Developers take another shot at an Alzheimer's vaccine

 Current leader, Vaxxinity, will have to convince its doubters if it is to hook a partner.

For those who still believe that targeting amyloid has a role to play in the treatment of Alzheimer’s disease, a new crop of anti-amyloid vaccines promises greater convenience and lower cost than the antibodies that have so far dominated Alzheimer’s research.

Earlier attempts to develop Alzheimer’s vaccines did not succeed, and this approach is for good reason considered a long shot. But the likes of Vaxxinity, Grifols and AC Immune reckon that, this time, things could be different. Vaxxinity is in the lead, and is looking for a partner to take its contender, UB-311, into phase 2b.

While Evercore ISI analysts describe Vaxxinity’s technology as “interesting”, they are wary about how a dispute about the ownership of its parent company and major shareholder, United Biomedical, could affect Vaxxinity. 

Vaxxinity's technology is licensed from United, which has employed it in animal vaccines. The dispute involves United’s founder, Chang Yi Wang, who is also the mother of Vaxxinity’s chief executive, Mei Mei Hu; there is significant overlap between the two companies’ boards.

However, Ms Hu tells Evaluate Vantage: “We've had many lawyers looking at it from both sides, and they're very confident that [the dispute] doesn't impair Vaxxinity’s ability to operate whatsoever.” A partner would typically want to see such a dispute settled before doing a deal.

A sheep in wolf’s clothing

These matters aside, Vaxxinity thinks it has solved a major problem that hit previous attempts to develop Alzheimer’s shots; namely, how to spur the body to produce antibodies against endogenous, or self, antigens.

“Most of the time, it's not going to respond because it doesn't want to attack itself,” says Ms Hu. Alzheimer’s vaccine developers have, therefore, tried to “rile up” the immune system, she says, “but the problem was they riled it up too much”. 

This led to toxicity concerns. Ms Hu points to Elan and Wyeth’s AN-1792, which was discontinued in 2002 after being associated with meningoencephalitis.

Ms Hu reckons Vaxxinity has got the balance right, however. “The way I like to think about it is we put a sheep in wolf's clothing.” The “sheep” in the case of UB-311 is a short fragment of the amyloid-beta peptide. This is linked to the “wolf”, a TH peptide carrier, designed to activate T-helper cells and trigger an immune response.

Ms Hu points to phase 2a data in 40 patients, highlighting a slowing in decline of roughly 50% with UB-311 versus placebo on the cognitive endpoints CDR-SB and Adas-Cog. This was seen when patients were injected with UB-311 every three months – a more convenient schedule than the monthly infusion of Aduhelm, for example. Another plus was a complete lack of Aria-E, the brain swelling side effect that has dogged anti-amyloid MAbs.

However, Evercore noted that the sample size was likely too small to feel confident, and that the effect sizes would likely dwindle in larger trials.

Ms Hu, who spoke to Vantage after the recent success of Biogen and Eisai’s lecanemab, but before the failure of Roche's gantenerumab, thinks that there is renewed excitement around the amyloid hypothesis, which could help with Vaxxinity’s partnering discussions. “The whole industry has got some more wind in its sails.”

And gantenerumab’s setback will probably do little to dent the amyloid hypothesis, given the low levels of amyloid-beta clearance seen with that project.

The chasing pack

There are a couple more groups with projects in mid-stage studies that will hope to catch Vaxxinity. Grifols reported phase 2 immunogenicity data with its contender, ABvac40, at the AD/PD meeting in March, with exploratory efficacy endpoints still under analysis. No cases of Aria-E were seen here, either.

Grifols has taken an approach that differs from Vaxxinity's, with the immune response to ABvac40 being driven by a keyhole limpet cyanine carrier protein and the adjuvant alum hydroxide.

Meanwhile, by the end of this year AC Immune expects to report interim data from the phase 1/2 Abate study of its liposome vaccine candidate ACI-24.060 in prodromal Alzheimer’s patients, and make a decision on whether to move into Down syndrome-related Alzheimer’s.

Still, therapeutic vaccine candidates for various diseases have failed to live up to expectations. In Alzheimer's, there is the added risk that these developers are pursuing a hypothesis – around amyloid – that itself has many doubters.

Amyloid-beta vaccines in clinical development
Project	Company	Status
Phase 2
UB-311	Vaxxinity	Ph2a data in mild AD reported; seeking partner for ph2b
ABvac40	Grifols (Araclon subsidiary)	Data reported from part A of ph2 in MCI and very mild AD, part B (crossover) continues
ACI-24.060	AC Immune	Interim data from ph1/2 Abate in prodromal AD due YE 2022; US IND planned Q1 2023
Phase 1
ALZ-101	Alzinova	Ph1 in early AD; topline data due H2 2023
Source: Evaluate Pharma & clinicaltrials.gov. https://www.evaluate.com/vantage/articles/interviews/developers-take-another-shot-alzheimers-vaccine