapy when amyloid plaques are removed 1^, [i]

Lilly will continue to work closely with the National Institute for Health and Care Excellence (NICE) during the consultation period ahead of a final reimbursement decision for use in the NHS

BASINGSTOKE, 23^rd October 2024 – Eli Lilly and Company Limited announced today that the Medicines and Healthcare products Regulatory Agency (MHRA) has granted marketing authorisation (MA) for donanemab; an injection for intravenous infusion every four weeks to treat mild cognitive impairment and mild dementia due to Alzheimer’s disease in adult patients who are apolipoprotein E ε4 (ApoE ε4) heterozygotes or non-carriers. Donanemab is the only amyloid plaque-targeting therapy with evidence to support stopping therapy when amyloid plaques are removed.

“After more than 35 years of commitment to scientific progress in Alzheimer’s disease, we’re delighted that donanemab has been authorised in Great Britain for eligible adults who need effective treatment options,” said Chris Stokes, President and General Manager of UK and Northern Europe at Lilly. “Donanemab is part of a new class of medication and has demonstrated meaningful results for people with mild cognitive impairment and mild dementia due to Alzheimer’s disease. Early diagnosis remains key to ensuring rapid and equitable access to new innovations, and we are proud to be working with relevant stakeholders to progress this.”

“I believe we can improve the standard of care for people living with Alzheimer’s disease. Despite years of medical research, until recently, there has been little progress in treatment options for this disease. The authorisation of donanemab for eligible adults is welcome news. The UK now needs to rapidly increase NHS capacity and expertise in diagnostics and treatment facilities to enhance the management of Alzheimer’s disease for the benefit of people today and tomorrow”, said Professor Cath Mummery, Consultant Neurologist at University College London Hospitals NHS Foundation Trust and Chair of the NIHR Dementia Translational Research Collaboration.

Also today, NICE has published draft guidance which does not currently recommend donanemab for reimbursement for use in the NHS. Lilly remains confident in the clinical and cost-effectiveness of donanemab and the value that it can bring to patients and to the NHS. Lilly will continue to work closely with NICE during the consultation period ahead of a final reimbursement decision for use in the NHS.

Currently, there are 982,000 people estimated to be living with dementia in the UK[ii], with 50-75% of cases attributable to Alzheimer’s disease.[iii] It is the leading cause of death^[iv] and an economic cost to society. The total cost of dementia on patients, families and the public sector is estimated to be £42 billion in 2024. Unpaid care is the largest component, with costs per person increasing threefold from mild to severe dementia.3

Amyloid is a protein produced naturally in the body that can clump together to create amyloid plaques. The excessive buildup of amyloid plaques in the brain may lead to memory and thinking issues associated with Alzheimer’s disease.[v] Donanemab can help the body remove the excessive buildup of amyloid plaques and slow the cognitive and functional decline that may diminish people’s ability to remember information, make meals, manage finances, and maintain independence.6

This authorisation is based on results from the TRAILBLAZER-ALZ 2 18-month phase 3 trial of 1,736 participants with early symptomatic Alzheimer’s disease. The data were published in the  Journal of the American Medical Association (JAMA).2 The randomised, double-blind, placebo-controlled study evaluated the safety and efficacy of donanemab. One of the treatment goals was to remove amyloid plaques to minimal levels consistent with a visually negative scan using amyloid positron emission tomography (PET). If participants were confirmed to have reached these levels, they were able to complete treatment with donanemab and switch to placebo for the remainder of the study.

