Access To The New Alzheimer's Drugs: Why HTA Bodies Are Saying No

Alzheimer's disease (AD) has long been an area of unmet medical need, with few therapeutic options capable of altering the course of the disease. Recently, two disease-modifying treatments, LEQEMBI (lecanemab) and KISUNLA (donanemab), have emerged as potential breakthroughs. However, despite their regulatory approvals, these treatments are facing significant hurdles in achieving positive health technology assessment (HTA) outcomes. This article will examine the current HTA landscape for LEQEMBI and KISUNLA, analyse the reasons behind their unfavourable evaluations, and explore the implications for future assessments in key European markets.

Generating data to prove disease modifying effectiveness in AD is very difficult. This is because AD is a slow, degenerative disease, with pathophysiological causes that are thought to act many years before symptoms arise. AD is characterised by patient heterogeneity and impacts patients and their caregivers in many different ways. This results in long duration clinical studies with large numbers of patients, so that small, gradual differences against standard of care can be measured. This all adds up to very high costs and risks for the drug developer, and delays for patients urgently needing care. 

Whilst it may sound surprising that so much effort should be invested to detect small changes, we have to remember that the cumulative effect of delaying disease progression over the rest of the patient’s life could be substantial. This prompts the idea of whether our traditional approaches to determine pricing and reimbursement work well for these types of therapies, and whether an alternative approach would be better for all parties.

Quick Overview of LEQEMBI and KISUNLA

• Both drugs are indicated for Mild Cognitive Impairment due to AD and Mild AD 
• Both appear to slow cognitive decline by approximately 25-30% over 18 months
• Both are administered by intravenous infusions (KISUNLA every 4 weeks, LEQEMBI every 2 weeks)
• Both require confirmation of the presence of amyloid beta pathology prior to initiating treatment, and require monitoring for the risk of Amyloid Related Imaging Abnormalities (ARIA) with MRI
• Testing for ApoE ε4 status should be performed prior to initiation of treatment; some jurisdictions (e.g., England, Scotland) limit the drugs to ApoE ε4 non-carriers or heterozygotes (not permitted for homozygotes) [2, ,3, 4]

Current HTA Status for LEQEMBI and KISUNLA 

Both LEQEMBI and KISUNLA have undergone assessments by several HTA bodies with the outcomes tending towards limited access or negative decisions. We note however that this is an evolving picture as some assessments have yet to reach their final decisions (e.g., NICE). 

Table 1: HTA Status of LEQEMBI and KISUNLA 

Key Reasons for Unfavourable HTA Outcomes 

In drafting this article I reviewed the HTA reports from the ICER, NICE and SMC [2,3,4,5] and across each of these a number of consistent issues emerge: 

1. Modest Clinical Improvement and poor cost-effectiveness

The observed cognitive improvements, whilst statistically significant, have been viewed as marginally clinically significant. Physicians and patients feeding into the HTAs have expressed differing views on whether the improvement in cognition is meaningful or not. As a result, HTA bodies have generally concluded that these therapies do indeed improve cognition, but it is only a modest improvement. This result is problematic when we then consider the cost effectiveness of these treatments as the price of these drugs is high. This pushes the incremental cost effectiveness ratios (or other measures of cost effectiveness) above acceptable limits, resulting in decisions not to reimburse the drug (NICE, SMC) or recommending access restrictions (ICER).

2. Uncertainty in Long-Term Clinical Benefit 

While both drugs demonstrated a modest reduction in cognitive decline over 18 months, HTA bodies like NICE and ICER raised concerns about the durability of these benefits. With limited data on outcomes beyond this period, the true long-term impact remains unclear. To illustrate this, whilst the primary end points of the pivotal trials have been measured at 18 months, the economic modelling considered a time span of 30 years, meaning the estimated long-term benefit is subject to many assumptions. To address this the drug manufacturers have had to rely on good quality evidence from other sources on the natural history of the disease e.g., real world data tracking the evolution of the disease. 

3. Concerns About Safety: ARIA Risks 

 ARIA, which includes brain swelling and microhemorrhages, were a notable concern, occurring in approximately 10-30% of all trial subjects depending on the product. Serious ARIA events and symptomatic events occurred in 1-3% of the trial population. While manageable with careful monitoring, this added risk raised concerns about patient safety and potential healthcare system burden, notably additional MRI scanning costs. 

