Prothena’s monoclonal antibody and vaccine show promise in AD treatment and prevention

We spoke to Prothena’s chief medical officer, Dr Hideki Garren, to hear more about both programs.

When asked why the Ireland headquartered company went down the treatment and preventative route in its development of Alzheimer’s disease (AD) therapies, he told us: “Essentially we want to try and reach as many Alzheimer’s disease patients as possible.”​

AD affects more than 5.8 million Americans and is considered the most common neurodegenerative disorder.

Garren noted the great science that has been occurring in the last couple of decades in relation to diagnosing AD. “There has been lots of innovation in terms of diagnosing patients, finding patients earlier, even identifying patients at risk. As these innovations and the identification of patients [continue to] evolve, we want to have treatments as well as prevention options available for patients.”​

PRX012 is designed to be administered by subcutaneous injection to provide a more convenient method and schedule of administration to facilitate patient access.

Garren shared key takeaways from the company’s poster presentation on that monoclonal antibody at the Alzheimer’s Association International Conference (AAIC) 2021.

“It is a very high potency and very high affinity antibody, and it has been shown to have 11 times higher binding affinity than the approved treatment, aducanumab, in side by side experiments. So, therefore, we think it should have higher efficacy, and potential safety, as well as convenience for patients [compared to other anti-Aβ therapies].”​

Because of the higher efficacy, Prothena believes that PRX012 can be given subcutaneously and reach concentrations comparable to other antibodies.  ​

“But what is really innovative about the data we are presenting at AAIC is that PRX012 can clear both pyroglutamate-modified and -unmodified Aβ plaque.”​

Such clearance was seen, he said, in brain tissue at concentrations that can be reached in the CNS with subcutaneous administration, potentially enable greater patient accessibility and compliance relative to approved therapies and treatments currently under development.

Prothena’s regulatory pathway plan around PRX012 is to file an IND with the FDA in the first quarter of 2022 and start clinical trials thereafter, he reported.

Vaccine program​

In terms of the company’s AD vaccine program, three candidates have been tested in preclinical animal models, he said. “Right now we are going through those three candidates, trying to identify which is the best one to take forward. And so we are still doing preclinical experiments but we are hopeful we can get this to patients as soon as possible.”​

There are other AD vaccine approaches being developed, but what is unique about Prothena’s one is that it has dual targets, explained Garren.

“In the Alzheimer’s field, Aβ is a pathogenic target but tau has also been shown to be a potential pathogenic target and what we have here is a single vaccine targeting both. What we showed at AAIC, based on animal data, is that, with this single vaccine, we can create a balanced immune response to both targets, which is very promising.”​

The poster described results from three dual Aβ-tau vaccine constructs, which generated appropriate antibody quantities with the ability to promote both phagocytosis of Aβ plaque and blockade of tau binding to a heparin-sulfate analog, a surrogate for neuronal uptake of tau.

The company said all three vaccine candidates generated a balanced immune response to both proteins, a common challenge with multi-epitope vaccines, and induced robust antibody titers to Aβ and tau in multiple animal experiments. The resultant titers strongly reacted with Aβ and tau pathology in human AD brain tissue. 

Additionally, cerebrospinal fluid (CSF) concentrations of tau and Aβ antibodies were within the expected range and similar to typical ranges achieved following administration of monoclonal antibodies, according to the data.

“We also showed that, with this vaccine, which is given as a shot in the arm, [animals in this case], we can get concentrations in the brain, in the CSF.”​

The findings, which included results in cynomolgus monkeys and mice, support the continued development of this multi-epitope vaccine for the prevention and treatment of AD, said the company.