The Phase III trial data on the emerging Alzheimer's disease drug lecanemab has been published in the New England Journal of Medicine and was presented at the recent Alzheimer's disease conference, CTAD, held in San Francisco, by Dr Sharen Cohen. Dr Cohen was an investigator on the Phase III Eisai/Biogen Alzheimer's disease study and co-authored the paper that was published.
The data is of interest to Cogstate (CGS: $1.80) and investors as Cogstate's core business is in conducting Alzheimer's disease studies, and its blue sky is the use of its cognitive diagnostic tool, licensed by Eisai, to help identify patients should an effective drug treatment for Alzheimer's disease become available.
The core outcomes from the published data are that lecanemab delivered slowing in degeneration of symptoms consistently across a range of cognitive and functional measures. It also showed a dose and time-dependent clearance of amyloid from the brain, with lecanemab targeting the most toxic amyloid species.
The side effect profile of lecanemab was reasonably good, with a similar number of deaths in the placebo and active arms and no deaths linked to drug treatment (although one death since the study has been possibly linked to drug treatment according to the treating physician) and the incidence of ARIA-E (brain swelling) was 12.6%. However, the cases of ARIA-E was generally mild or asymptomatic, occurring in the first three months and generally resolved within four months.
As previously reported, there was a 27% slowing in cognitive decline based on the primary measure, with a clinically meaningful result not established, and the authors concluded that longer studies with lecanemab are warranted. Longer term studies are underway, including:
- A four-year open label continuation of this Phase III trial;
- A five-year Phase II extension study;
- A four-year Phase III study in 1400 patients (moving from dosing every 2 weeks to every 4 weeks);
- A four-year study in 168 patients with a genetic predisposition to disease, and
- A four-year study with various amyloid binding drug candidates in 490 patients.
Alzheimer's Disease Incidence to Triple by 2050
Dr Cohen provided some other valuable insights in her CTAD presentation. The importance of developing therapeutics for this disease can be expected to escalate with the number of people living with Alzheimer's, rising to 75 million by 2030 (up from 55 million) and up to a staggering 150 million people by 2050. Alzheimer's is a "chronic, progressive, disabling and fatal disease."
Lecanemab Benefit Seen as Early as Six Months
The realistic immediate goals are to develop therapies that will have a positive impact on symptoms, can slow disease, and improve quality of life for patients and families said Dr Cohen.
In the Phase III study the treatment effect was seen as early as six months and continued to grow in magnitude out to the duration of the study at 18 months, based on the primary measure CDR-SB (which assesses changes in cognition and function). CDR-SB uses six different measurements and this study showed a slowing in decline in all six sub-measures, which clinicians really like to see said Dr Cohen.
Another appealing detail in the study outcome is that the benefit in function, which is more meaningful to patients on a daily living basis, saw 37% less decline than placebo, compared to a 26% slowing in cognitive decline compared to placebo.
In measuring time to progression of the disease, there was a 31% lower risk in disease progression during the trial (to the next stage of disease) when taking lecanemab, and this continued to diverge as the study progressed. If that data is extrapolated, it takes patients on lecanemab an additional 7.5 months (25.5 months) to reach the same level that the placebo group progressed to at 18 months. Dr Cohen said there is a trend to a cumulative benefit effect from treatment with lecanemab.
Modelling Shows Two - Three Years Benefit in Disease Progression
Dr Cohen said that lecanemab could lead to delaying disease progression by several years. In the Phase II study with lecanemab (in 856 patients), modelling the data on expected longer term outcomes, the delay in advancing to mild dementia was 2.5 years, to moderate dementia was 3.1 years, and a delay to progression to severe dementia of 2.3 years when taking lecanemab. This modelling will also be conducted on the Phase III study just reported, presumably with input from the open label extension.
"We're not talking about weeks or months, we're talking about gaining years in milder stages of disease on this projected model," suggested Dr Cohen. The projection also predicts lower rates of institutionalisation said Dr Cohen.
Quality-of-Life
In assessing the impact of drug treatment with lecanemab on quality-of-life, Dr Cohen highlighted that there were consistent, meaningful and statistically significant benefits across all of the measures. On a subjective patient input assessment, patients viewed their decline in quality-of-life as being 56% less than those who received placebo.
On a safety analysis, Dr Cohen said that lecanemab had a well characterised safety profile with low rates of symptomatic ARIA. She said the results are consistent with the requirements set by the EMA and FDA for disease modification. The results confirm a paradigm shift of diagnosing earlier in order to achieve disease slowing and to extend milder stages of disease.
Summary
The next drug candidate that can be expected to deliver positive data is donanemab from Eli Lilly, which has shown to reduce amyloid levels by 65% after just six months of treatment. Eli Lilly is confident of gaining a positive result in this study. According to Eli Lilly, the depth of plaque clearance in people with Alzheimer's is crucial and linked to improvements with phosphor-tau levels and reduced inflammation.
An advantage that this drug candidate has over lecanemab is that it needs to be dosed only once a month (rather than every two weeks for lecanemab). Eli Lilly also plans to start another Phase III study in Alzheimer's with another amyloid binding drug candidate, remternetug. Cogstate can be expected to run the cognitive assessments for this study as it conducts all of Eli Lilly's work in this field. Whether these types of drugs need to be delivered just for an interim period to remove the plaque is not known at this point.
With respect to reimbursement for lecanemab should the drug candidate gain approval, Medicare in the US is re-evaluating its coverage of Alzheimer's therapies. This follows the more promising patient data on lecanemab compared to Aduhelm, the first amyloid therapy for Alzheimer's approved in the US under controversial circumstances. Lecanemab will be reviewed by the FDA by 6 January next year under an accelerated approval process, however Medicare reimbursement will take considerably longer to secure. Eisai also expects to submit a traditional NDA by the end of March next year with the FDA.
The importance of finding a solution to the slowing of disease progression in Alzheimer's will continue to increase with the aging population that brings with it an increasing incidence to disease. The demand for Cogstate's technology and services can be expected to remain high, particularly with the positive developments with lecanemab and other emerging amyloid targeted therapies.
Cogstate is capitalised at $312 million.
Bioshares recommendation: Buy
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