This is Part 2 of a two-part series. See also Part 1. Download a PDF of the entire series.
28 December 2011. There are no treatments for frontotemporal degeneration (FTD), a common form of dementia in people younger than 65 years of age. That is one reason why speakers at a session titled “Clinical Trials in Frontotemporal Degeneration and Related Disorders” wanted to bring this somewhat neglected condition to the attention of the pharmaceutical industry and trialists working in Alzheimer’s disease (AD). The session was part of the 4th International Conference on Clinical Trials in Alzheimer's Disease (CTAD) held 3-5 November 2011 in San Diego, California.
In his presentation, Edward (Ted) Huey of Columbia University in New York City summarized the current state of affairs of FTD treatments. The few trials that have tested the approved therapies for AD in FTD patients have had disappointing results. “It appears that some of the patients who respond to cholinesterase inhibitors are those with AD pathology,” he said at the meeting. Memantine, too, has been tested in a small number of FTD trials. “So far it has been well tolerated in patients, but has not yet been shown to be efficacious,” said Huey. The results of the largest trial of memantine in FTD to date, conducted by Adam Boxer, University of California, San Francisco, will come out in 2012. “It should provide an answer,” said Huey.
Aside from therapies borrowed from AD, two FTD trials are testing compounds that target tau—a protein that accumulates both in some forms of FTD and in AD. Allon Therapeutics, headquartered in Vancouver, Canada, is sponsoring a Phase 2/3 randomized double-blind, placebo-controlled study to evaluate the safety and efficacy of davunetide in a type of FTD called progressive supranuclear palsy (PSP). Davunetide is an eight-amino acid peptide derived from a neuroprotective protein. It acts by maintaining and stabilizing the microtubular network (Divinski et al., 2004 and Divinski et al., 2006). Tau binds to microtubules and destabilizes them; davunetide presumably counteracts this effect, though its mechanism of action is not entirely clear. In PSP, the primary protein that accumulates in cells is a pathogenic isoform of tau, four-repeat tau. “There is little amyloid or other pathology, which makes the disease very attractive for a trial,” said Boxer, who is the study director (see ARF related news story).
Another company, Noscira, based in Madrid, Spain, is testing a different tau-busting agent in PSP. On 18 October 2011, the company announced that the last patient completed treatment in the yearlong Phase 2 efficacy trial of tideglusib, an inhibitor of glycogen synthase kinase 3-β (GSK-3β), one of the enzymes that phosphorylates tau. The trial tested two different doses of tideglusib (600 mg and 800 mg, taken orally once a day) versus a placebo in 146 patients with possible or probable mild to moderate PSP for 52 weeks at 24 sites in Europe and the U.S. “If these two trials demonstrate success with a tau-based drug in a pure tauopathy, this may help predict success in AD,” said Boxer.
Several presenters thought that targeting progranulin was a logical next step for FTD trials. Mutations in the progranulin gene may be the most frequent mutations among patients with autosomal-dominant FTD. The mutations lead to reduced levels of progranulin in blood and almost always produce TDP-43 inclusions in cells. Measuring progranulin blood levels in patients treated with a compound that boosts progranulin production may provide a way to monitor treatment effects (see ARF related news story). “A number of drugs that raise progranulin levels have been identified in high-throughput screens and tested in cell culture, and some have moved toward testing in animal models,” Boxer told ARF. “We hope that we will see clinical trials with some of these compounds next year.”
At the CTAD meeting, Michael Gold of Allon Therapeutics, which is sponsoring the davunetide trial, pointed out some of the regulatory advantages of conducting trials for orphan medications. Those are intended for the treatment of rare diseases that affect fewer than 200,000 people in the U.S., or that affect more but are not expected to recover the costs of developing and marketing a drug. (According to the presentation by David Knopman of the Mayo Clinic in Rochester, Minnesota, 20 people for every 100,000 aged 45 to 65 have FTD, and FTD has orphan disease designation.) “The FDA has indicated that drug approval based on a single trial is possible for many conditions that qualify for orphan indication,” Gold said at the meeting. According to the Orphan Drug Act, the sponsor of a clinical trial on an orphan disease can readily obtain guidance from the FDA along the way and market exclusivity for the drug being tested can be extended. Other advantages of conducting trials in FTD are that patients are younger and more enthusiastic to participate in trials than AD patients, Gold said. In addition, FTD patients’ symptoms are not complicated by changes due to aging, and the more rapid progression of disease makes trials shorter and requires fewer patients.
On the other hand, one challenge of conducting a trial with PSP patients is that the total number of patients with the disease is small, requiring that a given trial engages many different clinical sites, each of which recruits but a few patients. In the past, more sites have at times meant more sources for variability and error. “The FDA is responding to this problem and has released guidance on remote trial monitoring that may relieve that burden,” Gold said in his presentation. The draft guidance was released on 1 September 2011.
