Earlier this month, researchers and regulators took up an invitation from the Association for Frontotemporal Degeneration and the National Institute of Neurologic Diseases and Stroke to meet in Washington, D.C., for a day of work toward therapeutic trials for these diseases. After discussing the general requirements for FTD clinical trials (see Part 2 of this series), they got specific. To that end, they broke the heterogeneity of clinical syndromes and molecular pathologies of the FTLD spectrum of diseases into three case studies. Progressive supranuclear palsy (PSP) represents a sporadic pure tauopathy; progranulin-deficient FTLD represents a genetically defined entity, and behavioral variant FTD represents a clinical syndrome. Each stands for a patient population for whom the Frontotemporal Dementia Treatment Study Group (FTSG) would like to design therapeutic trials. In each case, an FTSG scientist presented a design and then solicited advice from regulators of the Food and Drug Administration and industry scientists.

Case Study 1: Progressive Supranuclear Palsy
Michael Gold of Allon Therapeutics, Inc., in Vancouver, Canada, noted that as a pure tauopathy, PSP would seem an ideal disease for evaluating tau-based drugs free of the complicating influences of mixed amyloid and vascular pathologies that are often found in Alzheimer’s. PSP is the second most common parkinsonian disorder after Parkinson’s itself. Its core phenotype is recognized, its diagnosis pathologically validated, its clinical progression well known and inclusion criteria widely accepted. PSP worsens so quickly, with up to 20 percent annual mortality, that trials can be substantially shorter than trials in AD or PD.

The medical need is great, said Irene Litvan, a movement disorders specialist at the University of California, San Diego. Litvan said that almost none of the long list of medications her PSP patients tend to be on when they are referred to her actually help them. This includes antidepressants, antipsychotics, and cholinesterase inhibitors. The ALS drug riluzole has been tested in the largest PSP study to date, the Neuroprotection and Natural History in Parkinson’s Plus Syndromes (NNIPPS) trial; it did not help patients but was generally regarded as a well-conducted study that taught the field how to run PSP trials. The approved MAO inhibitor rasagiline is currently completing a one-year Phase 3 trial. The experimental GSK-3 inhibitor NP031112/tideglusib by the Spanish biotech company Noscira completed a Phase 2 trial, called Tauros, in late 2011. In December 2011, the Spanish news site elEconomista.es reported that it failed to achieve its objectives.

In D.C., Gold spoke about Allon’s ongoing Phase 2/3 trial of davunetide, a peptide delivered by intranasal spray. Following on the NNIPPS trial, the davunetide study confirmed that PSP trials are doable. Screening and enrollment occurred apace, and site investigators and raters are generating reliable data. “The logistics and feasibility for PSP studies are absolutely there,” Gold said.

Alas, Allon’s experience also highlights the challenges of evaluating drugs in PSP. It is difficult to find early-stage patients because many physicians do not recognize that patients have a neurologic problem and, hence, only refer them once the disease is well established. There are no criteria for prodromal PSP or validated biomarkers to improve diagnosis, response to treatment, or progression. Of the few choices for outcome measures in PSP, none has yet been validated in a therapeutic trial. The Movement Disorders Society is about to publish a critique of all available PSP scales. One specific problem Allon discovered was that, as the characteristic gaze disturbance of PSP worsens, some patients lose the ability to read. “Be careful with tests that require reading,” Gold said. What’s more, the rapid progression is a double-edged sword. On the one hand, it may reduce the number of subjects needed in a clinical trial as well as the length of the study. However, rapid progression may lead to more patients becoming unable to travel to their sites for repeat visits. Falls, in particular, can be dangerous, even fatal, because PSP patients appear to lose their ability to break a fall, Gold said.

In the Allon trial, about 20 percent of patients consented to lumbar puncture, Gold said. This low level of participation can be addressed in future studies. In other studies, including DIAN, ADNI2, and the Bristol-Myers Squibb prodromal AD trials, lumbar puncture consent rates approach 100 percent. What gives? Scientists agreed that the difference lies in how lumbar puncture is presented and explained to both site physicians and participants. “In ADNI2, we get even second lumbar punctures without a problem. Clearly, the first one was not so onerous that patients do one but refuse another,” said Murray Grossman of the University of Pennsylvania, Philadelphia. William Hu of Emory University, Atlanta, Georgia, added, “When I moved to Atlanta, our lumbar puncture rate went from 10 percent to 90 percent. It is how you explain it. You say this is a part of the study and it is important, and patients will participate. It takes a culture change.”

