Anti-Amyloid Drugs in Alzheimer’s: Breakthrough, Dead End, or Reimbursement Reality Check?
Several HTA and reimbursement bodies have recently taken negative views on these drugs, including NICE in England, HAS in France, G-BA in Germany and ZIN in the Netherlands. Perhaps most strikingly, a recent Cochrane review published this month, concluded that anti-amyloid monoclonal antibodies provide little or no clinically meaningful benefit in patients with mild cognitive impairment or mild dementia due to AD, while increasing the risk of amyloid-related imaging abnormalities (ARIA). Cochrane reviews are usually regarded as highly influential evidence syntheses. Therefore, this sends a powerful signal to clinicians, payers, investors and drug developers on the value of these drugs.
This article considers what to make of these recent developments, and whether we are seeing the end of the road for anti-amyloid drugs, or rather a reimbursement reality check for the first wave of disease-modifying AD therapies.
What Did the Cochrane Review Find?
The Cochrane review assessed 17 placebo-controlled phase III randomised trials of anti-amyloid monoclonal antibodies in mild cognitive impairment or mild dementia due to AD. The review included seven different antibodies, including older discontinued drugs as well as the more recent approved drugs lecanemab and donanemab.
The main findings were sobering. At 18 months, the pooled treatment effect on cognitive function, as measured by the ADAS-Cog scale, was 0.85 points. This is to be interpreted considering the authors’ view that the minimal clinically important difference (MCID) is generally considered to be 2–3 points in MCI and around 4 points in dementia. For dementia severity, as measured by the CDR-SB, the pooled effect translated to a reduction of 0.29 points, compared with MCID estimates of around 1 point in MCI and 2 points in dementia. Functional effects were also small, and the review found increased ARIA risk. [1]
However, the response from the field has been divided. Some experts broadly support the conclusion that the benefits seen so far are too small to justify the risks, costs and implementation burden. Others have criticised the review for pooling older failed drugs with newer agents that have different mechanisms, different amyloid targets and more positive clinical data. Several commentators have argued that this risks treating anti-amyloid drugs as a single uniform class, rather than a set of drugs that has seen progressive improvement through successive rounds of research and development. [2]
Current HTA and Reimbursement Direction
The Cochrane review has not emerged in isolation. It arrives at a time when European HTA bodies are already questioning whether lecanemab and donanemab offer sufficient value.
NICE: Clinical Benefit, But Not Value for Money
NICE’s latest draft guidance does not conclude that lecanemab and donanemab have no effect. Rather, NICE accepts that both drugs slow decline compared with placebo. The problem is that the benefit is considered relatively small, while the costs of delivery are high.
For lecanemab, NICE highlighted fortnightly infusions, intensive monitoring for side effects, uncertainty around long-term benefit and a committee-preferred ICER of approximately £81,000 per QALY. For donanemab, NICE similarly cited monthly infusions, monitoring requirements, uncertainty in long-term treatment effect and a committee-preferred ICER of approximately £69,000 per QALY.
In both cases, draft guidance currently under consultation, says that the drugs are not recommended for routine NHS use. [3, 4]
HAS: Early Access Refused
HAS in France refused early access (accès précoce) for both products. The main reasons were modest clinical effect, lack of robust quality-of-life evidence, concerns about ARIA, and uncertainty over whether amyloid reduction translates into clinically meaningful cognitive and functional benefit. For donanemab, HAS also highlighted the burden of frequent MRI monitoring, genotyping and substantial changes to the care pathway. Such issues raise reasonable doubts on whether these drugs will be reimbursed in France. [5, 6]
G-BA: No Additional Benefit Demonstrated
In Germany, G-BA did not deny that lecanemab and donanemab showed signals of slowing decline, but concluded that the evidence did not establish a patient-relevant additional benefit versus the appropriate comparator. For donanemab, any cognitive signal was not considered robust, no suitable quality-of-life data were available, and adverse-event discontinuations were worse. For lecanemab, G-BA similarly found no benefit-assessment-relevant differences across the major outcome categories, and evidence gaps remained around the appropriate comparator setting. [7, 8]
ZIN: Not Sufficiently Clinically Relevant
In the Netherlands, ZIN advised against reimbursing lecanemab. It concluded that lecanemab did not result in a clinically relevant improvement in cognitive functioning or daily functioning, that quality-of-life benefit was uncertain, and that serious adverse effects such as symptomatic ARIA occurred more frequently. [9]
Spain and Italy: Not good use of public funds (ES); unlikely to reimburse (IT)
The negative direction of travel is not limited to the countries above. In Spain, the Interministerial Commission on Medicine Prices (CIPM) has reportedly rejected public financing for lecanemab, at least for now, on grounds of “rationalisation of public spending”. Reports suggest an annual drug cost of around €24,000 per patient, while also suggesting there may still be room for negotiation with Eisai. [10]
In Italy, the picture is also negative but not yet final. Reports state that AIFA’s Scientific and Economic Commission had not admitted lecanemab and donanemab for reimbursement “for the time being”, although AIFA later clarified that the process was not definitively concluded and that intermediate negative decisions could still be reassessed. AIFA are understood to have concerns over also potential system-readiness, including inadequate dementia care networks, uneven access to specialist centres and staffing constraints. [11]
What Does This Emerging Picture Mean?
