The UK Pharmaceutical Authority approved Alzheimer’s drug Kisunla (donanemab) last week for some patients. This follows the US Food and Drug Administration granting it marketing authorization in July this year. However, in the UK, Kisunla is likely to face significant reimbursement issues after cost-effectiveness watchdog the National Institute for Health and Care Excellence said the drug “cannot currently be considered good value for money for the taxpayer”.

For NICE to authorize a medical technology for population-wide reimbursement across the National Health Service, the product must provide benefits to patients that justify the higher price paid above and beyond standard care existing. In other words, it must represent a cost-effective use of NHS resources and taxpayers’ money. In the case of Kisunla, the cost-effectiveness estimate calculated by NICE was five to six times higher than the threshold usually used by the agency. Products calculated to have such high additional costs relative to their benefits are generally not reimbursed.

NICE will publish its final recommendation on Kisunla once the consultation period concludes later this month, after which the independent committee will consider all responses and further analysis at a second meeting. The product’s manufacturer, Eli Lilly, and the NHS have been asked to provide more information to address “areas of uncertainty” in the currently available evidence.

Donanemab works by removing a sticky protein, beta-amyloid plaque, from the brain. Such plaque buildup is believed to be a cause of Alzheimer’s disease. Tau plaque is also thought to contribute to Alzheimer’s disease. And in a phase 3 trial, Kisunla was found to be effective at clearing both beta-amyloid and tau plaque in the brain.

Among 1,700 trial participants with early symptoms of Alzheimer’s disease and amyloid and tau pathology, donanemab slowed rates of cognitive and functional decline. Specifically, 47% of those who received the drug, compared to 29% who received a placebo, showed no signs of cognitive decline after a year of treatment.

We watched a similar narrative unfold last summer when Leqembi (lecanemab) was approved by the UK regulator in August, but NICE objected to reimbursement for the drug soon after. Leqembi has fairly comparable safety and effectiveness numbers. Its dosage schedule is different, however, since it is an infusion once every two weeks instead of four, as is the case with Kisunla. At the time, the Telegraph quoted from a NICE spokesperson who said that “the costs of providing the treatment, including fortnightly infusions in hospital and intensive monitoring for side effects, combined with the relatively small benefits it provides to patients , mean that it cannot be considered good value for the taxpayer. Lecanemab slows the rate of progression of mild to moderate Alzheimer’s disease for an average of four to six months, but this is simply not enough benefit to justify the additional cost to the NHS.

US Insurance Coverage of Leqembi and Kisunla

NICE assessments reveal that so far, monoclonal antibodies against amyloid beta have shown limited profitability. This can pose a problem of direct access, particularly in countries with a single payer or a health system in which a (quasi) governmental authority makes reimbursement decisions on behalf of multiple insurers.

The American situation is completely different. There is no single payer or NICE that informs the decisions of a single government insurer. Typically, payers in public markets, such as Medicare and Medicaid, as well as insurers in the commercial sector each make coverage decisions.

Nevertheless, in the case of biologics targeting Alzheimer’s disease in early-stage patients, such as first-in-class Aduhelm (aducanumab) and later Leqembi and Kisunla, Medicare – the leading payer for Alzheimer’s-related medical technologies Alzheimer’s disease – decided to take the unusual step of conducting a national coverage determination. It is not known exactly what triggered the NCD, but the history Aduhelm’s controversial path to regulatory approval likely played a role. Additionally, clinical trial data suggest a high degree of uncertainty regarding safety and effectiveness. And with millions of Medicare beneficiaries potentially eligible for treatment, cost may also have factored into the decision to pursue an NCD. The original annual price of the now moribund Aduhelm was $56,000 (later halved to $28,000); Leqembi’s list price per year is $26,500; and a 12-month Kisunla course in the USA can cost around $32,000.

In April 2022, the Centers for Medicare and Medicaid Services issued a CRS that severely limited access to all of these products unless they received regular, rather than expedited, FDA approval and are considered to provide at least some clinically meaningful benefit.

Almost immediately after the FDA’s regular approval of Leqembi, CMS announced that it would cover most patients eligible for treatment. This includes people with mild cognitive impairment or mild dementia and confirmed amyloid plaques.

CMS requires Medicare beneficiaries who take Leqembi and Kisunla to enroll in a patient registry to collect more drug data. The patient registration requirement is also a prerequisite for reimbursement.

Although Leqembi’s sales have increased this year, they remain well below initial expectations. Perhaps, in some way, this reflects the value perceived by patients and doctors.

In the United States, there is a lack of consensus among neurologists on the advisability of recommending monoclonal antibodies against beta-amyloid to their patients such as Kisunla and Leqembi. Some question whether the extent to which the drug slows cognitive deterioration is clinically meaningful for patients.

There are also lingering safety concerns, which were highlighted when the FDA initially refusal of approval of donanemab. The agency questioned the long-term safety of the drug, noting a relatively higher treatment discontinuation rate due to adverse events such as amyloid-related imaging abnormalities, ARIA, which can lead to brain hemorrhage and swelling in people taking Kisunla compared to placebo.

Notably, the labeled indication in the United Kingdom is “mild cognitive impairment and mild dementia related to Alzheimer’s disease in patients who have only one copy of the apolipoprotein E ε4 allele or who don’t wear it at all. » This is more restricted than the label granted in the United States. The FDA recommended test ApoE ε4 status before starting treatment to inform about the risk of developing ARIA. Elie Lilly announcement This week, in a phase 3 trial, an adjusted dosing regimen successfully reduced the risk of brain swelling.

Leqembi also triggered ARIA characterized by edema in approximately 12% of clinical trial participants. Most cases were asymptomatic, but occasional serious reactions have occurred, including three deaths due to bleeding and swelling of the brain. Two deaths possibly linked to the use of lecanemab were reported since regulatory approval of the drug.

Overall, in light of the issues reported in the United States and United Kingdom regarding safety, effectiveness, and cost-effectiveness, adoption issues will likely persist for anti-amyloid plaque treatments indicated for patients with early-stage Alzheimer’s disease.