4. Uncertainty in Economic Models 

Assessment of the economic models for both drugs have shown significant uncertainty, particularly around: 

• Disease progression assumptions e.g., transitions between health states
• The durability of cognitive benefits post-treatment and assumptions around stopping criteria
• Whether all the costs properly reflect the expected provision of care as per current practice in the health system e.g., infusion costs
• The cost implications of frequent monitoring requirements
• This highlights the importance of rigorous economic modelling and high-quality input data to estimate cost effectiveness and budget impacts 

Implications for Future HTA Decisions: France and Germany 

Given the luke-warm / negative evaluations we have seen so far, we can speculate how these drugs may fare in other jurisdictions:

France (HAS) and Germany (G-BA) Outlook 

• Clinical improvement likely to be deemed limited: Like NICE, HAS and G-BA are expected to conclude that LEQEMBI and KISUNLA provide only modest clinical improvement 
• ARIA will be scrutinized: As with previous HTA assessments, concerns about the risks of ARIA and the additional burden of monitoring will play an important role

These issues along with the other issues raised above mean:

• France: an actual clinical benefit rating of mild (SMR 3) is likely to be the upper end of what is achievable, with an additional clinical benefit rating of minor (ASMR IV)
• Germany: a minor clinical benefit is likely to be the upper end of what is achievable

This being said, there are down-side risks to this outlook as the HTA bodies may question: 

Were the appropriate comparators used? In the trials some subjects with mild cognitive impairment were on symptomatic treatments typically used for Alzheimer’s disease, which is not standard of care in some European countries

Is there bias in the trial results? All the HTA reports reviewed highlighted the potential for unblinding in the trial due to high rates of ARIA in the active treatment arm. This is because the adverse events may have alerted patients receiving the active treatment to suppose they were not receiving placebo, thereby affecting the results. Should the HTA bodies conclude there was significant bias, they may downgrade the quality of the evidence in their final decision 

Does the trial population match the local population in which the HTA is being considered? This was raised for example in the NICE assessment where discrepancies between median ages of the trial subjects and the population in England may lead to difficulty in extrapolating the trial results

To handle these concerns, the health technology developers presented sensitivity analyses to sense check the results. Whether these will be sufficient for HAS and G-BA remains to be seen.

For the drug developers, the consequence of these outcomes might be the difficulty in securing their desired price. With the price benchmark currently set at generic AChIs and memantine, drug developers will need to provide a compelling value story stressing the long-term disease modification differentiators.

Key Challenges and Considerations for Drug Developers 

For pharmaceutical companies aiming to improve outcomes in future HTA assessments, several critical issues should be addressed: 

Is the standard HTA/reimbursement model fit for purpose? 

Given the challenges we have considered around the slow, long term nature of the disease, and the limited possibility to detect very large changes in cognition in the early stages, it could be argued that the traditional HTA model is not well suited for this type of therapy. Current frameworks often emphasise short-term clinical improvements, potentially underestimating the cumulative impact of slower disease progression. Alternative assessment and reimbursement models that share risk around the longer-term outcomes are in my view more appropriate. It is curious to see that NICE has provisionally ruled out managed access agreements that could have facilitated this, as it doesn’t believe sufficient evidence could be addressed within the timeframe of the agreement to address these issues. I understand NICE’s concerns but would encourage them to be more ambitious in assessing the options.

Strengthening evidence generation 

Drug developers should prioritise: 

• Robust long-term data collection to demonstrate sustained clinical benefit. A commitment to demonstrating continued cognitive stability or delayed progression would significantly strengthen future HTA submissions and also support patients and their caregivers
• Broader population inclusion in clinical trials to ensure real-world applicability. Several HTA bodies raised concerns about trial populations lacking diversity, particularly individuals from ethnic minorities, those with Down's syndrome, and those with earlier-onset AD. Ensuring trial populations reflect the real-world patient demographic is crucial for acceptance.
• Better evidence linking amyloid reduction to meaningful cognitive outcomes. This was raised in several HTA reports, for example ICER says: “We remain uncertain whether amyloid removal is an appropriate surrogate marker for cognitive benefit and instead look to the clinical outcomes found in randomized trials”. Stronger evidence may help build confidence in economic modelling on the duration of clinical benefits.  

Conclusion 

The emergence of LEQEMBI and KISUNLA as the first disease-modifying Alzheimer's treatments represents an important scientific milestone. However, achieving positive HTA outcomes and widespread reimbursement is proving to be extremely challenging. For drug developers, aligning clinical development strategies with HTA expectations, emphasising robust long-term data, cost-effectiveness, evidence for sustained impact, and exploring risk sharing reimbursement approaches will be essential to improving future outcomes. 

Contact

If you are interested in discussing any of the issues above, please contact me through my email address dniven@nivenbiopharma.com. Feel free to also visit my website at www.nivenbiopharma.com for more information.

Sources

1. FDA Labels for KISUNLA and LEQEMBI
2. Lecanemab for Early Alzheimer’s Disease, ICER, Final Evidence Report, April 2023
3. Draft Guidance Consultation: Lecanemab for treating Mild Cognitive Impairment or Mild dementia caused by Alzheimer’s Disease , NICE, March 2025
4. Draft Guidance Consultation: Donanemab for treating Mild Cognitive Impairment or Mild dementia caused by Alzheimer’s Disease , NICE, March 2025
5. Lecanemab solution for infusion (LEQEMBI), SMC, Jan 2025