Donanemab-AZBT

Biogen's recent decision to plough ahead with advancing its tau-targeting Alzheimer's therapy into Phase III despite coming up short in mid-stage testing came under renewed scrutiny as detailed results suggest clinical benefit remains difficult to interpret.Company shares slid around 6% on Tuesday after a detailed look at Phase II results from the CELIA study was presented at the Alzheimer’s Association International Conference (AAIC).The trial enrolled 416 patients with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's dementia. Topline results in May showed that the lowest dose diranersen (BIIB080), an antisense oligonucleotide partnered with Ionis Pharmaceuticals, produced the most improvement at slowing cognitive decline based on the Clinical Dementia Rating–Sum of Boxes (CDR-SB) measure.The trial had set out to see whether higher doses of diranersen would provide greater clinical benefit over 18 months, but found no such link.26% slowing at lowest doseInstead, the lowest dose – 60 mg given intrathecally every 24 weeks – produced the strongest effect, slowing clinical decline by 0.54 points (26%) on CDR-SB compared to placebo, according to the AAIC presentation.The 26% decline approaches the 27% benefit reported in the pivotal trial for Biogen and Eisai's Leqembi (lecanemab); Eli Lilly's rival Kisunla (donanemab) was associated with a 35% reduction.The diranersen 60-mg dose demonstrated slowing of clinical decline on other cognitive scores as well, including a 42% benefit on the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog13), 50% on Mini-Mental State Examination (MMSE), 30% on modified Integrated Alzheimer's Disease Rating Scale (iADRS), and 23% on Alzheimer’s Disease Composite Score (ADCOMS). Biogen said statistical significance for a majority of these measures was "nominal" versus placebo.A higher 115-mg dose given every six or three months was also tested. These groups showed slowing of clinical decline by 0.28 and 0.18 points (14% and 9%), respectively, on CDR-SB; 32% and 29% on ADAS-Cog13; 34% and 38% on MMSE; 29% and 18% on modified iADRS; and 21% and 7% on ADCOMS.Results for another measure – Alzheimer’s Disease Cooperative Study – Activities of Daily Living for Mild Cognitive Impairment (ADCS-ADL-MCI) – were "inconsistent" across dose regimens, Biogen said. However, it pointed out that when looking at the functional domains of CDR-SB, every dose of diranersen showed an edge in slowing decline.The drug did hit its molecular target across all doses, lowering tau levels in cerebrospinal fluid by an average of 50% to 65% from baseline, Biogen said.'More questions than answers'Still, the detailed CELIA findings "leave more questions than answers," according to RBC Capital Markets analyst Brian Abrahams. "The reasons for the most favourable benefits in the lowest dose arm remain unclear, as tau reductions if anything look greater in the higher dose arms," he noted.Moreover, even at the optimal dose, Abrahams said "the effective size…may not be enough to be viewed as transformative, particularly if larger studies converge efficacy to more of a blend across the three doses studied here."Confusion eventsAs for safety, the most frequent adverse events in the CELIA trial were procedural pain, post-lumbar puncture syndrome and "confusional state." Biogen said the confusion events occurred within a few days of dosing and resolved within a week.Amyloid-related imaging abnormalities (ARIA), which has dogged current anti-amyloid therapies for Alzheimer's, are not anticipated with diranersen based on its tau-targeting mechanism of action, Biogen said."The CELIA clinical, biomarker, and safety data presented at AAIC provide proof-of-concept and important evidence of diranersen's novel tau-reduction mechanism of action translating into clinical benefit," stated Priya Singhal, head of development at Biogen. "If confirmed in Phase III, diranersen could represent an important new therapeutic approach targeting one of the core pathologies of Alzheimer's disease."One key opinion leader (KOL) told FirstWord shortly after the topline readout in May that while the primary endpoint of dose response was confusing, "missing a Phase II endpoint is not the end of the world" as long as the study yielded enough insight to direct the Phase III design (see – KOL Views Q&A: Phase II miss for Biogen, Ionis' diranersen is win for tau-targeting in Alzheimer's).