On 6 October TauRx announced topline results from its Phase III LUCIDITY trial (NCT03446001) evaluating its oral anti-tau product, hydromethylthionine mesylate (HMTM), in patients with early, mild, and moderate Alzheimer’s disease (AD). In patients with early AD, HMTM treatment resulted in sustained improvement in cognition compared with the pre-treatment baseline measured using the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-cog13 scale). In patients with mild to moderate AD, HMTM stabilised cognition and function. Additionally, HMTM treatment reduced the rates of brain atrophy when compared with historical matched patients with AD.
One key unmet need in the AD market is for the development of disease-modifying therapies (DMTs) that can stop or even reverse the underlying pathology of the disease. Historically, the amyloid hypothesis has dominated the AD space. However, with multiple failures of amyloid-targeting drug candidates, the focus has widened to include anti-tau therapies. In AD, tau proteins become hyperphosphorylated and structurally compromised, often bending in shape, or ‘tangling’. Misshapen tau proteins lose their functionality, leading to microtubule deficiency, and ultimately to neuronal death. Following the LUCIDITY results, TauRx’s HMTM has the potential to become the first DMT targeting tau to be approved for AD.
If approved, HMTM would have a key advantage over the other DMT on the market, Biogen ’s anti-amyloid beta (Aβ) monoclonal antibody (mAb) Aduhelm (aducanumab), as it is not associated with the development of amyloid-related imaging abnormalities (ARIAs). The incidence of ARIA requires close patient monitoring and represents a significant barrier for Aduhelm and the other anti-Aβ mAbs in the late-stage AD pipeline. Even Eisai and Biogen’s lecanemab, which has shown some of the lowest rates of ARIA among the anti-Aβ mAbs, produced a rate of ARIA related to underlying vasogenic edema (ARIA-E) equal to 12.5% in the recently completed Clarity AD Phase III trial (NCT03887455). Furthermore, as an oral product, HMTM is more convenient for patients compared with the intravenous infusions required for most of the anti-Aβ mAbs.
Despite the potential shown in the LUCIDITY trial, some concerns surrounding HMTM remain. Due to the properties of the drug, which cause urinary discoloration, it is challenging to run a placebo-controlled clinical trial in which the participants remain blind to their treatment arm. Although TauRx tried to mitigate this issue in its trial design, it has been unsuccessful. The company now believes that it is not possible for a blinded placebo-controlled trial to be run for this drug. As such, the LUCIDITY results are not placebo-controlled and instead have been compared with historical matched individuals with AD from the Alzheimer’s Neuroimaging Initiative (ADNI).
The ADNI is a multicenter study of normal cognitive ageing, mild cognitive impairment, and early AD that is a publicly available resource. Additionally, previous Phase III trials of HMTM failed to meet their primary endpoints or showed mixed data, leading to a range of positive and negative opinions of the drug from key opinion leaders previously interviewed by GlobalData. GlobalData forecasts HMTM’s sales across the eight major markets (US, France, Germany, Italy, Spain, UK, Japan, and China) to reach $127 million by 2030.
TauRx will present the findings from LUCIDITY at the Clinical Trials in Alzheimer’s Disease conference in November, where a more detailed explanation of its data analysis methods could help increase physician confidence in the efficacy of HMTM.