The immediate consequence is that manufacturers of anti-amyloid drugs are now on the defensive. Lilly and Eisai have achieved something scientifically important, but the burden of proof has shifted. It is no longer enough to show amyloid clearance or statistically significant slowing on cognitive scales. Developers now need stronger evidence that treatment produces outcomes that patients, caregivers, clinicians and payers recognise as meaningful. [12]
This includes better evidence on quality of life, daily functioning, caregiver burden, delay to institutionalisation, durability of benefit after stopping treatment, and the identification of patients most likely to respond. Without this, the argument for broad reimbursement will remain difficult.
A second point is that many of the objections are not purely clinical. HTA bodies are also raising concerns about affordability, infusion capacity, MRI monitoring, genetic testing, specialist workforce and the readiness of dementia care pathways. This means that some flexibility may be needed on all sides. Manufacturers may need to reconsider pricing and risk-sharing approaches, while health systems may need to consider whether new assessment models are needed for slow-progressing neurodegenerative diseases where benefits accumulate over time.
Third, the Cochrane review is likely to have an impact beyond reimbursement. Because Cochrane reviews are influential, the conclusion that anti-amyloid antibodies provide little or no clinically meaningful benefit will be difficult for guideline committees, prescribers and payers to ignore. Even where experts disagree with the pooling methodology, the review gives a clear and highly visible scientific rationale for caution.
This may also matter outside Europe. In the US, where coverage and pricing dynamics are different, the review could still influence payer scrutiny, prescribing behaviour and future coverage restrictions. It may also become a useful test case for how international price referencing or “most favoured nation” style policies could affect high-cost therapies where Europe is reluctant to pay. If European prices need to fall substantially to secure access, manufacturers may face difficult strategic choices about whether to accept lower prices, restrict launches, or rely disproportionately on the US market.
Finally, the impact on R&D is likely to be selective rather than absolute. The lesson is probably not that amyloid should be abandoned altogether. Rather, future investment may move towards more precise amyloid-targeting approaches, better biomarker-defined populations, earlier intervention, or combination strategies targeting amyloid alongside tau, neuroinflammation, vascular dysfunction or other disease mechanisms.
Conclusion
Lecanemab and donanemab remain important scientific milestones. They have shown that amyloid-targeting therapies can produce measurable effects in early Alzheimer’s disease. That should not be dismissed.
However, the Cochrane review and the recent negative HTA decisions together send a clear message: the evidence and value bar has moved. Anti-amyloid drugs must now prove not just that they clear amyloid or slow decline on clinical scales, but that they deliver meaningful, durable and affordable benefits in real-world health systems.
In summary, we have achieved a significant scientific breakthrough but one that is facing a major reimbursement and evidence reality check. Much work is needed on all sides on the next steps in tackling this disease.
Contact:
If you are interested in discussing any of the issues above for your company/drug development program, please contact me through my email address dniven@nivenbiopharma.com . Feel free to also visit my website at www.nivenbiopharma.com for more information. I have no conflicts of interest in the production of this article.
Sources:
[1] Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer’s disease (Review), Nonino et al, Cochrane Library, April 2026
[2] Expert reaction to Cochrane review of anti- amyloid monoclonal antibodies for Alzheimer’s Disease, SMC, April 2016
[3] Lecanemab for treating mild cognitive impairment or mild dementia caused by Alzheimer’s disease, NICE, March 2026
[4] Donanemab for treating mild cognitive impairment or mild dementia caused by Alzheimer's disease, NICE, March 2026
[5] Décision n° 2026.0050/DC/SEM du 12 mars 2026 du collège de la Haute Autorité de santé portant refus d’accès précoce de la spécialité KISUNLA (donanemab), HAS, March 2026
[6] Décision n° 2025.0204/DC/SEM du 4 septembre 2025 du collège de la Haute Autorité de santé portant refus d’accès précoce de la spécialité LEQEMBI (lécanémab), HAS, Sep 2025
[7] Zum Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie: Anlage XII – Nutzenbewertung von Arzneimitteln mit neuen Wirkstoffen nach § 35a des Fünften Buches Sozialgesetzbuch (SGB V) Lecanemab (frühe Alzheimer-Krankheit), G-BA, Febraury 2026
[8] zum Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie: Anlage XII – Nutzenbewertung von Arzneimitteln mit neuen Wirkstoffen nach § 35a des Fünften Buches Sozialgesetzbuch (SGB V) Donanemab (frühe Alzheimer-Krankheit), G-BA, April 2026
[9] Advies - niet vergoeden lecanemab (Leqembi ®) voor de behandeling van Alzheimer, ZIN, Feb 2026
[10] Sanidad rechaza financiar el primer fármaco contra el Alzheimer, El Nacional, April 2026
[11] Alzheimer precoce, dall’Agenzia del farmaco «alt» ai due primi anticorpi monoclonali anti-amiloide, Il Sole 24 Ore, March 2026
[12] Developers back Alzheimer’s drugs despite report suggesting lack of efficacy, Clinical Trials Arena, April 2026
