Even as researchers work to unearth the underlying causes of frontotemporal dementia, they are beginning to develop treatments that target specific mechanisms. Only a handful have come to trial yet, but more are in the pipeline. At the 10th International Conference on Frontotemporal Dementias, held August 31 to September 2 in Munich, speakers presented results from three such trials. All were largely negative, including topline results from a much-anticipated Phase 3 trial of LMTM, a derivative of the dye methylene blue. Though conference attendees were disappointed, their overall outlook was hopeful. “Now that we know the major pathways involved in frontotemporal lobar degeneration, we know what to target and what to look for in trials,” said conference co-organizer Manuela Neumann of the German Center for Neurodegenerative Diseases (DZNE). There was widespread agreement that FTD trials are becoming more rigorous and biomarker-based, improving the odds of seeing a treatment effect.

Better Behavior?

FTD patients taking tolcapone (right bar) improved their scores on the Neuropsychiatric Inventory compared to their baseline measures (left). Statistically, the benefit was not significantly better than that of patients who took placebo (middle). [Courtesy of Edward Huey.]

Both academic and industry groups appear poised to take many shots on goal with immunotherapies, HDAC inhibitors, and antisense agents to suppress expression of harmful genes. In fact, the field’s immediate problem may be finding enough patients with these fairly rare disorders to test multiple therapies at once, noted Adam Boxer of the University of California, San Francisco. FTD is about 200 times less common than Alzheimer’s disease, with an estimated 25,000 people living with the condition in the United States (see Knopman and Roberts, 2011). To help with that, researchers have established observational cohorts and are about to launch an FTD registry to gather a pool of people interested in trials (see Part 1 of this series). Cohort studies are already helping researchers identify biomarkers of disease progression that might change with treatment (see Part 3). “We have made great progress since 2014,” Boxer told the audience.

That First FTD Therapy? It Won’t Be LMTM, aka Methylene Blue
First, the bad news. Claude Wischik of the University of Aberdeen, Scotland, who leads TauRx Pharmaceuticals, described a lack of efficacy for the company’s compound LMTM in patients with behavioral variant FTD (bvFTD). Also known as LMTX or TRx0237, this compound inhibits aggregation of tau and TDP-43, two pathologies in this disorder (see Oct 2012 news). In the largest randomized controlled trial and first Phase 3 study in this population to date, researchers enrolled 221 bvFTD patients who had MRI evidence of frontotemporal atrophy. They were primarily Caucasian, skewed male, and had an average age of 63. Half the cohort took 100 mg of LMTM twice daily, while the other half took a 4 mg LMTM pill twice daily as a placebo. Because LMTM turns urine blue, 4 mg added to placebo was the lowest dose that allowed participants to remain blind to their treatment status, Wischik noted.

Participants underwent clinical, cognitive, and motor assessments at 16, 32, and 52 weeks. The trial used three primary outcome measures: The Addenbrooke’s Cognitive Examination Revised (ACE-R), the Functional Activities Questionnaire, and change in whole-brain volume on MRI. The ACE-R is similar to the MMSE, with the addition of verbal fluency; it can distinguish between FTD and AD. Secondary measures included the ADCS-Clinical Global Impression of Change, the Frontotemporal Dementia Rating Scale, and the Unified Parkinson’s Disease Rating Scale.

On every measure, rates of decline were identical in the treatment and placebo groups. Wischik said the company is still analyzing what he called a “rich data set,” and will publish more results later, including subgroup analyses of patients with different brain atrophy patterns. In addition, he claimed that the whole cohort declined less on the ACE-R than expected based on the literature. ICFTD attendees disputed this, with one audience member pointing out that the rate of decline on the ACE-R matched that seen in the Sydney GENFI cohort, suggesting it falls within the normal range. To see if both groups might have experienced a treatment benefit, TauRx is measuring how much of the drug entered the central nervous system in each group, Wischik said. CNS exposure across a relevant range of doses is typically investigated in Phase 1.

