Can Clinical Trials and Longitudinal Studies Crack Rare Tauopathies?

Series - PSP & CBD International Research Symposium 2018:

When scientists gathered in London on October 25–26 for the first International Research Symposium on progressive supranuclear palsy and corticobasal degeneration, it was obvious that momentum was building in the study of these rare tauopathies (see Part 1 of this series). The change happened in large part because tau is now a tractable therapeutic target. Though PSP and CBD are often overshadowed by more common forms of dementia, such as Alzheimer’s, fledgling longitudinal cohorts and ongoing clinical trials are giving scientists tools to define and start to learn how to treat these disorders.  

Researchers at the meeting were eager for any morsel of news on ongoing clinical trials; alas, there were no major announcements. Three tau immunotherapies are being tested for PSP/CBD. Tim Buchanan from UCB Pharma, Braine-l’Alleud, Belgium, reviewed the status of UCB0107, a humanized IgG4 that binds an epitope just before the first repeat in tau’s microtubule binding region. Two Phase 1 trials are underway in healthy volunteers, and a Phase 2 PSP trial is being planned.

Dosing in both Phase 1s, which tested up to 120 mg/Kg UCB0107 intravenously, is complete and the patients are being followed up. No clinically relevant safety issues have emerged to date, said Buchanan. He said the Phase 2 trial will be multinational, multicenter, randomize PSP patients to one year of drug or placebo, and measure change on the PSP Rating Scale. Buchanan said the design is not quite final, but the trial will begin in 2019.

Also a humanized IgG4 but binding the N-terminus of tau, ABBV-8E12 has appeared safe in initial Phase 1 trials and is being tested in the Phase 2 AWARE trial for AD (Aug 2017 conference news). Jorge Zamudio, AbbVie, Chicago, reviewed ARISE, a Phase 2 trial for PSP that is being run simultaneously with AWARE. It will test two doses against placebo for 52 weeks, and possibly a long-term extension. Patients must be 40 or older, have had symptoms for less than five years, and be able to walk at least five steps with minimal assistance. Recruitment is ongoing at 27 sites in the U.S. and another 27 sites worldwide, with expected enrollment totaling 330. So far, 233 patients have joined, Zamudio said. He showed their baseline data, suggesting they have similar characteristics to volunteers in previous PSP trials. As for UCB0107, the primary outcome is the PRPRS.

Another IgG4 that binds N-terminal tau, BIIB092, was developed to block spread of tau toxicity in the brain. It recognizes tau fragments released from human neurons. Tien Dam from Biogen, Boston, outlined safety data from an extension to a Phase 1 PSP safety trial run by Bristol-Myers Squibb, which sold rights to the drug to Biogen (Dec 2017 conference news). 

The Phase 1 extension recruited 47 PSP patients who continued on their original dose of 150, 700, or 2,100 mg once a month. Dosing was staggered so that people on higher doses started later. By 48 weeks, 13 of the patients had discontinued treatment. Some withdrew consent, others dropped out due to adverse events or because their disease had gotten worse, or they no longer met eligibility criteria. The most common adverse events were falls, contusions, urinary tract infections, cough, and headache; these may be unrelated to the treatment, said Dam. Nine people had a serious adverse event.

Dam also mentioned the Phase 2 safety trial PASSPORT. In this one-year study with open-label extension, 234 of a planned 396 people have enrolled. They average 69 years old, have had symptoms for about 3.5 years, and have clinical characteristics similar to PSP patients from prior trials, Dam said.

In his overview of PSP/CBD clinical trials, Adam Boxer, University of California, San Francisco, outlined a new “basket” trial of BIIB092. The term is borrowed from oncology, where people with different cancers but the same underlying etiology, for example a specific mutation in an oncogene, are lumped into one clinical trial “basket.” TauBasket, primarily a safety trial, will include people with CBD, traumatic encephalopathy syndromes (TES), non-fluent variant primary progressive aphasia, or FTD due to tau mutations. Thirty-two volunteers will be randomized 6:2 to immunotherapy or placebo for six months, and blood, CSF, and MRI biomarkers will be assessed besides clinical and safety measures. The trial has begun and is slated to complete by 2020.

