Pauline Anderson

July 28, 2016

TORONTO — A drug that inhibits tau aggregation significantly reduces disease progression in patients with mild to moderate Alzheimer's disease (AD), but only in those not already receiving standard therapy with AD medications, a new phase 3 study shows.

The study is viewed by some experts as disappointing because it failed to meet its primary endpoint of significantly reducing disease progression in all patients but as positive by others because it informs future directions for this drug.

"What we have here is a potentially completely new approach to treatment that's based on the tau pathology, which is very closely linked to cognitive decline. What we have shown is that if you attack that pathway, you really do impact disease progression," said study investigator Claude M. Wischik, professor, psychiatric gerontology, University of Aberdeen, United Kingdom.

Dr Wischik is chairman of TauRX Pharmaceuticals, the company developing the new agent — leuco-methylthioninium-bis(hydromethanesulfonate) (LMTX) — a stabilized reduced form of methylthioninium.

An earlier form of the molecule was shown to be effective as monotherapy in a phase 2 trial, with the results presented in 2008 at the Alzheimer's Association International Conference and reported by Medscape Medical News at that time.

The latest findings from the phase 3 trial were presented here at the Alzheimer's Association International Conference (AAIC) 2016.

Primary Endpoint Not Met

The multicenter randomized, double-blind, placebo-controlled study included 891 patients (62% female) with probable AD who had a Mini-Mental State Examination (MMSE) score of 14 to 26, had a Clinical Dementia Rating of 1 to 2, and were younger than age 90 years.

Participants were recruited at 115 sites across 16 countries in Europe, North America, Asia, and Russia and randomly assigned to one of three study groups: oral LMTX 150 mg/day, LMTX 250 mg/day, or control/placebo LMTX 8 mg/day.

Only 15% of study patients were not taking an AD medication, such as a cholinesterase inhibitor or memantine. The proportion of patients who completed the 15-month trial was 69%.

The trial's primary outcome measure was statistically significant change from baseline on standard measures of cognition and function: the Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) and Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores.

Secondary outcomes included assessment every 3 months by MRI of the lateral ventricular volume (LVV) as a disease-modifying outcome, the ADCS-Clinical Global Impression of Change (ADCS-CGIC) and MMSE.

ADAS-Cog and ADCS-ADL assessments were performed at baseline every 13 weeks thereafter. Cranial and MRI scans were performed at baseline/screening and every 13 weeks.

Overall, the trial failed to meet its primary efficacy outcome. However, investigators found clinically meaningful and statistically significant reductions in the rate of disease progression in key study measures, but only in the 15% of patients treated with LMTX monotherapy.

Looking at the stratification variable of taking or not taking other AD drugs, the result was highly significant, said Dr Wischik. For ADS-cog, the P value was <.0001 and for the ADCS-ADL it was .0174.

"So not being on AD treatment meant that these patients were doing significantly better than either the controls or patients who were taking it as an add-on," Dr Wischik noted.

Dr Wischik added that there were no baseline group differences in ADAS-Cog, MMSE, or ADCS-ADL. However, in the mild but not the moderate group, sites in Russia, Poland, Croatia, and Malaysia were overrepresented.

Preliminary unpublished results of another study of LMTX study that included only patients in North America and Europe also showed the same effect in those not receiving standard AD medication.

"Massive Effects"

In this current study, when researchers further "parsed out the data," the decline on the ADAS-Cog in the control group was 6 units and the decreases in the two active groups were 6.25 (150-mg group) and 5.79 units (250-mg group) (P < .0001 for both).

"These are effects that can't be ignored; they're just massive," said Dr Wischik.

It was a similar story with the ADCS-ADL, for which the treatment effect of LMTX was 6.5 (P = .0013) for the 150-mg dose and 6.9 (P = .0007) for the 250-mg dose.

In addition, there was a significant impact on brain volume. The expansion of the LVV decreased by 38% (P = .0014) for the 150-mg dose and 33% (P = .0014) for the 250-mg dose.

"The reduction of brain atrophy is robust. It's the first time that this has been seen in a clinical trial in AD," said Serge Gauthier, MD, director, Alzheimer's Disease Research Unit, McGill University Research Center for Studies in Aging, Montreal, Quebec, Canada.

According to Dr Gauthier, LVV is the "most reliable" measurement of brain atrophy.

