TauRx’s oral anti-tau therapy HMTM has shown in a phase 3 trial that it can stabilize cognitive decline in patients with Alzheimer’s disease.
Long before the approval of Biogen’s Aduhelm (aducanumab), long before people began to question whether clearing the brain of amyloid plaques slowed cognitive decline in Alzheimer’s disease, a small company in Aberdeen, Scotland, was quietly tackling a different research path.
TauRx Pharmaceuticals, founded in 2002, focused its research on the protein tangles in the brains of those with Alzheimer’s disease. The company’s founder, Claude Wischik, Ph.D., had previously identified tau as being at the core of the tangle filaments seen in patients with Alzheimer’s disease. His company worked to develop inhibitors of tau aggregation.
Two decades later, the phase 3 LUCIDITY trial has demonstrated that TauRx’s oral tau aggregation inhibitor, hydromethylthionine mesylate (HMTM), normalizes brain atrophy and stabilizes cognition. Data from this trial were recently presented at the Clinical Trials in Alzheimer’s Disease (CTAD) conference in San Francisco.
Tau has always been a hallmark of Alzheimer’s pathology, but a biomarker for beta amyloid plagues was found early on. That led to research primarily focused on clearing the brains of the amyloid plaques.
“Alzheimer’s disease is a complex disease,” Dr. Sonya Miller, head of medical affair at TauRx, told Formulary Watch. “There is a greater understanding now about how beta amyloid and tau interact and of other signs of neuro degeneration, including neuroinflammation.”
TauRx has taken a slow and deliberate course for developing this novel compound. “What an earlier study showed us that we had some quite complex issues to deal with. One was the dose, and that had to do with an earlier formulation. We have a new formulation that has a designated stabilized salt form that delivers a reduced form of the drug,” Miller said.
Miller said they also took time to understand how HMTM works. They found that the compound led to a biological event at the synapses itself. An earlier study of HMTM that included pretreatment with acetylcholinesterase inhibitors found there was a down regulation that impacted the ability of the drug to work. This led company researchers to the current design of the trial with HMTM as a monotherapy.
In the study presented at CTAD, TauRx found that, in the 105 patients with mild cognitive impairment who received the 16 mg/day dose, there was statistically significant cognitive improvement over the pre-treatment baseline at six months, 12 months and 18 months on the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-cog). The mean change on the instrumental activities of daily living subscale of ADCS-ADL also remained above the pre-treatment baseline at six, 12 and 18 months.
In the 147 patients with mild-to-moderate Alzheimer’s disease there was a cognitive decline in the first nine months and no further decline over the following nine months. There was a functional decline in the activities of daily living.
Statistically significant reductions in disease progression as measured by change in cognitive function and brain atrophy were confirmed by comparisons of participants receiving the 16 mg/day dose against Alzheimer’s Neuroimaging Initiative (ADNI) subjects who were closest to the study population by age and clinical severity. Trial participants with mild cognitive impairment entered the study with more brain atrophy than ADNI healthy aging subjects and consistent with ADNI mild cognitive impairment subjects.
Those treated with HMTM had a rate of progression of brain atrophy that was significantly less than in ADNI MCI subjects and comparable to that seen in ADNI healthy aging subjects. And, according to analysis comparing HMTM to publicly available data of amyloid-targeted treatments, the treatment effects of HMTM on cognitive and functional decline are about three-fold larger over 18 months.
There were no treatment-related serious adverse events or evidence of amyloid related imaging abnormalities. The trial experienced a 20% drop out rate, due to the logics of the COVID-19 pandemic, and people couldn’t travel to participate in the study, Miller said.
The open-label extension part of the LUCIDITY trial is ongoing, with planned completion in mid 2023.
The trial, however, had an unexpected outcome. The study had two treatment arms, HMTM and an active control, methylthionium chloride (MTC). HMTM and MTC share a parent compound, methylthionium. This control was chosen because both compounds discolor urine, and this was required to maintain blinding, Prof. Bjoern Schelter, data analytics and biostatistics lead of TauRx, said in an interview with Formulary Watch.
But the active control resulted in accumulation of MT in plasma. “When we designed the trial, all the modeling suggested that there should be no activity from the control arm. We need some feedback and advice from regulators.”
The company plans to discuss the results first with the UK Medicines and Healthcare Products Regulatory Agency and then the FDA for guidance in the first and second quarter of 2023. TauRx has received an Innovative Licensing and Access Pathway (ILAP) for HMTM, which is a new fast track designation for innovative medicines approvals in the UK.