Alzheimer’s disease takes another scalp. Intepirdine has failed to show any benefit in mild to moderate patients in combination with Aricept, prompting Axovant to cancel all efforts in Alzheimer’s.
The failure prompted investors to throw Axovant out of the billionaire’s club, with its shares tumbling 74% in early trading today. Alzheimer’s looks like a quiet field for some time to come – the next major readouts will be for agents following the divisive amyloid hypothesis, which has had more than its share of setbacks (see table below).
Done with Alzheimer's
Intepirdine’s Mindset study missed the co-primary endpoints of improvement over baseline in ADAS-Cog and ADCS-ADL endpoints. Intepirdine was combined with Aricept and compared against Aricept alone in this trial in mild and moderate disease.
A secondary endpoint, clinician interview-based impression of change plus caregiver interview, showed an improvement of 0.12 points and a nominal p value of 0.02, but this sole glimmer of hope was not enough to convince Axovant to press on. “We do not plan to further develop intepirdine for Alzheimer’s disease,” Axovant's chief executive, David Hung, said unequivocally.
More equivocal was the reluctance to terminate all work on the asset, which the group is testing in Lewy body dementia in the phase IIb Headway trial due to read out by the end of 2017.
Investors obviously see less promise in that venture, wiping away $1.9bn in market valuation. By comparison Lilly lost more than $8bn in valuation when it finally pulled the plug on its amyloid-beta antibody solanezumab last year. Axovant shares are now less than half the price at which they were in 2015 when the group was spun out of Roivant in an initial public offering.
The writing was probably on the wall for intepirdine when Lundbeck’s similarly acting idalopirdine bombed in phase III earlier this year (Snippet roundup: Pressure is on for Axovant and Glaxo, February 10, 2017).
The twin failures of intepirdine and idalopirdine suggests that blocking the 5-HT6 receptor to stimulate production of the neurotransmitter acetylcholine is not a promising pathway in Alzheimer’s. The main approach has for years been seeking to limit the damage of beta amyloid lesions in the brain, one of the markers of this degenerative disease – yet repeated failure has not dissuaded pharma from persisting here.
The next big readout in Alzheimer’s is likely to be a phase II trial of Biogen and Eisai’s BAN2401, which binds to beta amyloid profibrils. Phase II often leads to success in Alzheimer’s, and Biogen will take a Bayesian approach to statistical analysis of the data, something that could favour responders to increase the odds of success.
12-month data are due for BAN2401 by the year’s end. 2019 looks like a bigger period for Alzheimer’s, when no fewer than three phase III trials of beta amyloid agents estimated to report data, comprising two Bace inhibitors and one beta amyloid antibody in the form of Biogen and Eisai's lead agent aducanumab.
Identifying likely responders and improving the potency of these agents represent the primary progress in Alzheimer's research, and given the unmet need even a small edge could be rewarded with approval and substantial sales. It is disappointing that there do not seem to be signs of companies testing innovative pathways; perhaps this will only come if amyloid beta is declared an irredeemable failure.
|Late-stage trials in Alzheimer's|
|BAN2401||Biogen/Eisai||Phase II||Anti-beta-amyloid protofibril MAb||Early AD; NCT01767311||12mth readout YE17, 18mth data Jul 2018|
|Azeliragon*||vTv Therapeutics||Phase III||Receptor for advanced glycation endproducts (RAGE) antagonist||Steadfast; mild AD; part A; NCT02080364||Early 2018|
|Elenbecestat (E2609)||Eisai/Biogen||Phase II||Bace inhibitor||Mild to moderate AD; NCT02322021||Mar 2018|
|Azeliragon||vTv Therapeutics||Phase III||Receptor for advanced glycation endproducts (RAGE) antagonist||Steadfast; mild AD; part B; NCT02080364||Late 2018|
|Verubecestat (MK-8931)||Merck & Co||Phase III||Bace inhibitor||Apecs; prodromal AD; NCT01953601||Feb 2019|
|LY3202626||Lilly||Phase II||Bace inhibitor||Navigate-AD; mild AD; NCT02791191||May 2019|
|AADvac1||Axon Neuroscience||Phase II||Tau vaccine||Adamant; NCT02579252||Jun 2019|
|Lanabecestat||Astrazeneca/Lilly||Phase III||Bace inhibitor||Daybreak-Alz; mild AD; NCT02783573||Aug 2019|
|Lanabecestat||Astrazeneca/Lilly||Phase II/III||Bace inhibitor||Amaranth; early AD; NCT02245737||Sep 2019|
|Aducanumab||Biogen/Eisai||Phase III||Beta-amyloid MAb||Engage; early AD; NCT02477800||Nov 2019|
|Aducanumab||Biogen/Eisai||Phase III||Beta-amyloid MAb||Emerge; early AD; NCT02484547||Feb 2020|
|Elenbecestat (E2609)||Eisai/Biogen||Phase III||Bace inhibitor||MissionAD1; early AD; NCT02956486||Jun 2020|
|Elenbecestat (E2609)||Eisai/Biogen||Phase III||Bace inhibitor||MissionAD2; early AD; NCT03036280||Aug 2020|
|Crenezumab||Roche||Phase III||Beta-amyloid MAb||Cread; prodromal to mild AD; NCT02670083||Aug 2020|
|Crenezumab||Roche||Phase II||Beta-amyloid MAb||Preclinical PSEN1 E280A mutation carriers; NCT01998841||Sep 2020|
|ABBV-8E12||Abbvie/C2N Diagnostics||Phase II||Anti-tau MAb||Early AD;NCT02880956||Dec 2020|
|Crenezumab||Roche||Phase III||Beta-amyloid MAb||Cread 2; prodromal to mild AD; NCT03114657||Oct 2021|
|Solanezumab||Lilly||Phase III||Beta-amyloid MAb||A4; preclinical AD; NCT02008357||Jul 2022|
|JNJ-54861911||Johnson & Johnson/Shionogi||Phase II/III||Bace inhibitor||Early; at-risk population; NCT02569398||Apr 2023|
|Gantenerumab or solanezumab or JNJ-54861911||Washington Uni Med School with collaborators incl. Lilly and Roche||Phase II/III||Beta-amyloid MAbs||DIAN-TU; early-onset AD; NCT01760005||Sep 2023|
|CAD106 + CNP520||Novartis||Phase II/III||Beta-amyloid vaccine||Generation S1; at-risk population; NCT02565511||May 2024|
|CNP520||Novartis/Amgen||Phase II/III||Bace inhibitor||Generation S2; at-risk population; NCT03131453||Jul 2024|
|Source: Evaluate Pharma, company reports. *This table has been updated to include Azeliragon.|