The recent Medicines and Healthcare products Regulatory Agency (MHRA) approval of the Alzheimer’s disease-modifying therapies (DMT) lecanemab and donanemab has attracted significant media attention, with headlines such as “New drug gives hope and time to Alzheimer’s patients”.
Unlike symptomatic treatments, which primarily provide temporary relief of cognitive or behavioural symptoms without addressing the root cause of the disease, DMTs aim to alter the underlying pathophysiology of Alzheimer’s disease, with the goal of slowing or halting disease progression and preserving cognitive and functional abilities over time. However, despite the excitement, both lecanemab and donanemab have encountered challenges at the health technology assessment (HTA) stage, ultimately limiting patient access in the UK.
A key barrier we have identified is the absence of consensus on what constitutes a clinically meaningful treatment effect or the measurable and significant slowing of cognitive and functional decline.
Why is Clinical Meaningfulness Hard to Measure in Early Alzheimer’s Disease Anchors and thresholds
A minimal clinically important difference (MCID) in dementia is derived by linking a numerical change in a cognitive or functional assessment to an external anchor, such as clinician judgement, patient self-report or caregiver observation. These assessments are designed to measure core aspects of brain function affected by Alzheimer’s disease, including memory, attention, language, and the ability to carry out everyday activities. As the disease progresses, people tend to score progressively worse on these assessments. MCID determination attempts to find the smallest amount of decline on these tests that would be considered meaningful, with clinician judgement, patient self-report, and caregiver observation representing the most important anchors in the context of mild cognitive impairment.
A recent review showed that when all three anchors agreed that a change was meaningful, the MCID on the Clinical Dementia Rating Sum of Boxes (CDR‑SB) was estimated at 1.29 points (SD 1.98). In contrast, when there was disagreement between anchors, the estimated MCID dropped to 0.37 points (SD 1.38), nearly a four-fold difference in threshold size.1 The lack of a standardised reference perspective means that identical trial results can be judged either clinically meaningful or not, depending on which anchor is applied.
Disagreement between anchors also widens the confidence intervals around MCID estimates, further eroding certainty when trying to interpret small treatment effects in early Alzheimer’s disease.1 Until a consensus emerges on which anchor, or combination of anchors should guide MCID estimation, every future DMT in Alzheimer’s disease will carry this inherent ambiguity in the interpretation of their clinical value, especially when treatment effects fall in the modest but statistically significant range.
Outcome Measures Sensitivity
Most pivotal trials still rely on legacy cognitive and functional assessments, originally developed for use in moderate to severe stages of dementia, such as the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog), the Mini-Mental State Examination (MMSE), and the Clinical Dementia Rating – Sum of Boxes (CDR-SB). In early disease, many participants score close to the maximum; several items plateau, producing a ceiling effect, leaving little room to detect improvement or subtle slowing of decline.
This issue is further compounded as modest treatment effects in early Alzheimer’s disease are somewhat inevitable. Disease-modifying antibodies aim to slow cognitive decline, not restore lost ability. In the context of gradual, variable symptom onset, this is a subtle signal to detect. Attempting to detect these changes with instruments built for late-stage dementia is like searching for a needle in a haystack using an industrial-sized digger.
Composite measures such as the Alzheimer Disease Composite Score (ADCOMS) and the integrated Alzheimer Disease Rating Scale (iADRS) are able to capture change in the early stages of disease more efficiently. They focus on the most responsive test items in MCI, removing noise from less sensitive questions. This targeted design translates into significantly greater statistical power. For example, in modelling studies, ADCOMS would have required four hundred patients per arm to detect a twenty-five per cent slowing of decline, compared with more than two thousand ADAS-Cog2. However, their relative novelty and limited use in routine memory clinics introduce additional uncertainty for HTA bodies, making it more difficult to interpret trial outcomes and assess how changes on these scales translate into real-world clinical benefit.
Trial Duration
The CLARITY-AD (lecanemab) and TRAILBLAZER-ALZ 2 (donanemab) trials were pivotal Phase III placebo-controlled studies in early Alzheimer’s disease, each running for 18 months and provided the core clinical evidence reviewed by NICE. Both trials demonstrated statistically significant but modest improvements on CDR-SB translating into roughly a 4- to 6-month delay in clinical progression. In practical terms, this means people remained able to manage everyday tasks, socialise and live independently for almost half a year longer before needing additional support.3,4 The Royal College of Psychiatrists welcomed this added time in the lecanemab NICE appraisal describing it as “hugely important” for patients and families, while patient-advocacy representatives told NICE that even a 4-month delay is clinically meaningful because it preserves quality time with loved ones.3 Despite this, the committee questioned whether these modest deltas would persist long enough to justify long-term treatment.3,4 Disease progression in Alzheimer’s disease typically unfolds over decades, and stakeholders are largely unconvinced that an 18-month duration of treatment can predict if improvements in the slowing of cognitive decline will persist in the long term. To address this concern, multinational registries are now enrolling treated patients for at least five years to capture real-world durability and safety. Such longitudinal evidence will be critical if these products are reappraised by HTA bodies in the future.
Path Towards Consensus
Uncertainty around clinical evidence and endpoint selection is not unique to Alzheimer’s disease. Disagreement over what constitutes an MCID in Alzheimer’s disease will likely persist until stakeholders agree on common anchors, adopt more sensitive composite endpoints and observe treated patients beyond the current 18-month horizon. Until that consensus is reached, uncertainty around clinical benefit will remain a fundamental barrier to timely and equitable patient access in Alzheimer’s disease.
Remap Consulting can help navigate this uncertainty through a range of service offerings, including:
- Facilitating Delphi panels to build expert consensus on clinically meaningful endpoints
- Guiding endpoint selection using the PICOS framework (Population, Intervention, Comparator, Outcomes, and Study design)
- Designing sustainable market access strategies, including pricing and risk-sharing agreements tailored to specific healthcare systems and validated by our network of experts
If you are planning an Alzheimer’s disease trial or preparing for launch, speak to Remap Consulting about how we can help overcome the key barriers to patient access in this space.
Get in touch with our team to explore how we can help you strengthen your evidence strategy, access planning, and value demonstration.
References:
- Stojanovic M, Mikula C, John S, Kiselica A. Clinical importance in Alzheimer’s disease: effects of anchor agreement and disease severity. Aging Clin Exp Res. Jan 24 2024;36(1):5. doi:10.1007/s40520-023-02643-0
- Wang J, Logovinsky V, Hendrix SB, et al. ADCOMS: a composite clinical outcome for prodromal Alzheimer’s disease trials. Journal of Neurology, Neurosurgery & Psychiatry. 2016;87(9):993-999. doi:10.1136/jnnp-2015-312383
- Lecanemab for treating mild cognitive impairment or mild dementia caused by Alzheimer’s disease [ID4043] (2024).
- National Institute for Health and Care Excellence (NICE). Donanemab for treating mild cognitive impairment or mild dementia caused by Alzheimer’s disease [ID6222]. 2024;