Reacción a "Reactions: data from Alzheimer's clinical trial with lecanemab antibody published"

Following the press release from Eisai Pharmaceuticals on 28 September 2022 regarding the results of the phase 3 study, Clarity, with lecanemab in patients with early Alzheimer's disease (mild cognitive impairment and mild dementia due to Alzheimer's disease), we are awaiting the presentation of the scientific results that has taken place simultaneously at an international congress (CTAD 2022) and with the publication of the peer-reviewed results in the New England Journal of Medicine.  

The first conclusion from reading the published article is that the announced results hold after peer review. The analysis of the primary efficacy endpoint (sum of Clinical Dementia Rating-CDR-SOB boxes) shows a significant benefit of lecanemab treatment at 18 months of treatment. The difference between the active group and placebo on the primary endpoint with the specified statistical treatment was -0.45 points on CDR-SOB (decline of 1.21 points in the lecanemab arm and 1.66 in the placebo arm), which is 27% less worsening in the active arm. This result is statistically positive (the study was designed to identify a difference of 25% or more).  All four pre-specified endpoints also showed a positive effect for lecanemab. This indicates that the trial shows an overall positive outcome, with results on the different pre-specified endpoints congruent with each other, in line with the results of previous studies with this drug.  

Regarding the clinical effect, the publication concludes that it is modest. The study was designed to identify a 25% difference at 18 months on the CDR-SOB scale after consultation with regulatory authorities and experts. My reading is that the proposed target, based on the data shown in the publication, has been met. There is currently no consensus on what magnitude of change on the scale chosen by previous consensus (CDR-SOB) is to be considered clinically relevant. Moreover, previous literature indicates that patients, clinicians and payers (who include cost as well as benefit in the assessment) may have a different opinion in this regard. I do not believe that the effect can be compared with symptomatic drugs available for mild-moderate stages of dementia, as the target population and study design are different, and changes on a given scale are not linear over the course of Alzheimer's disease. Longer-term data will be needed to know whether this clinical effect is maintained, increased or transient to understand its potential clinical impact.  

Tracer uptake marking amyloid in plaques, which was included as a secondary endpoint, was significantly reduced in treated patients, and although no data is provided on the percentage of patients who tested negative in this test, it is indicated that the mean level of tracer uptake was below the amyloid-positive threshold at 18 months, indicating that the clinical effect could be associated with a dramatic reduction in the amyloid burden in treated patients.  

21.5% of those treated with lecanemab had one of the MRI abnormalities that have been associated with amyloid (ARIA), compared to 9.5% in the placebo arm. These alterations were more frequent in carriers of the ε4 genotype of the APOE gene, indicating that, although these alterations can appear spontaneously in patients with Alzheimer's disease, this anti-amyloid treatment increases their frequency, especially in the most genetically susceptible patients. While most of these alterations were not accompanied by symptoms, 3.5% of patients receiving lecanemab had symptoms related to these MRI alterations. Of those receiving lecanemab, 5 subjects (0.6%) experienced a brain haemorrhage and 1 (0.1%) of those receiving placebo. More infusion-related reactions were also reported in the active arm (26.4% vs. 7.4%). There were 6 deaths in the treatment arm and 7 in the placebo arm, although none of the deaths were attributed to the drug.  These effects are in my opinion relevant and require close monitoring of the drug, especially in the first months, and knowledge on the part of patients receiving the drug, but I believe that they are per se a reason, at this time, to avoid its use.  

Recently, different press sources have reported a case of a patient who died during the open-label phase of the study. This patient had a brain haemorrhage immediately after being treated with rtPA, a drug administered to try to break up a thrombus after a stroke. It is well known that a percentage of patients treated with rtPA have a brain haemorrhage as a complication, and that this percentage is higher in patients with amyloid in their cerebral vessels. From the data that have been made public, I do not believe that the haemorrhage that led to this patient's death can be attributed to the direct effect of lecanemab, but rather to rtPA. Another thing is that we will have to analyse the case and assess whether it is safe to use rtPA in patients receiving lecanemab or whether it should be avoided, as we know it should be avoided in other clinical situations and with other drugs.  

The FDA announced that on 6 January 2023 it will communicate its decision on the approval of lecanemab under the accelerated approval pathway. Patient and professional associations are likely to comment on the outcome of lecanemab in the coming weeks. Regulatory authorities are likely to not only analyse the study results, but also consider stakeholders' views on efficacy and tolerability.