AT AAIC 2016
TORONTO (FRONTLINE MEDICAL NEWS) – A highly anticipated phase III trial of an anti-tau drug has posted negative topline results, conferring no cognitive or functional benefits when given in conjunction with standard-of-care Alzheimer’s disease medications.
The drug, LTMX ( TauRx , Singapore), also did not slow the progression of brain atrophy on imaging in either of two doses tested, according to a company press release.
Although the study didn’t meet its clinical endpoints in the overall cohort of 891 patients with mild-moderate disease, TauRx promoted it as “promising,” based on a subgroup analysis of the 15% of patients who took the drug as monotherapy.
Among these patients, LMTX was associated with dose-dependent, statistically significant improvements in the Alzheimer’s Disease Assessment Scale measures of cognition (ADAS-cog) and Alzheimer’s Disease Cooperative Study Activities of Daily Living inventory (ADCS-ADL). The drug was also associated with a slowing of brain ventricular expansion, compared with controls, suggesting that it could be preserving brain mass.
Nevertheless, the trial must be read as another negative one, said David S. Knopman, MD, who moderated a press briefing where the data were presented.
“I must say I am disappointed by the results because in my view of clinical trials forged from 30 years of experience, the only thing that really counts is the prespecified primary outcome,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn. “I think the secondary results are interesting, especially imaging findings. But our experience of secondary analyses in this field is that they are fraught with hidden biases. And because this is a small subset of just 15%, it’s very difficult to interpret.”
Details of the study
The 15-month study comprised 891 patients with mild-moderate Alzheimer’s disease. Most of these (85%) were taking standard-of-care symptomatic Alzheimer’s disease medications. Patients were randomized to 75 mg twice daily, 125 mg twice daily, or placebo, which necessarily consisted of a small amount of the medication. LMTX is a derivative of the dye methylene blue and colors urine when excreted. The inactive dose is enough to provide that color so that blinding can be maintained.
Patients were grouped according to whether they took the study drug as add-on therapy (85%) or as monotherapy (15%). However, the results were presented in a somewhat unusual way, with the placebo patients in each therapeutic regimen grouped together. Thus, there was no way to compare the placebo-treated patients who did not receive standard-of-care medications against those who received LMTX monotherapy without standard-of-care medications; instead, the benefits reported in the active monotherapy group were compared with the results seen in placebo patients in both the mono- and add-on groups.
The reason for this was that the numbers in each group were small, said Serge Gauthier, MD, who presented the LMTX data at the Alzheimer’s Association International Conference 2016. Among the monotherapy group, 42 took 75 mg twice daily, 40 took 125 mg twice daily, and 54 took placebo. He suggested that these numbers could be pooled with those in a similar phase III trial of LMTX in about 800 patients with mild disease, which will be completed this fall.
“My proposal would be to combine these groups and then we would really be able to understand what we’re seeing in the control monotherapy versus the study drug monotherapy groups,” said Dr. Gauthier of McGill University, Montreal.
The study was conducted at 115 sites across 16 countries in Europe, North America, and Asia. All of the patients had a clinical diagnosis of Alzheimer’s disease; no one underwent amyloid PET imaging. The patients’ mean age was 70.6 years, and their baseline Mini Mental State Exam score was 18.7.
At the study’s end, patients in the monotherapy group taking 75 mg twice daily had declined 6.3 points less on the ADAS-cog than did the grouped placebo patients, indicating preserved cognition. Those taking 125 mg twice daily declined 5.8 points less than did the grouped placebo patients. On the ADCS-ADL, patients taking 75 mg twice daily scored 6.5 points higher than did the placebo group, indicating better function, and those taking 125 mg twice daily scored 6.9 points higher than did the placebo group.