The scientists in London were curious how the three antibodies compared. “Based on the structure of abnormal tau, are some of these antibodies more likely to work than others?” asked Jonathan Rohrer, UCL. Boxer agreed this was an important question. “Maybe it is a coincidence that Abbvie and Biogen’s antibodies bind very close on the N-terminus, but we don’t really know the toxic species of tau, and all these antibodies have efficacy in mice,” Boxer said. Whether that translates into the clinic remains to be seen.

Others worry that the therapies are being tried too late. “All these studies require participants to be already significantly impaired. Is this the right population to study?” asked an audience member. Dam and others agreed this is a limitation, but noted they are hamstrung by the disease itself. “We need to be sure these patients do have tau pathology, so it’s a risk recruiting these [specific] patients but it’s unavoidable,” she said. Neither tau PET tracers nor CSF tau tests that reliably identify early stage PSP/CBD are available yet. Jean-Christophe Corvol from Hôpital Pitié-Salpêtrière, Paris, urged the field to figure out how to move earlier in clinical trials. “I agree we need the specificity but also think we may be treating too late,” he said. Boxer agreed that more natural-history data is essential so earlier stages can be diagnosed.

As for non-immunotherapy approaches, Boxer outlined a small safety trial of salsalate and young human plasma for PSP. Salsalate blocks acetylation of tau, a post-translational modification previously linked to pathology, while young plasma has been shown to protect old mice from neurodegeneration. In an open-label trial slated for six months, 10 PSP patients took 1,500 mg salsalate twice a day, and five PSP patients received four units per month of plasma from men younger than 30. Patient demographics were similar to those from prior trials. One adverse event led to a person dropping out of the salsalate arm; the others had unchanged progression rates as judged by change from baseline on the PSP rating scale (PSPRS) or volumetric MRI of historical controls. The point, said Boxer, was that large data sets from prior studies can be used to help power smaller ones. Some scientists are concerned that because PSP and CBD are rare, it may be hard to find enough patients to fill all tau-based trials.

Registries and Brain Banks
Researchers are banking that ongoing observational studies will help them characterize the early stages of PSP/CBD and related tauopathies. Dianna Wheaton gave an update of the FTD Disorders Registry. Founded in 2015, this independent, grant-funded registry set out as both a web-based community for patients and family members and a portal for the research community (Apr 2016 conference news). Opened to the public in March 2016, the registry exceeded its initial enrollment goals within 24 hours, said Wheaton, and to date more than 1,900 have signed up.

The registry admits people with PSP/CBD as well as FTD. Based on an intake survey, 51 percent have behavioral-variant FTD, 8 percent have PSP-RS, and 4 percent have CBD/CBS. They are predominantly white, with only 4 percent Latino, 2 percent African-American, and 1 percent each Asian and Native American.

The registry has two formats. One serves to provide information, the other follows an IRB protocol for informed consent to establish a trial-ready cohort. It complies with HIPAA, and Wheaton said the registry is undergoing an audit to ensure it satisfies new EU privacy standards as well. Ninety-three percent of registrants, including patients, family members, and spouses, said they want to participate in research, but only 26 percent have done so as yet. Wheaton hopes the registry will raise awareness and facilitate collaboration with researchers.

Over in the U.K., the PROSPECT study is a combined cross-sectional and longitudinal study to gather extensive data on PSP/CBS patients. Over five years, the prospective arm will conduct biannual clinical and cognitive tests for the first three years, assess daily living/quality of life up to five years, collect blood, DNA, and cell lines at baseline, and give patients a baseline smell test since loss of sense of smell has been associated with early Parkinsonism. MRIs and lumbar puncture at zero and 12 months, and eye-movement tests every six months up to three years, are optional. Patients in the cross-sectional study are seen but once, when their medical records are reviewed. They donate a blood sample and answer a questionnaire about their daily living and quality of life. This cohort will support genetics studies and help researchers track disease progression and milestones through analysis of ongoing medical records.

