Lecanumab (LeqembiTM) FDA-approved for individuals with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease (AD) – collectively called early AD R. Scott Turner

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R. Scott Turner

A breakthrough, finally! Leqembi is the first disease-modifying treatment for individuals with MCI and mild AD with solid evidence of effectiveness. Thus, Leqembi (previously called BAN2401) was FDA-approved 6 January 2023 in the accelerated pathway – a mechanism allowing speedy approval of drugs based on surrogate endpoints that may predict clinical benefits. “Qembi” is (very) roughly translated from Japanese as “beautiful, healthy and elegant.” Aducanumab (Aduhelm^TM) is a similar anti-amyloid antibody FDA-approved June 2021 (also in the accelerated pathway) but its clinical effectiveness remains unclear. Thus, Medicare decided not to reimburse the costs of Aduhelm treatment outside of a new clinical trial (in progress).

While we recommend and prescribe the traditional oral drugs for dementia due to AD (since 1996) these treatments (donepezil, rivastigmine, galantamine, and memantine) improve cognitive symptoms but are not considered disease-modifying. Since these drugs have no benefit for individuals with MCI, Leqembi is the first treatment for individuals with MCI with clear evidence of effectiveness. In fact, Leqembi is the first effective new drug for MCI and AD since memantine was approved in 2003. This is not due to lack of trying, and we learned a great deal from studies that did not lead to new treatments.

Is Leqembi effective? 

On the same day the results were presented at an annual international conference, the findings were published (Lecanumab in early Alzheimer’s disease, 29 November 2022, New England Journal of Medicine, see nejm.org). The findings of a large phase 3 study of 1,795 participants with MCI or mild AD are clear – the rate of cognitive and functional decline is significantly slower in the treatment group compared to the placebo group. In other words, the cognitive and functional abilities of the placebo group declined as expected during the 18-month study, but the treated group declined the equivalent of ~ 5 months less. Biomarker outcomes were also favorable, especially clearance of amyloid plaques from the brain (as measured by PET scans at the beginning and end of the study). It should be emphasized however that Leqembi does not reverse cognitive decline – it only slows it down.

Is Leqembi safe?

There are possible side-effects of treatment with Leqembi. The most concerning are called ARIA-E and ARIA-H (amyloid related imaging abnormality-edema and amyloid related imaging abnormality-hemorrhage). In the phase 3 study, ARIA-E was found in 12.6% of the treated group and 1.7% of the placebo group. Most ARIA-E is asymptomatic and detected only by MRI monitoring; of those with symptomatic ARIA-E the frequent symptoms are headache and worsening confusion. ARIA-H (usually a new microhemorrhage) was found in 17% of the treated group and 9% of the placebo group; almost all ARIA-H is asymptomatic. Individuals on blood thinners have a higher risk of ARIA-H with Leqembi; in fact, ARIA-H may be fatal in these people.

Individuals who carry 1 or 2 ApoE4 genes (about two-thirds of the individuals in the published study) have a higher risk of ARIA-E and ARIA-H. Those who carry ApoE2 or ApoE3 genes have a lower risk. Another possible side effect of Leqembi is infusion-related reaction – temporary flu-like symptoms immediately post-infusion (found in 26% of the treated group and 7% of the placebo group). Interested and eligible individuals must decide for themselves whether the risk-benefit ratio is favorable after discussion with their healthcare providers.

What are the costs of Leqembi treatment?

Leqembi is given by intravenous infusion over one hour, every two weeks. In addition to the cost of Leqembi ($26,500/year), additional costs will include charges for amyloid PET imaging or spinal fluid analysis (to confirm amyloid accumulation), infusion center visits, clinic visits, and MRI scans (at baseline and before the 5^th, 7^th, and 14^th infusions) to monitor safety (looking for the potential development of ARIA-E and ARIA-H). Healthcare systems and payors – including Medicare – must decide if the cost-benefit ratio of Leqembi treatment is favorable. However, cost-benefit analyses usually favor treatment if nursing home admission can be delayed or prevented (for now, a theoretical benefit of Leqembi treatment).

What happens next? 

The manufacturer (Eisai, partnering with Biogen) has also applied for FDA-approval in the traditional pathway. Each anti-amyloid antibody is unique, and the studies differ in dosage, frequency, route of administration, etc.; thus, each anti-amyloid antibody should be evaluated by the FDA individually – not as a class. This was proven again by the failure of gantenerumab (another anti-amyloid antibody) to achieve significant clinical benefits for individuals with MCI/AD (presented at the same meeting in November). For now, Medicare considers Leqembi in the same category of drugs as Aduhelm – meaning reimbursement only in the setting of a new study. However, Medicare will review the just-published results with Leqembi and likely issue a decision regarding coverage in mid- to late-2023. 

Leqembi is also being investigated as a potential treatment to prevent the onset of MCI and mild AD in healthy older individuals at risk (as defined by amyloid accumulation in the brain). This study (AHEAD, clinicaltrials.gov # NCT04468659) is currently seeking volunteers aged 50-80, and seeks to enroll a diverse cohort similar to that of the greater US populace. For more information on the AHEAD study, see our website or contact us directly.

How does Leqembi approval impact other studies?

            The approval and eventual availability of Leqembi (with Medicare and other third-party coverage anticipated mid- to late-2023) will impact longitudinal studies (no treatment involved) and ongoing studies testing new therapeutic strategies. Leqembi is only approved for individuals with early AD; thus, normal healthy individuals and those beyond MCI or mild dementia will be ineligible. There will be many other restrictions to eligibility (similar to those employed in the published study). Evidence of amyloid accumulation in the brain (by PET or spinal fluid analysis) is a requirement for Leqembi treatment.

For studies enrolling healthy normal but at-risk individuals (AD prevention trials) Leqembi availability will impact only those participants who develop MCI or mild AD. For studies testing a different anti-amyloid antibody, the risks of treatment with two antibodies simultaneously are unknown but considered too high; participating individuals have the option of dropping out of a study to begin treatment with Leqembi (if eligible). Studies enrolling individuals with moderate to severe AD will not be affected. Investigators of each ongoing and planned study must now anticipate Leqembi availability in 2023 and adjust research protocols accordingly. Leqembi treatment may become the standard of care for those who are interested and eligible.

What other impact of Leqembi is expected?

Currently, screening for cognitive decline in older individuals is mostly neglected. With the availability of new effective treatments such as Leqembi, population-wide screening efforts must ramp up. Screening strategies include brief cognitive testing (3-5 minutes) performed annually at wellness visits or with any new memory complaint by a patient or their family member. Blood-based biomarkers of MCI and AD are improving rapidly and moving into the clinic as newly-available screening and diagnostic tests. With the availability of Leqembi, Medicare and other third-party payors must also cover the costs of essential screening and diagnostic tests.

Summary

            In the past there were no treatments for AD, and therefore little interest in diagnosis. MCI and AD were written off as “normal aging,” “hardening of the arteries,” or “ministrokes.” This approach is changing, and now changing more quickly. In the near future, a blood-based screening test will identify those individuals in need of further evaluation and potential treatment. The larger goal is to prevent cognitive decline in healthy normal individuals at risk, and to slow or stop decline in the earliest/mild stage of MCI and AD. Leqembi is the first effective disease-modifying treatment – our “foot in the door” – a historic moment and a true breakthrough. 

We thank those individuals and their study partners who enrolled in the Leqembi study (CLARITY, clinicaltrials.gov # NCT03887455) with the Memory Disorders Program at Georgetown University. We cannot make progress without you, and we (and future generations) remain eternally grateful.