Overall, researchers considered a hidden treatment benefit unlikely and agreed this compound may have reached the end of the road as an FTD drug. “It was disappointing. There was just nothing there,” said Janine Diehl-Schmid, who presided over ICFTD2016 and had been a site leader in the LMTM trial. LMTM previously failed to budge endpoints in a Phase 3 Alzheimer’s trial. The company reported those findings at the Alzheimer’s Association International Conference 2016, where claims of statistical significance of a subgroup effect were broadly challenged (see Jul 2016 conference news).  

Two More Strikes
Zachary Miller of UCSF presented data from a Phase 1 dose-finding study of nimodipine, an FDA-approved calcium channel blocker that enters the brain well. Because this compound raises progranulin levels in mice, researchers tested it on eight people who carry mutations in the progranulin gene and have half or less of the normal level of the protein in their blood and CSF. Participants had an average age of 57; four had developed symptoms of FTD. They took escalating doses of the drug for four weeks and then remained at their maximum tolerated dose for another four before tapering off. The researchers set the maximum dose at 360 mg/day, based on previous neurological uses of nimodipine.

This regimen appeared safe, with the main side effect being swelling in the hands and feet. Dizziness made one participant withdraw from the trial. However, the researchers saw no change in plasma or CSF progranulin at any dose. Other fluid biomarkers, including CSF Aβ42, tau, and NfL, also remained flat. One industry scientist in attendance asked whether the dose had been too low; but Boxer, who ran the trial, said it would not be feasible to give higher doses. The pills are large, difficult to swallow, and have to be taken every four hours due to the drug’s short half-life in the body. The negative results suggest this drug is finished as an FTD treatment, Boxer told Alzforum.

Data from the third trial were ambiguous. Edward Huey of Columbia University, New York City, described the effects of tolcapone on FTD patients. Tolcapone is approved for the treatment of Parkinson’s symptoms; it raises dopamine levels in the prefrontal cortex by inhibiting an enzyme called COMT. The drug improves executive function in healthy controls, suggesting it might benefit FTD patients, many of whom suffer deficits in this area (see Apud et al., 2007). 

The researchers tested tolcapone in a Phase 2b trial of 28 patients with clinically diagnosed, symptomatic bvFTD. Participants either took the drug for two weeks and then switched to placebo for two weeks, or vice versa. While on drug, participants did improve their scores on the Clinical Global Impressions scale, the Neuropsychiatric Inventory, and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Their treatment effect was statistically significant vis-à-vis their baseline measure; however, people on placebo improved somewhat over baseline, as well, and the tolcapone effect missed statistical significance compared to placebo. There was no change in scores on the N-back, a test of working memory, and researchers are still analyzing scans of brain connectivity.

What could this mean? Some people carry a polymorphism in the COMT gene, V158M, that substitutes a methionine for a valine and renders the enzyme less active, raising dopamine levels. People without this polymorphism, i.e., with two copies of the val allele and lower dopamine levels, tend to have worse executive function and smaller brain volumes in the dopamine system than their met/met peers. The val/val participants benefited most from tolcapone treatment, as expected. This difference showed up on the CGI and NPI, but not the RBANS, Huey noted. He conceded the RBANS results were disappointing. Tolcapone is not particularly well-tolerated, either, and better COMT inhibitors are being developed. Some of these might be worth testing, Huey suggested. Others agreed. “There were some measureable effects of tolcapone that might warrant further investigation with new COMT inhibitors that have fewer side effects,” Boxer wrote to Alzforum.

Despite the overall negative findings, researchers said these studies represent progress. “This shows trials can be run in FTD. The targets are there,” said Philipp von Rosenstiel of Biogen Idec in Cambridge, Massachusetts.