The Allon trial has set the stage for subsequent PSP trials to learn from its woes. “We have a mechanism that will make the data available to the research community. Even if our study did not work, it will put foundational pieces in place for the next one,” Gold said. Gold called for a global PSP registry for tracking progression in patients that multiple companies could tap to evaluate their compounds.

Regulators recommended that in the longer term, researchers develop a therapeutic trial strategy where individual drugs are first proven to have a pharmacological effect and are then tested together in adaptive combination trials, as pioneered by the I-SPY breast cancer study. “I believe it is very difficult to affect a neurodegenerative process with a single drug. Having a real clinical impact is probably a matter of a combination therapy, like in cancer,” said Christina Sampaio, a movement disorders specialist who in 2011 left the European Medicines Agency after 13 years to join the Cure Huntington's Disease Initiative, which funds and shapes therapeutic research in that disease. Sampaio spoke personally, not on behalf of the EMA. Industry scientists emphasized the need for pharmacodynamic biomarkers in PSP.

Case Study 2: Symptomatic Progranulin Deficiency
Adam Boxer of the University of California, San Francisco, argued the case for trials to boost levels of the growth factor progranulin, whose genetically induced reduction leads to FTLD. No such trials have been done yet. “Correcting progranulin deficiency is the low-hanging fruit in neurodegenerative disease treatment,” said Boxer.

Progranulin is the second most common FTLD gene after C9ORF72, and 4 percent of sporadic FTLD patients have low levels of progranulin as well, said Boxer. The growth factor’s role in inflammation indicates it might be widely useful in neurodegenerative diseases that have an inflammatory component.

Toward this goal, the field has generated a range of mouse models of progranulin deficiency. Some existing drugs raise progranulin levels in mice (e.g., Cenik et al., 2011), and several companies are working on their own compounds that penetrate the blood-brain barrier and are safe enough for long-term therapy.

“Why are we excited about progranulin as a target? Because we can measure it in blood and think its elevation can become a surrogate endpoint in trials,” Boxer told the audience. CSF data indicate that progranulin levels of mutation carriers and non-carriers are clearly separated—a promising sign for clinical studies. Boxer peppered regulators and industry scientists with questions on what they would want to see done before granting an IND. What level of animal or iPS cell data is necessary to move a compound into humans?

Boxer started a conversation on trial design by proposing a dose-finding/proof-of-concept trial that would enroll progranulin mutation carriers. It would measure safety, tolerability, and serum and CSF progranulin levels with ascending doses of the compound in weekly increments until a maximum tolerated dose was found. Boxer asked industry and regulatory scientists these questions: What if we see a change in plasma but not CSF? Do we need to think about genes that modify progranulin expression? Does the trial need to show an increase of CSF progranulin, or would measuring blood levels suffice? Could serum progranulin be a basis for conditional approval? How large an increase in progranulin is enough?

This proposal generated ample discussion. Dana Hilt from EnVivo Pharmaceuticals in Watertown, Massachusetts, noted that moving progranulin levels up to the bottom of the normal range may be sufficient, since heterozygotes and non-carriers do not overlap. To do that, researchers must know the test-retest variability of the assay, as well as the variability of a given patient over a period of days and weeks. Regarding plasma versus CSF, Hilt recommended that the trial sample both, making plasma the primary endpoint and studying the latter. “In this early stage, I would explore dose ranging and various imaging outcomes in a learning study, which would help design a larger, more confirmatory study,” Hilt said.

Steve Salloway of Brown University, Providence, Rhode Island, advised the FTSG to stay agnostic at this early stage of progranulin research. “I know we have a desperate need to treat. But we are in new territory. Let’s gather information and be careful, not hasty,” Salloway said. Initial drug studies should show that the drug moves the biomarker. “The idea of moving from that point to conditional approval without showing a clinical benefit seems premature to me,” Salloway said. Extending natural history research to gain as much data on the disease as possible will pay off later, Salloway said.

Lynne Yao from the FDA’s Center for Drug Evaluation and Research agreed, noting that because every patient in these rare diseases is so precious, every study, even the first dose-finding study, should extend those patients and keep observing them to gather longitudinal data. “With rare diseases especially, all data will be important in the end. We look at the entire package from all studies, so make the most use of every patient,” she said.

Yao further noted that the scientists would have to show if serum and CSF progranulin correlate and explain how raising progranulin in plasma would make things better for the patient. If indeed it turns out that progranulin does not change in CSF in response to the drug, then plasma progranulin would be a diagnostic marker for inclusion, but not a surrogate, Yao said.

