MDS SIC Blog: Immunotherapy in Progressive Supranuclear Palsy
Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease that lacks any disease modifying therapy. PSP is a tauopathy, characterized pathologically by aggregates of the 4R-tau isoform in both astrocytes and neurons. Mounting evidence from animal models suggests that spread of abnormal 4R-tau contributes to disease progression. This extracellular tau is a natural target for immunotherapy. Three humanized mouse monoclonal antibodies have entered clinical development for PSP: ABBV-8E12 (AbbVie), BIIB092 (Biogen), and UCB0107 (UCB Biopharma), with others in pre-clinical stages of development. Thus far, early trials have demonstrated safety1 but not efficacy. Both ABBV-8E12 and BIIB092 were abandoned for further studies in PSP, although Phase 2 programs in Alzheimer’s disease are ongoing.
What are the implications of AbbVie’s aborted phase 2 and Biogen’s negative phase 2 trials for PSP? Does this invalidate the tau immune therapy approach for PSP?
Dr. Boxer: AbbVie’s trial was stopped for futility, but we don’t know what the exact stopping criteria were. Given the size of the trial, the multiple doses and the timing of stopping the trial, it seems unlikely that they could have detected anything but a very large treatment effect. Until we see more of the data at the Tau2020 meeting on February 13, 2020, it will be hard to conclude much. The AbbVie antibody (Abb8E12) was the first anti-tau monoclonal antibody (mAb) to be tested in PSP. Biogen’s trial was a larger phase 2 study but with a similar mAb (BIIB092) that was reported to be negative in December, 2019. Although both studies failed to demonstrate efficacy, it doesn’t mean that tau immunotherapy won’t work. Abb8E12 and BIIB092 are N-terminal tau mAbs. Newer mAbs bind to different regions of the tau protein, often nearer to the aggregation domain, which might lead to greater efficacy.
Dr. Stamelou: Every clinical neuroprotective trial in PSP has failed up to now, and, from every negative trial, there is a lot to learn. In that sense, the analysis of the reasons why a trial may have failed or been aborted, is what forms the implications. I think we should keep a balanced approach towards immune therapy approaches. There are arguments from preclinical and clinical data supporting this approach, but there are also many open questions. Moreover, immune therapy approaches are widely under evaluation in most neurodegenerative proteinopathies, including Alzheimer’s and Parkinson’s disease. The recent example of the antibody aducanumab (BIIB037) in Alzheimer’s highlights that there is a lot that we still need to understand in order to interpret these clinical trials. Of course, at the same time, we should think of other approaches and work on developing better pre-clinical evidence that would unravel the events before the accumulation of misfolded proteins, where we may need to intervene.
Are there other immunotherapies for PSP that we should be watching out for?
Dr. Boxer: Yes. It is likely that there will be 1-2 new studies beginning in 2020. There will also likely be other non-immunotherapy trials (small molecules, etc.) in 2020.
Dr. Stamelou: Yes, currently there are other studies studying tau-antibodies about to start and/or under way, and also further studies targeting tau dysfunction. We should have results from these in the near future. This is due to the better understanding of the pathophysiology of PSP, leading to trials not only with anti-tau antibodies but also antisense oligonucleotides, tau post-translational modifiers and others.
Compared to other tauopathies, are there unique challenges in PSP for immunotherapy?
Dr. Boxer: The biggest challenges are the lack of good biomarkers for target engagement and pharmacodynamic effects of anti-tau therapies. Additionally, most patients with PSP-Richardson’s Syndrome (who are the typical ones enrolled in trials) are fairly advanced in their disease by the time they are diagnosed. Unlike in AD, there are no validated tau PET ligands for PSP that can demonstrate potential pharmacodynamic effects of tau clearance. Moreover, CSF tau biomarkers are complex. Much of the tau protein is cleaved off before it reaches the CSF, so current CSF (and blood) assays can only detect changes in the N-terminal fragments, which may not reflect the key pathogenic species. Additionally, unlike in AD, typical CSF tau assays do not reveal elevated “total” tau or pTau181 in PSP. Instead, CSF tau levels are similar to healthy controls, and pTau levels are slightly reduced. The lower CSF pTau181 level in PSP, the more aggressive the disease2, whereas in AD, higher CSF pTau levels are generally associated with worse disease.
Dr. Stamelou: Of course, PSP is rare and its early diagnosis is challenging. However, new clinical criteria published in 2017 may help in identifying patients earlier and along a larger phenotypic spectrum3. Moreover, a brand new clinical deficits scale, ‘The Progressive Supranuclear Palsy Clinical Deficits Scale’4, was just published to propose an easy and quick scale to administer while capturing the whole phenotypic spectrum. This scale may be used in clinical practice and research. More importantly, I would say that PSP is rather a unique tauopathy to study, as it is considered the prototype of a primary tauopathy and it is possible that benefits of research in this disease may apply to other tauopathies.
Tau immunotherapy remains a promising therapeutic strategy for PSP, although efficacy has yet to be demonstrated. Ongoing efforts toward improving early diagnosis, biomarker development, and understanding pathogenesis through pre-clinical studies will be essential for optimal clinical trial design.