In the Pipeline
Many other therapeutics are in trials and expected to release findings soon. A Phase 1 study in 32 progressive supranuclear palsy (PSP) patients of C2N’s 8E12, an antibody to aggregated, extracellular tau, has just finished data collection. Boxer, who ran the trial, said results will be announced at the upcoming Clinical Trials on Alzheimer’s Disease conference December 8-10 in San Diego. Bristol-Myers Squibb has a similar antibody, BMS986168, which is in a Phase 1 study of 48 PSP patients and expected to conclude next year.

Meanwhile, a Phase 2 trial of HDAC inhibitor FRM-0334 in 30 FTD patients with progranulin mutations has also wrapped up. The treatment was designed to boost progranulin levels (see Nov 2014 conference news). Scientists at ICFTD2016 expressed hope that the data will come out this fall; however, the future of the compound hangs in doubt because the sponsor, FORUM Pharmaceuticals, closed its doors in June following the failure of its Phase 3 drug encenicline (see Xconomy story). The company was funded by FMR LLC, as is Alzforum.

Researchers are investigating other ways to boost progranulin. In Munich, Daniel Bittner of the DZNE presented preliminary human data indicating that the malaria medication chloroquine can rescue progranulin levels in people who carry a pathogenic mutation or have low progranulin levels (see Feb 2011 news). In three FTD patients with a progranulin deficiency who received chloroquine for a year, CSF progranulin levels rebounded to control levels, and CSF tau decreased. CSF progranulin and tau remained stable in seven untreated FTD patients and 60 AD patients. Larger studies may be warranted, Bittner concluded.

Ongoing clinical trials not discussed at ICFTD include a Phase 1 of the microtubule-stabilizer TPI 287 in patients with PSP or corticobasal degeneration, and Phase 1 studies in PSP of the NSAID salsalate and of plasma transfusions from young adults.

The conference did feature compounds about to enter human testing, though. Christoph Wiessner of Asceneuron SA, Lausanne, Switzerland, noted that his company will take its O-GlcNAcase inhibitor ASN-561, which lowers tau pathology, into Phase 1 in healthy volunteers in 2017 (see Aug 2014 conference news). If it proves well-tolerated, they will test the therapy in PSP patients. These people are particularly in demand for trials since they have a pure tauopathy and tend to decline quickly. However, the pool of potential participants is small, since most studies report a prevalence of about six PSP cases per 100,000 people, or about 400,000 cases worldwide (see Bower et al., 1997; Nath et al., 2001). 

Bucking this trend, Norbert Zilka of Axon Neuroscience, Bratislava, Slovakia, announced that his company’s tau vaccine, AADvac1, currently in Phase 2 for Alzheimer’s, will enter a Phase 1 trial for primary progressive aphasia, a form of FTD (see Aug 2014 conference news). Estimates vary on how common tau pathology is in PPA, but tend to agree it is present in fewer than half the cases (see Knibb et al., 2006; Snowden et al., 2007). 

Other treatments target specific disease symptoms. Because many patients with bvFTD lose their ability to empathize, the hormone oxytocin, which mediates compassion, affection, and social bonding, is being tried. A previous study reporting that a single dose of intranasal oxytocin improved recognition of facial emotions in people with FTD suggested it might counteract social deficits (see Jul 2012 conference newsJesso et al., 2011). Oxytocin appeared safe in a small Phase 1 trial (see Nov 2014 conference newsFinger et al., 2015). At ICFTD, Elizabeth Finger of Western University, London, Canada, described plans for a Phase 2 trial in 100 FTD patients at four Canadian and 11 U.S. sites. It will start with a crossover design of six-week treatment intervals for dose finding; the second phase will advance the best dose. The primary outcome measure will be change on the NPI apathy/indifference score, with secondary measures to include recognition of facial emotions and caregiver distress. The trial will begin enrolling in January 2017, Finger said.