Several scientists recommended that progranulin models be used to explain the biology between progranulin and disease, and to test the assumption that progranulin itself is indeed the best step in the pathway to tackle therapeutically. Industry scientists agreed that more understanding of CSF progranulin and its downstream connections to TDP43 and disease would have to be in hand before they would launch large-scale trials.

Case Study 3: Behavioral variant FTD
What about symptomatic therapies? Treatments based on tau or progranulin would target a core molecular pathophysiology of FTLD and, hence, presumably modify disease. Conceptually, disease modification beats symptomatic treatment, and it dominates conversation at conferences. But proving disease modification of a progressive disease sets a higher technical bar than showing a temporary symptomatic benefit. Symptomatic treatments may be valuable, particularly for sporadic cases of FTD when no molecular cause is known.

In behavioral variant FTD, there have been two small trials of a symptomatic treatment that may provide a starting point for future work, said Elizabeth Finger of the University of Western Ontario, London. The neuropeptide oxytocin is a maternal hormone that is thought to promote social cognition in animals and humans (Donaldson and Young, 2008). It is made in the hypothalamus in neurons that project to the frontal lobes. Conceivably, oxytocin might help with the interpersonal deficits that make bvFTD emotionally wrenching, such as a patient’s inability to process facial expressions and recognize vocal affect in loved ones.




Axial FDG-PET scan through frontal lobes of a 59-year-old patient with behavioral variant FTD demonstrating frontal lobe (right greater than left) hypometabolism (right side of brain is on left side of image). Image courtesy of Jason Warren

Oxytocin can be given intranasally (Chang et al., 2012). Some human studies see a trend toward improved social recognition and emotional empathy (e.g., De Dreu, 2012). With that, Finger and colleagues ran a proof-of-concept study of a single dose of oxytocin spray, in which 20 people with bvFTD completed various tasks testing their ability to recognize facial and auditory expression and theory of mind (Jesso et al., 2011). This initial study recorded an improvement in the Neuropsychiatric Inventory (NPI) Questionnaire. Subsequently, Finger’s group tested three doses given to people with bvFTD for a week, with the same measures taken at one week and adverse events measured at two weeks. This generated no serious side effects, and the lower dose registered a small effect on apathy measures on the NPI. Responders inquired somewhat more about relatives and showed an interest in reading and daily activities, Finger said.

Given those data, Finger asked the audience if a multicenter study on oxytocin would be worth doing. In fact, she asked, are symptomatic treatments worth the cost and effort at all? In subsequent panel and audience discussion, this latest question generated a resounding “Yes.” Symptomatic drugs are clinically valuable, said Ilan Irony of the Food and Drug Administration, speaking for many. This is seen as true, particularly in the interim years until enough disease-modifying drugs are available to max out site, investigator, and funding capacity. “I might not go after symptomatic drugs if there were better alternatives, but right now there are not,” said Steve Whitaker from the biopharmaceutical company Omeros. With regard to moving forward with oxytocin, the consensus was weaker. Before tackling a larger trial, dose finding could be revisited with a study geared explicitly toward bvFTD, not based on cancer or other indications.—Gabrielle Strobel.

This is Part 3 of a five-part series. See also Part 1, Part 2, Part 4, Part 5. Read a PDF of the entire series.


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News Citations

  1. Toward FTD Therapeutic Trials: Diagnosis Firm, Outcomes Still Soft
  2. Scientists Strategize With Regulators for Frontal Assault on FTD
  3. Take It From the Agency: First FTD Drug May Be an Orphan
  4. For FTD Drug Development, a Q&A With Regulators

Paper Citations

  1. . Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. J Biol Chem. 2011 May 6;286(18):16101-8. PubMed.
  2. . Oxytocin, vasopressin, and the neurogenetics of sociality. Science. 2008 Nov 7;322(5903):900-4. PubMed.
  3. . Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta). Proc Natl Acad Sci U S A. 2012 Jan 17;109(3):959-64. PubMed.
  4. . Oxytocin modulates cooperation within and competition between groups: an integrative review and research agenda. Horm Behav. 2012 Mar;61(3):419-28. PubMed.
  5. . The effects of oxytocin on social cognition and behaviour in frontotemporal dementia. Brain. 2011 Sep;134(Pt 9):2493-501. PubMed.

Other Citations

  1. Read a PDF of the entire series.

External Citations

  1. Allon Therapeutics, Inc.
  2. Noscira
  3. elEconomista.es
  4. I-SPY breast cancer study
  5. EnVivo Pharmaceuticals
  6. Omeros

Further Reading