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.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