Meanwhile, Don Cleveland of the University of California, San Diego, advocated for directly shutting down pathogenic genes by targeting their RNA with antisense oligonucleotides (ASOs). ASOs bind to RNA messages and trigger their degradation (see Oct 2013 news; Nov 2015 conference news). Cleveland noted that this strategy appears to work in the childhood disorder spinal muscular atrophy, where a Phase 3 study in 110 infants recently met its endpoints at the halfway point (see press release). Biogen has now licensed the treatment from Ionis Pharmaceuticals and has applied for FDA approval. Ionis has initiated a new Phase 1 trial for ALS caused by mutations in the SOD gene (see Miller et al., 2013, for previous Phase 1 results).

Next year, Ionis plans to take an ASO targeting the C9ORF72 expansion to trial, Cleveland said. In mice with the expansion, a single injection at six months of age squelched production of the abnormal RNA and peptide, and delayed a cognition phenotype for six months (see Apr 2016 news). The expansion accounts for about one-quarter of familial FTD cases and half of familial ALS.

Many groups are gearing up to test therapies in people with the C9ORF72 expansion, and the first trials are expected to begin next year, Neumann told Alzforum.—Madolyn Bowman Rogers


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Therapeutics Citations

  1. Rember TM
  2. Nimodipine
  3. FRM-0334
  4. Encenicline
  5. TPI 287

News Citations

  1. Frontotemporal Dementia: The Hard Work of Pushing Toward Trials
  2. Fluid NfL Shines, Tau PET Dims, in the Hunt for FTD Biomarkers
  3. Will Tau Drug Show Its True Colors in Phase 3 Trials?
  4. In First Phase 3 Trial, the Tau Drug LMTM Did Not Work. Period.
  5. Progranulin-Boosting Drug Moves into Phase 2 for Frontotemporal Dementia
  6. Back to Basics? Boosting pH Puts Cells in Progranulin-Pumping Mode
  7. Therapies Take Aim at Tau
  8. Case Studies Crystallize Trial Ideas at FTD Conference
  9. Second Study Confirms Antisense Oligonucleotides Bust RNA Aggregates
  10. Listen Up, Gene Silencing Strikes a Chord at RNA Meeting
  11. Paper Alert: Could Antisense Therapy One Day Squelch Toxic Repeats in ALS or FTD?

Paper Citations

  1. . Estimating the number of persons with frontotemporal lobar degeneration in the US population. J Mol Neurosci. 2011 Nov;45(3):330-5. PubMed.
  2. . Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology. 2007 May;32(5):1011-20. Epub 2006 Oct 25 PubMed.
  3. . Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology. 1997 Nov;49(5):1284-8. PubMed.
  4. . The prevalence of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) in the UK. Brain. 2001 Jul;124(Pt 7):1438-49. PubMed.
  5. . Clinical and pathological characterization of progressive aphasia. Ann Neurol. 2006 Jan;59(1):156-65. PubMed.
  6. . Frontotemporal lobar degeneration: clinical and pathological relationships. Acta Neuropathol. 2007 Jul;114(1):31-8. Epub 2007 Jun 14 PubMed.
  7. . The effects of oxytocin on social cognition and behaviour in frontotemporal dementia. Brain. 2011 Sep;134(Pt 9):2493-501. PubMed.
  8. . Oxytocin for frontotemporal dementia: a randomized dose-finding study of safety and tolerability. Neurology. 2015 Jan 13;84(2):174-81. Epub 2014 Dec 10 PubMed.
  9. . An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 2013 May;12(5):435-42. Epub 2013 Mar 29 PubMed.

Other Citations

  1. LMTM

External Citations

  1. Phase 3
  2. Phase 3 
  3. Phase 1
  4. Phase 2b
  5. Phase 1
  6. Phase 1
  7. Phase 2
  8. Xconomy story
  9. salsalate
  10. plasma transfusions 
  11. Phase 2
  12. Phase 1
  13. Phase 3
  14. press release
  15. Phase 1

Further Reading