22 Mar 2024

Old drugs die hard. Despite a string of negative Phase 3 trials, HMTM, a derivative of the malaria drug methylene blue, resurfaced again at AD/PD 2024, held March 5-9 in Lisbon, Portugal. TauRx CEO Claude Wischik reported results from exploratory and post hoc analyses, as well as from an open-label extension, of the Lucidity trial, which evaluated HMTM in people with MCI and mild to moderate AD. As had been reported previously, the trial failed to meet its co-primary endpoints. At the meeting, Wischik reported that over the yearlong trial, participants with MCI who took the highest dose of the drug were half as likely to progress to AD as were volunteers in the control group. Among a subset of participants for whom blood samples were available, the drug also appeared to stem a small rise in plasma neurofilament light—a marker of neurodegeneration, he said. Further, in the open-label extension, participants with MCI who received the drug all along declined more slowly than those who had previously been in the control group, the company claimed. Given the troubled past of TauRx trials, many scientists who spoke with Alzforum were reticent to weigh in on the latest presentations of the data. Those who did were not convinced by the various subgroup analyses or, in a new twist for methylene blue trials, comparisons to external, historical controls. “Overall, there continues to be no evidence that these methylene blue derivatives have biomarker or clinical efficacy in Alzheimer’s disease,” wrote Lawrence Honig of Columbia University in New York (comment below).

Lucidity and its predecessors have been marred with complications, mostly wrought by the lack of a true control group. Because the compound gives urine a greenish-blue tinge, TauRx gave control volunteers just enough of the drug, or of a related compound, called MTC, to pee blue, to maintain blinding. Issues with this emerged in 2016, which saw HMTM, also known as LMTM, fail to slow cognitive decline in three Phase 3 trials—two in AD and one in FTD. Much to the chagrin of clinicians at the time, TauRx identified glimmers of hope within controversial subgroup analyses. They claimed that the treatment and placebo arms declined equally because the supposedly inactive placebo—8 mg/day of the drug versus 75 mg or 125 mg twice per day in treatment arms—was actually active. They also used subgroup analyses to claim that results were skewed by participants taking acetylcholine esterase inhibitors or memantine, and that in the 15 percent of people not taking those medication, LMTM slowed cognitive decline (Jul 2016 conference news; Dec 2016 conference news). They subsequently reported that HMTM boosts acetylcholine in the brains of mice (Kondak et al., 2022). Other scientists noted that people who are not taking cholinesterase inhibitors (AChEIs) typically have less-advanced dementia and therefore decline more slowly than people taking these drugs, explaining the differences in rates of cognitive decline between the LMTM monotherapy group and placebos who were mostly taking AChEIs.

Undeterred, TauRx opted for a new trial, excluding people taking AChEIs, and using much lower doses of HMTM in the active treatment group. It began in 2018, and, after several major changes, including to inclusion criteria, outcome measures, and duration, the final version of the trial protocol was published in 2022 (Wischik et al., 2022). Lucidity enrolled 598 people with MCI due to AD, mild AD, or moderate AD, all of whom were amyloid-positive according to PET scans. The 266 participants randomized to the control group took 4 mg MTC—a compound that Wischik said has the same activity as HMTM—twice weekly to maintain urine discoloration, while 252 received 16 mg/day of HMTM. A group receiving 8 mg/day was included for comparison to past trials, but these 80 volunteers were not included in analysis of the co-primary endpoints—change in ADAS-Cog11 and ADCS-ADL23 over 52 weeks. Secondary endpoints included change in whole-brain volume, while exploratory endpoints included change in clinical dementia rating scale (CDR) analyzed by disease severity.

At AD/PD, Wischik said that plasma NfL was measured as a prespecified biomarker endpoint; however, this is not listed within the published protocol or on clinicaltrials.gov.

After completing the 12-month randomized portion of the trial, all participants were invited to join an open-label extension, in which they received 16 mg HMTM per day for an additional 12 months. Wischik reported that 21 percent of participants dropped out of the blinded portion of the trial. Of those who completed it, 95 percent joined the extension. The drug was safe and well-tolerated. As determined previously, there were no significant differences between treatment and control groups for either co-primary outcome over the first 12 months of the trial (image below).

No Benefit. On co-primary outcomes (two left graphs) and secondary outcome of whole-brain volume (right), there were no differences between controls and the 16 mg/day group during the 12-month randomized portion of the trial, nor during the 12-month open label extension. [Courtesy of TauRx.]

In Lisbon, Wischik presented findings from a post hoc analysis of only those participants with MCI, who made up just under half of the total enrollees. In these participants, both the control and 16 mg/day groups improved over baseline in the first six months, this time on the ADAS-Cog13 (image below). Wischik claimed that because it is more sensitive, the ADAS-Cog13 better suits MCI patients than does the ADAS-Cog11 that was stipulated as the primary endpoint. He attributed the improvement on the ADAS-Cog13 to a tau-independent, symptomatic effect, purportedly mediated by a rise in acetylcholine in the hippocampus.

At 12 months, among those with MCI, scores in the control group had started to worsen while those in the treatment group held steady. In the open-label extension, MCI participants who had previously received 16 mg/day held steady on the ADAS-Cog13 out to 18 months, before dropping back to their baseline scores at 24 months. Scores continued to worsen between 18 and 24 months in people who had previously been part of the control group (image below). Wischik interpreted this finding to suggest that the placebo dose conferred a brief symptomatic effect, and that by the time the participants switched to the 16mg/day dose, it was too late to change the course of disease.

