Alector ditches GSK-partnered dementia drug and cuts staff

Alector abandoned development of latozinemab as a treatment for frontotemporal dementia (FTD) after it failed a phase 3 trial, and will turn its attention to a midstage Alzheimer's programme.

The immediate consequences of the disappointing result are a big reduction in workforce at South San Francisco-based Alector, set to be reduced by 49% to less than 170, and the resignation of R&D chief Sara Kenkare-Mitra, who will leave the company on 22nd December.

Shares in the company fell 50% on the news, and analysts at multiple investment firms downgraded the stock, whilst pointing to the potential for its preclinical-stage ABC programme, which is used to help large molecules cross the blood-brain barrier and could offer partnering opportunities.

The INFRONT-3 trial of GSK-partnered latozinemab (AL001), a sortilin receptor inhibitor, failed to slow down dementia progression in patients with FTD caused by a progranulin gene mutation (FTD-GRN).

The antibody is designed to increase progranulin levels, which are deficient in the disease. GSK was attracted by the promise of the drug in treating FTD – a devastating and largely inherited form of dementia that affects areas of the brain governing behaviour, language, and movement – and paid $700 million upfront for rights to the drug and one other candidate in 2021.

There were signs that the antibody was working as expected, as treatment was associated with a rise in plasma progranulin levels, which undermines the hypothesis that this will be an effective treatment strategy in FTD-GRN.

The other drug in the GSK collaboration is nivisnebart (AL101/GSK4527226), which also targets sortilin to increase progranulin levels, but is being developed as a potential treatment for Alzheimer's disease.

In Alzheimer's, the hypothesis is that genetic mutations that reduce levels of progranulin – which has been shown in some studies to act as a neuronal survival factor – are associated with an increased risk for the disease.

Nivisnebart is being tested in the phase 2 PROGRESS-AD trial involving people with early-stage Alzheimer's, with enrolment completed earlier this year and interim results due in the middle of next year.

The disappointment is the second for Alector in the space of a year, coming after an AbbVie-partnered Alzheimer's candidate – TREM2-activating antibody AL002 – after it failed to move the needle in the phase 2 INVOKE-2 trial.

The company also has some non-partnered drugs in its pipeline, including anti-amyloid antibody AL137 for Alzheimer's and GCase replacement therapy AL050 for Parkinson's and Lewy body dementia, which are in preclinical development. It had around $290 million in cash as of the end of September, which should fund operations through 2027.