Lateral ventricular volume expansion on MRI was significantly less than that seen in placebo-treated patients. For those taking 75 mg twice a day, ventricular expansion was reduced by 38%; for those taking 125 mg twice a day, expansion was reduced by 33%. This was accompanied by significant slowing of whole brain atrophy, Dr. Gauthier said, adding that this finding has never been reported in an Alzheimer’s drug trial.
Speculation on lack of effect with standard-of-care medications
Confoundingly, however, LMTX showed no benefit at all in the patients who were taking the usual Alzheimer’s medications. Nor were there similar changes in brain volume.
“We are struggling with this information,” Dr. Gauthier said. “Why this difference in the 15%? They were not older, they did not have milder disease, and there were no obvious differences. The only thing we saw was that they were more likely to have come from Eastern Europe, where access to these drugs is reduced.”
That, however, could play a key role in the findings, Dr. Knopman said in an interview.
“To be honest, I think people who entered the study not on standard of care were in regions where they were not getting any good medical care, and when they became part of this trial they began to get better medical care and experienced a pronounced placebo effect.”
He couldn’t explain how a placebo effect could be related to the MRI findings, although he did say that other medical conditions can be related to changes in brain volume. Quitting alcohol is a big one – alcoholics who stop drinking do experience increases in whole brain volume. And, Dr. Knopman pointed out, alcoholism is rampant in Eastern Europe, where most of these patients lived.
The finding is more problematic because there’s no way to compare the active monotherapy group with the placebo monotherapy group, he said.
“My suspicion is that if they had shown the differences between the monotherapy placebo and the monotherapy active groups, the curves would have looked a lot like what we saw in the add-on therapy groups.”
In an interview, Claude Wischik, MD, PhD, cofounder and executive chair of TauRx and primary investigator on all of the LMTX studies, dismissed Dr. Knopman’s suggestion.
“There’s no geography in the world that can change brain volume,” he said. “You can’t shift the brain simply by wanting it.” And while he fell short of suggesting that LMTX is affecting neurogenesis, he did say that the drug is directly responsible for modifying brain physiology.
Dr. Knopman also pointed out that the lack of baseline amyloid PET imaging almost certainly means that there were patients with other, non-Alzheimer’s dementias in the trial. Baseline amyloid PET imaging is now standard because up to 30% of patients in older antiamyloid studies have now been shown to have not even had the disease. Without baseline amyloid PET imaging to confirm diagnosis, “there’s no telling what they were treating” with LMTX, he said.
The drug’s failure as an add-on therapy is problematic, Dr. Knopman said. The symptomatic Alzheimer’s medications are generally considered to have a very low interaction profile with any other drug. This lack of efficacy, he suggested, is another hint that the benefit in the monotherapy group could be a fluke.
Dr. Wischik said this is not due to pharmacokinetics, but rather to the induction of a cellular clearance pathway called the P-glycoprotein 1 transport pathway.
“The most plausible explanation is this transporter hypothesis. If you’re taking a drug chronically – like an Alzheimer’s medication – this extrusion pathway is turned on. Its net effect is to excrete the drugs from the brain and enhance kidney excretion.” This would accelerate LMTX clearance to the point of inactivity, he said.
When asked if this would be problematic for other drugs taken chronically – statins, for example – Dr. Wischik said the cholinesterase inhibitors were responsible for activating the P-glycoprotein 1 transport pathway. He said there were no other drug interactions observed to inhibit the effect of LMTX.
Dr. Gauthier said research will proceed on LMTX, probably targeting patients with mild Alzheimer’s – or even prodromal disease – who are not yet taking an Alzheimer’s medication. In fact, he suggested that any future it might have would most likely be as part of a staged treatment. LMTX could be given early with the aim of delaying symptom onset, at which time treatment could accelerate to a symptomatic medication, and then, perhaps, to more aggressive measures like an antiamyloid, should one ever come to market.
Dr. Gauthier is on the TauRx advisory board. Dr. Knopman is an investigator on a trial of LMTX in frontotemporal dementia, but has no financial ties with the company.
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