MCI Alone. A post hoc subgroup analysis of participants with MCI over the randomized and open-label portions of the trial suggest a benefit on the ADAS-Cog13 (left) among those taking 16 mg/day HMTM the whole time. [Courtesy of TauRx.]

Curiously, per the ADCS-ADL23, only the control MCI group experienced an apparent functional boost, doing slightly better than baseline at six months, but at no other time point. For the 16 mg/day group there was no statistically significant change from baseline during the two years to the ed of the extension. No difference emerged at any time point between the placebo and treatment groups.

This post hoc MCI subgroup analysis also teased out an effect on brain atrophy, said Wischik. At the 18- and 24-month timepoints in the extension, less brain shrinkage occurred among those with the treatment group relative to placebo.

As part of an exploratory analysis of CDR scores broken down by AD severity at baseline, Wischik claimed a 48 percent reduction in transition from MCI to AD at 12 months. What is this based on? Essentially, of 79 controls with MCI, 20 progressed from a CDR 0.5 to 1. By comparison, of 63 people with MCI in the treatment group, eight progressed from MCI to AD over 12 months. Most AD trials now eschew the CDR for the CDR sum of boxes, a much more refined test, especially for people in early stages of dementia.

HMTM Halts NfL’s Rise?
Plasma NfL, widely used as a marker of neurodegeneration in the brain, was measured in approximately 70 percent of the trial cohort “with available samples suitable for analysis,” according to Wischik. He did not explain why some samples were unavailable. He did report that the biomarker’s rise, not its concentration, over the 12-month trial was curbed by 95 percent among 136 people in the 16 mg/day group relative to 157 controls. Essentially, plasma NfL had inched up by 3 pg/mL in controls, but stayed put among people in the treatment group. Separating by disease severity, the effect was only significant among people with MCI. Among these milder cases, NfL held steady in 55 people in 16 mg/day groups and among 22 people in the 8mg/day group, while it rose by 3pg/mL among 68 controls.

Henrik Zetterberg, University of Gothenburg in Sweden, told Alzforum that the NfL findings were interesting, and may indicate that neurodegeneration became less intense in the treatment group. He has reported plasma NfL levels of around 40 pg/mL in MCI, increasing by about 2.7 pg/mL per year (Mar 2017 news; May 2019 news). Wischik did not show the absolute NfL levels. He also reported that among people whose NfL increased least, fewer transitioned from MCI to AD.

Finally, he presented comparisons between the pooled, three arms of Lucidity (including the placebo group) with two cohorts of external, historical controls. When compared to ADNI volunteers who were matched by sex, age, baseline MMSE, ApoE genotype, and who were not taking acetylcholinesterase inhibitors or memantine, Lucidity participants declined less on the ADAS-Cog11 and preserved more brain volume between baseline and 24 months. Those with MCI who received 16 mg/day were 75 percent less likely to transition to AD over 12 months than matched ADNI MCI cases. Similar effects were found when “meta-analytic” MCI controls from multiple trials were used as the external comparator.

Honig was not convinced by the trial data or the post hoc historical comparisons. “This duality thus involved both declaring the per protocol ‘placebo control’ group to actually be an active ‘non-placebo’ group, and using historical controls to imply efficacy in what was otherwise a negative randomized controlled trial,” he wrote.

Lon Schneider, University of Southern California, Los Angeles, was similarly incredulous. “Many pharmas—not having significant clinical outcomes from their randomized trials—just go on to find subsets and compare their outcomes to old data or ADNI instead of proper controls,” he wrote. “It’s a can’t-miss strategy that is sure to hack a p-value. We should do better in reporting trials results, and am confident we will in the future,” he wrote.

Although all of the apparent benefits of HMTM were found among exploratory endpoints, subgroup, or post hoc analyses, Wischik announced that TauRx will apply for marketing authorization for HMTM from the U.K.’s Medicines and Healthcare Products Regulatory Agency, and that discussions with the European Medicines Agency and Chinese regulators are moving forward as well.—Jessica Shugart

 

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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. Tau Inhibitor Fails Again—Subgroup Analysis Irks Clinicians at CTAD 16 Dec 2016
3. Blood Neurofilament Light a Promising Biomarker for Alzheimer’s? 31 Mar 2017
4. Plasma NfL Goes the Distance in Alzheimer’s 2 May 2019

Paper Citations

1. Kondak C, Riedel G, Harrington CR, Wischik CM, Klein J. Hydromethylthionine enhancement of central cholinergic signalling is blocked by rivastigmine and memantine. J Neurochem. 2022 Jan;160(2):172-184. Epub 2021 Dec 15 PubMed.
2. Wischik CM, Bentham P, Gauthier S, Miller S, Kook K, Schelter BO. Oral Tau Aggregation Inhibitor for Alzheimer's Disease: Design, Progress and Basis for Selection of the 16 mg/day Dose in a Phase 3, Randomized, Placebo-Controlled Trial of Hydromethylthionine Mesylate. J Prev Alzheimers Dis. 2022;9(4):780-790. PubMed.

Further Reading

News

1. First Round of FTD Therapeutics Fell Short, But Many More Are Up and Running 27 Sep 2016