Dr Gauthier noted that investigators didn't find any micro-bleeds or swelling of the brain in patients taking LMTX.

"That's important information — that anti-tau drugs don't interfere with the blood vessel wall, so there's no need to monitor patients as closely as you would for antiamyloid treatments."

"Stage-Specific" Treatment

The safety profile of patients in the treatment group was similar to that of controls. The most common adverse event was diarrhea, which could lead some people to discontinue the medication, said Dr Gauthier.

It's not clear why the benefit was only in patients receiving LMTX monotherapy and not those taking other AD agents, said Dr Gauthier.

According to Dr Wischik, it's not because these other AD drugs interfere with the ability of LMTX to act on its target. In in vitro models, LMTX still inhibits tau even in the presence of these drugs. In mice, the drug doesn't interfere with cholinesterase and doesn't appear to interfere with absorption.

These other drugs might be turning on transporters "whose job it is to get stuff out of brain and the body and LMTX is just an innocent bystander. You've turned on the clearance mechanism, and this drug [may be] sensitive to that," said Dr Wischik.

Study participants are currently in an open-label extension of the trial. However, investigators now must decide whether patients receiving other AD medications should continue to participate in the trial, said Dr Gauthier.

In light of these new findings, Dr Gauthier speculated that AD treatments may eventually be "stage specific." In that scenario, an anti-tau drug may be given earlier, maybe during the prodromal stage of the disease, with standard treatments possibly introduced later.

TauRx Pharmaceuticals was scheduled to release phase 3 results of a study of LMTX in patients with behavioral variant frontotemporal dementia. Dr Wischik cited "patent" issues as the reason it was withdrawn and would provide no further details.

Concerns

David Knopman, MD, professor, neurology, Mayo Clinic, Rochester, Minnesota, and vice chairman, Alzheimer's Association Medical and Scientific Advisory Council, who chaired the press briefing, said the field "desperately needs new therapies."

Many features of this new trial "are really ground-breaking" and "should inform future trial designs," said D. Knopman.

However, he expressed disappointment at the results.

"My view of clinical trials that has been formed from 30 years of experience is that the only thing that really counts is the primary outcome that was prespecified."

Although the secondary results, especially the imaging findings, are interesting, "our experience in this field, and in clinical trials in general, is that secondary analysis — and this was a secondary analysis — are fraught with interpretive difficulties."

Dr Knopman also raised the issue of applicability of the findings in North America, where most patients receive standard of care with cholinesterase inhibitors or memantine.

"It has to raise question about the generalizability of these findings."

Also commenting on the findings, Howard M. Fillit, MD, a neuroscientist and geriatrician, and founding executive director and chief science officer, Alzheimer's Drug Discovery Foundation, said he is also disappointed in the results because they failed to reach meet the primary endpoint.

There should be a synergistic effect when you add LMTX to a cholinesterase inhibitor or to memantine, said Dr. Fillit. "The fact that this study didn't find that really speaks to a lack of efficacy."

He pointed out that the positive finding was in a small subsample of patients, which is "a unique population" because they're not getting donepezil or memantine.

"So who are these people, and what is unique about them that they're not getting those drugs?"

Some of these patients may have had psychiatric problems or preexisting diseases. Dr Fillit pointed out that methylene blue (methylthioninium chloride) is a phenothiazine, which has been around for a long time.

"It was the precursor to chlorpromazine, which was the first antipsychotic to be marketed in 1950s."

His theory is that study participants with AD and behavioral disorders who were not treated with standard medications and received LMTX had improved psychiatric symptoms, which may have influenced the results.

He also questioned the brain volume measurements used in the study. The "classic" method of assessing atrophy is not LVV, he said.

"I want to see hippocampal atrophy rates. If the authors found an effect on LVV but no effect on hippocampal atrophy, that would further call into question the validity of the results."

However, according to Dr Wischik, researchers did measure hippocampal atrophy and found significant retardation in the rate of atrophy, but "only in the milds and only at the highest dose with no effect in the moderates. The effect size was again a 36% overall reduction." These data, he added, "will become available when the paper, now in press in a peer-reviewed journal, are published."

Dr Gauthier is on the scientific advisory board of TauRX; his site has been involved in studies testing LMTX. Dr Fillit has disclosed no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2016. Abstract 04-08-02. Presented July 27, 2016.

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