16 Dec 2016

The first oral communication session at this year’s Clinical Trials on Alzheimer’s Disease meeting (CTAD), held December 8-10 in San Diego, opened on a surreal note. Lon Schneider, University of Southern California, Los Angeles, first told the audience that LMTM, a reduced form of methylene blue reported to prevent aggregation of the neurofibrillary tangle protein tau, failed to slow cognitive decline in a Phase 3 trial of mild Alzheimer’s disease. This results come as no surprise, since a separate Phase 3 trial in mild to moderate AD earlier this year had also failed.

Next, however, the data were parsed in a way that left many scientists at CTAD dismayed and incredulous. Trying to provide the view of the sponsoring company, TauRx, Schneider presented a “cohort analysis,” i.e., an analysis not based on the randomized data. It showed an apparent effect of both the active and placebo treatment—which in fact contains a very low dose of the drug—in patients who were not taking acetylcholinesterase inhibitors (AChEIs), a current standard therapy for AD. In a bizarre turn, TauRx plans to abandon the higher doses and develop the placebo dose.

All experts at CTAD who saw the presentation and spoke with Alzforum said emphatically that any conclusion about monotherapy efficacy was at best based on a wrong comparison and, at worst, bogus.

CTAD co-organizer Paul Aisen, from the Alzheimer’s Therapeutic Research Institute, San Diego, told Alzforum that it was unfortunate that presentations of this and the prior Phase 3 trial suggested that there was an indication of efficacy. “This second LMTM study is consistent with the first—both studies are entirely negative,” he said. “The reported subgroup analyses are, in fact, uninformative, because they lacked an appropriate placebo group,” he added. Speaking later to Alzforum, Schneider also emphasized that the trial “did not work, period,” just as was reported last July for the first AD Phase 3 study, and again in September for a Phase 3 frontotemporal dementia trial (see Jul 2016 conference news; Sep 2016 conference news). 

This second AD trial enrolled 800 patients with mild AD (MMSE 20-26) at 98 sites in 12 countries, including the United States, Canada, Australia, and in Europe. Schneider showed that half the patients, who were randomized to 100 mg LMTM twice a day for 18 months, declined on cognition (ADAS-Cog) and functional scales (ADCS ADL) just as quickly as did patients on placebo. As in the first AD Phase 3 trial, which had tested 75 mg and 150 mg LMTM twice daily, the curves for the treatment group were almost indistinguishable from those taking the 4 mg LMTM placebo. Unusual as it sounds, the Phase 3 trials admixed a small dose of LMTM, which TauRx originally claimed to be inactive, to the placebo in order to keep the study blinded. This was necessary because the drug colors the urine and would otherwise alert patients that they were in the active arm. Anecdotally, clinicians at CTAD told Alzforum that this does not work in practice, because of an obvious difference in urine color between those on the high and low doses.

Researchers who thought this third failure might be the nail in the coffin for LMTM were mistaken. Schneider explained that TauRx changed the statistical analysis plan for this latest Phase 3 trial before the data were locked. The revised analysis appears to be in response to subgroup analysis of the first Phase 3 AD trial, which claimed a positive effect in a small number of patients who were not on AChEIs. Presented at AAIC in Toronto, that earlier subgroup analysis was widely panned by statisticians for comparing apples and oranges: The drug sponsors compared people on LMTM monotherapy against the whole placebo group, which included those on AChEIs as well. At AAIC, experts explained that people who take AChEIs do so for a reason—their disease is worse and they are declining faster (see Schneider et al., 2011). Clinicians predicted that patients who are not taking AChEIs would decline more slowly owing just to their slow disease progression, not because they were taking LMTM.

This second AD trial provided an opportunity to test whether LMTM monotherapy was better than no therapy. Alas, Schneider showed comparisons between the 100 mg monotherapy group and the whole placebo group, i.e., again including people on AChEIs. He also compared the 4 mg LMTM/placebo “monotherapy” with those taking 4 mg LMTM in addition to AChEIs. “These are completely unfair comparisons,” said Suzanne Hendrix, president and CEO of Pentara Corp., Salt Lake City. “They have to compare within the same subgroups, namely LMTM monotherapy against placebos who are also not taking other therapy.”

This questionable comparison did show an effect as per Schneider’s presentation, but without a dose response, which in the world of clinical trials often means that something is not right. Both the 100 mg and 4 mg monotherapy groups declined more slowly than those taking placebo and AChEIs, but at exactly the same rate, making some experts wonder if they were simply the inherently slow responders. Over the 18-month trial, both monotherapy groups dropped about 2.5 points on the ADAS-Cog, 5.0 points on the ADL, and their left brain ventricular volume expanded by the same amount.

Lawrence Honig, Columbia University, New York, told Alzforum that the subgroup analysis was spurious, and that this trial, like the prior trial, showed no evidence to support any efficacy of the LMTM, nor any reason to proceed with further development of this drug. Aisen called the data meaningless. Others at the meeting said they were horrified at how the data had been sliced but requested their names not be used.

Unperturbed, Claude Wischik, CEO of TauRx, told Alzforum that he plans to abandon the higher doses and develop the 4 mg “placebo” dose. “We are making no further claim other than the data are sufficiently interesting to warrant a further study,” he said. Since 4 mg of LMTM also turns urine green/blue, it is not clear what would be used as a color placebo. Wischik said details of any new trial would be decided after consulting with regulatory agencies. Typically, sponsoring companies consult senior scientists at the FDA and EMA for input during the development process. Wischik said he had not yet discussed further development of LMTM with those agencies.

Hendrix did not believe the data warrants a new trial. “If there is evidence of a treatment effect for LMTM to support moving into another Phase 3 study, either overall or in a subgroup, it has not been presented publicly," she told Alzforum.—Tom Fagan

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References

Therapeutics Citations

1. HMTM

News Citations

1. In First Phase 3 Trial, the Tau Drug LMTM Did Not Work. Period. 29 Jul 2016
2. First Round of FTD Therapeutics Fell Short, But Many More Are Up and Running 27 Sep 2016

Paper Citations

1. Schneider LS, Insel PS, Weiner MW, . Treatment with cholinesterase inhibitors and memantine of patients in the Alzheimer's Disease Neuroimaging Initiative. Arch Neurol. 2011 Jan;68(1):58-66. PubMed.

Further Reading

Papers

1. Gauthier S, Feldman HH, Schneider LS, Wilcock GK, Frisoni GB, Hardlund JH, Moebius HJ, Bentham P, Kook KA, Wischik DJ, Schelter BO, Davis CS, Staff RT, Bracoud L, Shamsi K, Storey JM, Harrington CR, Wischik CM. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet. 2016 Dec 10;388(10062):2873-2884. Epub 2016 Nov 16 PubMed.