In addition to a favorable regulatory environment, new clinical diagnostic criteria for FTD, released earlier this year, may make trials easier to carry out. “Having clinical diagnostic criteria is critical to conducting clinical trials. If there is significant disagreement, as there is in the field of vascular dementia, for example, that scares away regulators,” said David Knopman of the Mayo Clinic in Rochester, Minnesota. “Although refinements are needed, there is broad agreement that the new criteria are good and valid, and people are comfortable using them.” One set of criteria is for behavioral variant FTD (bvFTD), the largest clinical subgroup of the disease (Rascovsky, et al., 2011). The second set of criteria is for the primary progressive aphasia (PPA) subtype of FTD (Gorno-Tempini, et al., 2011).
Another advance in the field has been the development of outcome measures that are appropriate for FTD. “We have to think outside the ADAS-Cog box,” Joel Kramer of the University of California, San Francisco, told Alzforum. “Up until recently, all available instruments were very memory focused, but those are not helpful for many types of FTD.” In his CTAD presentation, Kramer discussed tools his group has developed for measuring changes in executive function. One measure dubbed EXAMINER, for EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research, consists of a modular battery of tests that takes 30 to 40 minutes to administer and yields a composite score. Such tests may also be helpful in AD, Kramer believes. In the earliest stages of AD, memory is not sufficiently impaired for most current tests to capture changes, whereas it may be possible to detect shifts in executive function. His group has also made headway in developing measures for social behavior and emotion.
“The first step is to get pharmaceutical companies excited to conduct trials in FTD,” Kramer told ARF. “Once we have enough trials, we can build a consensus for outcome measures. Traditionally, the measures that are used in the first five to six trials become the gold standard.”
Another outcome measure that will be useful for FTD trials consists of changes in brain volume and function obtained through imaging. Taking the example of the landmark Alzheimer's Disease Neuroimaging Initiative (ADNI; see ARF related news story and ARF news story), two FTD-focused imaging studies have gotten off the ground. Howard Rosen of the University of California, San Francisco, described preliminary results from the FTLD Neuroimaging Initiative (FTLDNI). Funded in late 2009 by the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, the project is following 120 FTLD patients with bvFTD, semantic dementia, and progressive non-fluent aphasia (PNFA), plus 75 controls. They are being examined at baseline, and then at six, 12, and 18 months using positron emission tomography (PET) and structural magnetic resonance imaging (MRI), as well as diffusion tensor imaging (see ARF related news story). “The changes we see in FTD are different from changes we see in Alzheimer’s,” Rosen said at CTAD. “And different variants of FTD are associated with different types of changes.” He presented data from one patient who showed a visible decline volume in both left and right lobes as detected by MRIs taken six months apart. “We will have easier time than ADNI in delineating changes because disease progression is faster,” said Rosen.
The second imaging initiative, headed by Boxer, is the Four Repeat Tauopathy Neuroimaging Initiative (4RTNI). Taking advantage of the FTLDNI infrastructure already in place at UCSF, this study will recruit 40 corticobasal degeneration (CBD) and 40 PSP patients, and study each for a year using a combination of clinical measurements, biomarkers, and 3T MRI scans. Both imaging projects have adopted standards developed by ADNI to enable comparisons.
One reason for conducting these studies is to find biomarkers specific for FTD. “One thing that is really missing is a biomarker approach that would enable clinicians to subdivide bvFTD into different entities according to molecular pathology,” said Knopman. It is not surprising that current trials are being conducted in patients with PSP, a type of FTD that is relatively uniform in terms of molecular pathology.
“It is difficult to tell the underlying pathology of FTD based on the clinical group, except for rare disorders,” said William Hu of Emory University, Atlanta, Georgia, speaking at CTAD. “The clinical syndrome is useful for tracking progression of disease, but it is hard to say who has FTLD-TDP-43 and who has FTLD-Tau based on clinical criteria.” To that end, his group is looking for sets of analytes that can differentiate between the two groups of pathologies.
With the molecular biology delineated, diagnostic guidelines and outcome measures developed, and longitudinal imaging studies underway, biomarkers are the last piece of the puzzle for a broad-based effort in FTD clinical trials. But even without such biomarkers, conducting clinical trials in certain types of FTD is already feasible. “The disease is not that rare, and there are enough patients out there who should make [the investment] worthwhile for pharmaceutical companies,” said Kramer. “Plus, there are incredible applications for AD and other diseases.”—Laura Bonetta.
This is Part 2 of a two-part series. See also Part 1. Download a PDF of the entire series.