John Woodside, University College London, reported that as of mid-October PROSPECT had recruited 725 participants, including 82 controls, 218 patients in the longitudinal, and 425 in the cross-sectional cohort. The goal is to improve diagnosis, understand PSP subtypes, and get a handle on disease progression, said Woodside. PROSPECT will bank tissue and establish a trial-ready cohort. The youngest patient is 42 years old, which is quite young for PSP/CBD and hopefully may help researchers understand the early disease stages. Historically in PSP, fast deterioration and lack of antecedent markers or familial mutations made finding early stage patients almost impossible.

Since PROSPECT began, in March 2015, 88 participants with PSP or CBD have died. Only 15 of them had donated their brains for autopsy. Of the 13 who were clinically diagnosed with PSP, one turned out to have had CBD, while one of the two clinically diagnosed CBD cases turned out to have had Alzheimer’s disease instead. Woodside said this highlights the likelihood of misdiagnosis, and importance of autopsy. He has begun to use the PROSPECT cohort to develop a staging scheme based on the PSP rating scale (PSPRS).

A similar European registry for CBD, using a nearly identical protocol, has recruited 161 patients at 20 sites to date. One hundred and eight have been assessed on the PSPRS, 26 have had 3T MRI scans; 30 had CSF Aβ and tau tests, and of these nine had a CSF Aβ/tau ratio indicative of AD. Those patients also scored higher on the PSPRS, suggesting predominantly cognitive rather than motor symptoms.

Gesine Respondek from the German Center for Neurodegeneration (DZNE) in Munich outlined DESCRIBE PSP. This German observational study traces the natural history of PSP by way of its clinical presentation, genotypes, and fluid and imaging markers. DESCRIBE PSP aims to validate the most recently revised PSP diagnostic criteria established by the Movement Disorder Society (Jul 2017 news). 

Started in December 2015, DESCRIBE PSP has enrolled 176 people who met MDS PSP diagnostic criteria at around a dozen sites. Forty participants have already been followed for a year; 29 of those have donated CSF, which is optional, said Respondek. Participants complete a clinical battery every six to 12 months, and have MRI and tau PET scans at least once but ideally every year. At baseline, 67 percent were diagnosed with PSP-RS, 13 percent with PSP-Parkinsonism; the remainder had rare subtypes such as PSP with pure akinesia and gait freezing or PSP frontal, which predominantly affects the frontal cortex. One goal is to determine how often a variant PSP diagnosis changes to PSP-RS, or vice versa. Parallel DESCRIBE FTD, multiple-system atrophy, and ataxia studies are also ongoing at the DZNE.

In London, Respondek outlined a separate German study called ProPSP, run by the Deutsche Parkinson Gesellschaft, i.e. the country’s Society for Parkinson’s and movement disorders. Recruiting at different sites than DESCRIBE PSP, ProPSP routinely tests patients on clinical battery, measures brain volume by MRI, and assesses tau accumulation using the three different PET tracers AV-1451, PBB3, and PI-2620. The latter appears to bind better than other ligands to the form of tau found in PSP (Dec 2017 conference news). “With these two parallels studies, we will have comprehensive geographical coverage of PSP in Germany”, said Respondek.—Tom Fagan

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References

News Citations

  1. International Symposium Puts PSP/CBD on the Map
  2. High-Dose Aβ and Tau Immunotherapies Complete Initial Safety Tests
  3. In the Running: Trial Results from CTAD Conference
  4. Drug Trials in Frontotemporal Dementia: Can Field Push Forward Together?
  5. Revised Guidelines for Diagnosing Progressive Supranuclear Palsy
  6. At CTAD, Tau PET Emerges as Favored Outcome Biomarker for Trials

Therapeutics Citations

  1. Bepranemab
  2. Tilavonemab
  3. Gosuranemab

External Citations

  1. ARISE
  2. TauBasket
  3. FTD Disorders Registry
  4. Society for Parkinson’s and movement disorders

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