Annovis Bio will target Alzheimer’s disease and Parkinson’s disease with two Phase III trials in early 2022, CEO Maria Maccecchini says.

The Pennsylvania-based biotech has requested a meeting with the FDA for its Parkinson’s trial, and it intends to file a similar request for Alzheimer’s within the next two weeks, Maccecchini says, adding that a Phase III in Parkinson’s could start as soon as February or March, while a Phase III in Alzheimer’s could begin in March or April.

Both trials will test Annovis’s lead candidate ANVS401, an oral translational inhibitor of neurotoxic aggregating proteins (TINAPs). Each trial will likely recruit approximately 450 patients, split evenly among three groups: placebo, 10mg, and 20mg a day of ANVS401, Maccecchini explains.

The planned trials will each last six months, with the option for a one-year extension. Annovis has plans to run two 24-month Phase III studies in each indication, but currently only has funding for the shorter trials.

Unique recruitment challenges

While the planned Alzheimer’s and Parkinson’s trials have similar designs, Annovis has to approach recruitment for each disease very differently, Maccecchini says. Compared to patients with Alzheimer’s, those with Parkinson’s are easier to recruit as they tend to be younger and so are more receptive to clinical trials, she notes.

Also, families of patients with Alzheimer’s usually play a more active role in treatment decisions, Maccecchini adds. This means investigators have to pitch clinical trials to potentially hesitant family members.

“It was really hard to recruit patients with Alzheimer’s [in earlier trials],” she says. “Often, [patients’] kids are very protective and scared of giving them something they don’t understand.”

One way to reassure potential participants in Alzheimer’s trials is having principal investigators explain ANVS401’s safety profile in detail, Maccecchini says. Two previous Phase IIa trials in Alzheimer’s and Parkinson’s disease met their safety primary endpoints as there were no serious adverse events (AE), as well as no AEs that led to dosage withdrawal, according to a company presentation at the Clinical Trials in Alzheimer’s Disease (CTAD) conference earlier this month.

Annovis does not plan to require spinal fluid testing in its Phase III trials, which should also alleviate enrolment hesitation, Maccecchini says. In earlier trials for both diseases, Annovis had required two spinal fluid samplings. This testing can measure biomarkers like amyloid-beta, tau, and alpha-synuclein levels.

ANVS401 is an oral pill, which was reassuring to many patients and families in earlier trials, Maccecchini says. Both Biogen’s recently-approved Aduhelm (aducanumab) and Eli Lilly’s late-stage Alzheimer’s candidate donanemab are administered intravenously.

Annovis to explore additional endpoints

The Phase III trials will stick to standard, approvable efficacy primary endpoints. But Annovis will ask the FDA if it can use an additional, unconventional efficacy measure.

As a secondary endpoint, the Weschler Adult Intelligence Scales (WAIS) could work as a  measure of axonal transport, Maccecchini says. Axonal transport, a motor protein process, is the speed by which the nerve cell fires and transfers information.

In the WAIS coding subtest, patients record associations between different symbols and numbers within a specific timeframe. In Parkinson’s, patients could code faster due to improved motor function. In Alzheimer’s, patients could do so because of stronger cognition.

In Alzheimer’s, a standard primary endpoint is the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) subscale: a short neuropsychological assessment of cognitive symptoms in dementia. Meanwhile, the Parkinson’s trial will use the Unified Parkinson’s Disease Rating Scale (UPDRS): an assessment of Parkinson’s disease progression and severity.

In a previous 14-patient Phase IIa study in Alzheimer’s, ANVOS401 improved ADAS-Cog by 30% from baseline (p<0.05), according to the company presentation. In a similar Phase IIa study in Parkinson’s, ANVOS401 improved a motor function subscore of UPDRS by 13.4% from baseline (p<0.01). There were also improvements in WAIS coding speed for both groups.

Strategic site selection to ease lockdown issues

When the Covid-19 pandemic hit in March 2020, almost all hospital outpatient centres and private sites shut down, making it nearly impossible to run clinical trials, Maccecchini says. But while many hospital trial centres remained closed for extended periods, many private locations reopened in September and October 2020.

While teaching hospitals could remain closed for longer because they had students as a source of income, private trial centres gain all their revenue from trials, Maccecchini says. “Private sites realised after a few months that they were making no money if they didn’t run clinical trials.”

As a result, Annovis shifted many of its ongoing trial locations to private sites, allowing its trials to move more smoothly, Maccecchini says. These sites took strong precautions to protect patients and investigators against Covid-19, such as separate waiting rooms and chauffeurs to transport trial participants to trial sites, she adds.