Study participants were stratified by their level of the brain protein tau, a predictive biomarker for Alzheimer's disease progression. The primary analysis population (n=1182), for which the study was powered, was comprised of people with a low-medium level of tau and clinical symptoms of Alzheimer’s disease. In the indicated population within the License1, the primary trial endpoint (Integrated Alzheimer's Disease Rating Scale, or iADRS) was met. The change from baseline in iADRS at 76 weeks was -6.24 in the donanemab group and -9.88 in the placebo group, with a difference from placebo of 3.64 (95% CI: 2.11, 5.18; p < 0.0001). Consistent with the primary efficacy endpoint results, donanemab was associated with a statistically significant difference from placebo in an important key secondary endpoint (Clinical Dementia Rating-Sum of Boxes, or CDR-SB); the change from baseline at 76 weeks in CDR-SB was 1.19 in the donanemab group and 1.97 in the placebo group, with a difference from placebo of -0.78 (95% CI: -1.09, -0.47; p < 0.0001).

Additional prespecified secondary analyses for the indicated population1 of the low-medium tau population measured ability to perform activities of daily living at 18 months by the Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living Inventory (ADCS-iADL). The difference between the donanemab group and the placebo group in the change from baseline was 1.96 (95% CI: 0.92, 2.99; p = 0.0002) for the ADCS-iADL score.

The study also enrolled a smaller number of people with high levels of tau at baseline (n=552), representing a later stage of disease progression. Because these participants were predicted to progress more quickly and be less responsive to therapy, the target population for the study was the low-medium tau population. The high tau participants were combined with the low-medium tau population in an additional primary analysis of all participants enrolled (n=1736), which showed that treatment with donanemab significantly reduced amyloid plaque levels regardless of baseline pathological stage of disease. In this combined indicated population1 donanemab demonstrated meaningful positive results with iADRS and CDR-SB showing a difference from placebo of 3.38 (95% CI: 1.83, 4.92; p < 0.0001) and -0.77 (95% CI: -1.04, -0.49; p < 0.0001), respectively.  

Amyloid-related imaging abnormalities (ARIA) is observed with the amyloid plaque clearing antibody class of therapies and is most commonly observed as temporary swelling in an area or areas of the brain (ARIA-E) or as a form of bleeding (haemorrhage) (ARIA-H), in either case detected by MRI. The two placebo-controlled studies (TRAILBLAZER-ALZ, an 18-month phase 2 study of donanemab[vi] and TRAILBLAZER-ALZ 22) showed that the most frequently reported adverse reactions in the studied combined population were ARIA‑E (24.4 %), ARIA‑H (31.3 %) and headache (13.1 %). Of which, in the indicated population1, the most common adverse reactions were ARIA-E (20.8%), ARIA-H (26.7%) and headache (13.5%). ARIA is usually asymptomatic, although serious and life-threatening events can occur. The majority of ARIA cases were mild to moderate and resolved or stabilised with appropriate management. According to both studies, the incidence of serious ARIA in the indicated population1 was 1.3%. As people with two copies of the ApoE ε4 gene are at higher risk of ARIA, patients require genetic screening before being administered donanemab. 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 incidence of infusion-related reactions was similar regardless of ApoE ε4 carrier status.

[i] Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512-527. doi:10.1001/jama.2023.13239.

[ii] Carnall Farrar (2024). The Economic Impact of Dementia. Available from: https://www.carnallfarrar.com/wp-content/uploads/2024/05/Alz-report.pdf [Accessed September 2024]

[iii] National Institute for Health and Care Excellence (2023). Potential issues and challenges in evaluation of disease-modifying dementia treatments. Available from: https://www.nice.org.uk/Media/Default/About/what-we-do/HTA%20Lab/HTA-lab-dmdt.pdf [Accessed September 2024]

[iv] Office for National Statistics (2020). Leading causes of death, UK: 2001 to 2018. Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/causesofdeath/articles/leadingcausesofdeathuk/2001to2018#uk-leading-causes-of-death-for-all-ages [Accessed September 2024]

[v] Porsteinsson AP, Isaacson RS, Knox S, et al. Diagnosis of early Alzheimer's disease: clinical practice in 2021. J Prev Alzheimers Dis. 2021;8:371-386.

[vi]Mintun, MA, Lo, AC, Dugan Evans, C, et al. Donanemab in Early Alzheimer’s Disease. NEJM. 2021; 384(18): 1691-1704. doi:10.1056/NEJMoa2100708.