Progressive Supranuclear Gaze Palsy (PSP) is a chronic progressive neurodegene-rative disease which, like Alzheimer’s disease, is one of the so-called tauopathies. To date, there is no causal treatment for these diseases. Monoclonal antibodies against the tau protein are considered a promising therapeutic strategy. A global phase II study [1] with the monoclonal antibody tilavonemab published today in Lancet Neurology highlights the opportunities and challenges. “We were able to show that the antibody is safe and that it reaches the tau protein in the central nervous system,” said the study leader, Professor Günter Höglinger.
Common to all tauopathies is the deposition of a pathological protein (tau protein) in certain brain regions (tau aggregates or fibrils); tau protein is also usually detectable in the cerebrospinal fluid (CSF). Tauopathies sometimes differ quite significantly in terms of biochemical mechanisms and clinical symptoms; however, there is also overlap. The clinic of Progressive Supranuclear Gaze Palsy (PSP) partly resembles classic Parkinson’s disease, which is why it is also called atypical Parkinson’s syndrome. Disturbances of the movement processes (impoverishment of movement, gait insecurity) or mental functions (cognitive disorder) occur. PSP also focuses on gaze paralysis and speech and swallowing disorders. Currently, treatment of PSP consists only of symptom management; however, with research into the complex genetic, molecular, or biochemical mechanisms of disease, there are now several causal therapeutic approaches. To date, however, no drug has been shown to be clinically effective.
Now, for the first time, an international phase II study has been published in Lancet Neurology [1] that investigated therapy with a monoclonal antibody (tilavonemab) against the tau protein in PSP patients. Nearly 500 participants were screened at 66 clinics in eight countries (Australia, Canada, France, Germany, Italy, Japan, Spain, United States), 378 were randomized to the study, and 120 could be evaluated according to the defined study criteria. Randomization was double-blind into three groups of equal size. Patients received intravenous tilavonemab either 2000 mg (n=126) or 4000 mg (n=125) or placebo (n=126) on days 1, 15, and 29; then every 28 days for a total of 52 weeks. At baseline, the symptom score PSPRS (“Progressive Supranuclear Palsy Rating Scale”) of patients was similar in the three groups; the change in PSPRS score after 52 weeks was the primary study endpoint.
The study was terminated early after 52 weeks (with 120 evaluations) according to the predefined “futility criteria” (too little or no treatment effect); as a result, there were no significant group differences in PSPRS score between verum and placebo. Most participants reported at least one adverse event during the study period: 111 patients each in the 2000 mg group (88%) as well as in the 4000 mg group (89%), but also 108 subjects in the placebo group (86%). Among these, falls (as a typical event in PSP) were most common (42 in the 2000 mg group; 54 in the 4000 mg group; and 49 in the placebo group). Substance-associated adverse events were similar in the treatment groups. Nine patients each died in the 2000 mg and 4000 mg groups and eight in the placebo group – the deaths were not related to the study medication.
In both tilavonemab groups, compared with placebo treatment, the concentration of free tau protein in the neural fluid decreased significantly (-38% with 2000 mg and -46.3% with 4000 mg). “Although no clinical treatment effect was demonstrated over the 52-week study period, biological efficacy was evident. i.e. the antibody obviously reached its molecular target,” explains Professor Günter Höglinger, M.D., Director of the Department of Neurology at Hanover Medical School, First Chairman of the German Parkinson’s Disease and Movement Disorders Society (DPG) and author of the study.
Experts discuss several reasons for the lack of clinical effectiveness of tilavonemab in this study. The antibody was initially explored in the tauopathy mouse model; it may not reach the human brain in sufficient quantities to sufficiently inhibit the transfer of extracellular tau protein between neurons. It is possible that antibody targeting in PSP must be directed to different molecular structures (epitopes) of the tau fibrils than is the case with tilavonemab, which binds to the N-terminal end of the tau protein. “In any case, despite the lack of clinical efficacy, the immunological therapy approach should not be regarded as a failure,” Prof. Höglinger states. “The PSP patients in the study may have been at too advanced stages of disease, the treatment duration may have been too short, and the tau reduction may have been too low to produce clinically relevant therapeutic effects; earlier initiation of therapy and longer treatment duration with higher dose and more appropriate epitope could possibly produce a clinical effect.” In summary, important findings for further research could thus be derived. In addition, the safety profile was confirmed.
Further studies with tilavonemab are already underway with patients in early stages of Alzheimer’s disease. In PSP, the antibody bepranemab, which binds to the middle molecular region of the tau protein, is currently being tested in a phase I trial. The “target tau” for the development of therapies for PSP and other tauopathies remains relevant and attractive, Prof. Höglinger emphasizes in conclusion; for example, a trial with a so-called tau antisense oligonucleotide in PSP has now started in Germany.
[1] Höglinger GU, Litvan I, Mendonca N et al. Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet Neurol 2021; DOI: https://doi.org/10.1016/S1474-4422(20)30489-0Original publication:
