Axovant scraps Alzheimer’s bid – now back to the amyloid hypothesis

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).

Next up

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
Project  Company  Status Mechanism  Trial ID Data?
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.

To contact the writer of this story email Jonathan Gardner in Virginia at [email protected] or follow @ByJonGardner on Twitter

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