Event – All about that BACE in 2016

When it comes to Alzheimer’s disease, Lilly is going all in. Not only is it facing the critical phase III readout for its beta-amyloid antibody solanezumab this year, the company – along with its partner AstraZeneca – will shortly have to make a call on whether to progress the beta secretase (BACE) inhibitor LY3314814 into pivotal trials.

Interim safety data from the phase II portion of the Amaranth study are due in the second quarter, which should prompt a go/no-go decision. But there is competition: other companies in the BACE race include Merck & Co, Johnson & Johnson, Biogen and Amgen (see table below).

Ace of BACE

Merck is leading the charge with verubecestat – previously known as MK-8931 – which, like LY3314814, is in a phase II/III trial. However, Merck should be first to report efficacy results: last month the company said it had completed enrolment in the Epoch study and expected primary completion in July 2017.

The primary endpoints of Epoch are change from baseline on the ADAS-Cog and ADCS-ADL scores after 78 weeks of treatment – the first part of the study. The second portion is a double-blind extension over an additional five years, in which efficacy will be assessed using the same scores.

Verubecestat is also in a phase III study, Apecs, in patients with earlier-stage prodromal Alzheimer’s.

Selected BACE inhibitors
Project Company Phase Name Trial ID Primary completion
Verubecestat (MK-8931) Merck & Co II/III Epoch; Apecs NCT01739348; NCT01953601 Jul 2017;
Jul 2019
AZD3293/ LY3314814 AstraZeneca/ Lilly II/III Amaranth NCT02245737 Aug 2019; interim safety data Q2 2016
JNJ-54861911 Johnson & Johnson II/III N/A NCT02260674; NCT02569398; NCT02406027 Jun 2016; Apr 2023; Feb 2024;
CNP520 Novartis/ Amgen II/III PII safety study; Generation NCT02576639; NCT02565511 Mar 2016; Aug 2023
E2609 Eisai/Biogen II N/A NCT02322021 Aug 2017; interim safety data 2016
LY3202626 Lilly I N/A NCT02323334 Feb 2016
TAK-070 Takeda Abandoned, phase I

J&J, meanwhile, expects readout from a phase II safety study of its contender, JNJ-54861911, in mid-2016. A longer-term phase II/III trial of the project is ongoing in asymptomatic patients at risk of developing Alzheimer’s, but this is not due for completion until 2023.

Also awaiting safety data are Amgen and Novartis, who teamed up to develop CNP520 last year (Amgen’s cautious bet on the beta amyloid hypothesis, September 2, 2015). More interestingly, genetically at-risk patients are being enrolled into the Generation phase II/III study, which also includes the beta-amyloid vaccine CAD106.

Prevention

It is notable that many of the projects above are being studied in at-risk populations such as healthy people with a family history or certain gene mutations, or those with mild cognitive impairment. This looks likely to be the way forward for Alzheimer’s drugs, which have proven notoriously difficult to develop so far.

While current drugs only address symptoms, beta-amyloid antibodies and BACE inhibitors are both designed to slow or halt the progression of Alzheimer’s by reducing levels of beta-amyloid, albeit via different mechanisms: the former binds to beta-amyloid circulating in the blood, while the latter blocks the enzyme that cleaves amyloid precursor protein to create beta-amyloid.

Potentially disease-modifying drugs have generated a lot of hope, but this will be dashed if the amyloid hypothesis of Alzheimer’s turns out to be a red herring.

And things are not looking promising after the failure of previous studies of beta-amyloid antibodies such as bapineuzumab and solanezumab, which is hanging by a thread ahead of pivotal trial results (Sola fails to wow, but does sustain hope, July 22, 2015). However, there are those who argue that the lack of effect seen so far is down to studies focusing on later-stage patients with irreversible damage.

Targeting BACE seems similarly risky, but this has not stopped various big pharma players from getting involved. Indeed, Lilly has two bites at the cherry – as well as LY3314814, which it is co-developing with AstraZeneca, it has its own BACE inhibitor, LY3202626, in phase I.

Three shots on goal might seem a lot – but in a disease as tricky as Alzheimer’s even this might not be enough.

To contact the writer of this story email Madeleine Armstrong in London at madeleinea@epvantage.com or follow  @medtech_ma on Twitter

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