Friday, July 29, 2016

Clinical Trial for Alzheimer's Disease - Is LMTX Ineffective or Unprecedented?






So which is it? Ineffective or unprecedented?

TauRx Alzheimer's Drug LMTX Fails in Large Study Although Some Benefit Seen

Wednesday, 27 Jul 2016 | 11:23 AM ET

TauRx Pharmaceuticals' experimental Alzheimer's drug LMTX failed to improve cognitive and functional skills in patients with mild to moderate Alzheimer's disease, a large, late-stage study showed.

But in a perplexing twist, the drug did show a significant benefit in about 15 percent of patients in the trial who were not taking other standard Alzheimer's drugs, according to the findings released on Wednesday at the Alzheimer's Association International Conference in Toronto.


LMTX was ineffective in a clinical trial of 891 patients with Alzheimer's disease (AD), although a post hoc analysis in a small subgroup of patients showed a benefit for those taking no other medications for AD (when compared to an inappropriate control group).


Ben Goldacre, Chris Chambers, and others on Twitter took the UK media to task for their misleading articles on the outcome of the trial conducted by TauRx Pharmaceuticals.

As the name implies, TauRx is developing Alzheimer's treatments based on disrupting tau protein, which accumulates in pathological tangles in the brain. Tau aggregation inhibitors are presumed to disrupt these tangles, thereby slowing neurodegeneration and memory loss. The degradation of tau aggregates in vitro was first demonstrated 20 years ago (Wischik et al., 1996), using the stain methylene blueLMTX is a variant of methylene blue, which turns urine blue. For that reason, the placebo group in the TauRx trial received a tiny amount of the drug for blinding purposes.

The clinical trial protocol is NCT01689246, Safety and Efficacy Study Evaluating TRx0237 in Subjects With Mild to Moderate Alzheimer's Disease. The original enrollment across 121 sites was estimated at 833, and the original duration was 12 months. The duration was changed to 15 months about a year later, and five other outcome measures were added. And a secondary outcome measure (ADCS-ADL23) and a primary outcome measure (ADCS-CGIC) were swapped.

The company press release used a vague headline (TauRx Reports First Phase 3 Results for LMTX®) to announce the results, but led off with the subgroup analysis (no surprise):

TauRx Therapeutics Ltd today announced Phase 3 clinical trial results that show treatment with LMTX®, the company's novel tau aggregation inhibitor, had a marked beneficial effect on key measures of Alzheimer's disease in patients with mild or moderate forms of the disease.

While the TRx-237-015 study in 891 subjects failed to meet its co-primary endpoints, clinically meaningful and statistically significant reductions in the rate of disease progression were observed across three key measures in patients who were treated with LMTX® as their only Alzheimer's disease medication. These three key measures comprised a cognitive assessment (ADAS-Cog), a functional assessment (ADCS-ADL) and an assessment of the level of brain atrophy (lateral ventricular volume, LVV, as measured by MRI). An abstract of the results will be presented during an open session at the 2016 Alzheimer's Association International Conference (AAIC) in Toronto, Canada this afternoon by Dr. Serge Gauthier, CM, MD.

The ADCS-ADL was originally a secondary outcome measure, and hippocampal volume (not reported) was included as an “Other” outcome measure along with the lateral ventricle volume measurements. Keep in mind these results are preliminary (not peer-reviewed). However, given the possibility of a true positive treatment effect, I can understand why publication would be of secondary importance. There should be no delay in starting AD patients on an effective new and proven treatment (which this is not).

It took a while to find the conference abstract by Gaultier et al. (2016), but an excerpt is below. The actual results were not included the abstract aimed to “highlight the potential therapeutic value” of LMTX (also called LMTM and TRx-0237)  but the text did mention the “85% were taking approved AD treatments” aspect of the study.

Gaultier et al., AAIC 2016

LMTM (TRx-0237) is a novel stabilized reduced form of the methylthioninium moiety with potential for efficacy in treatment of Alzheimer's disease. ... It acts as a selective tau aggregation inhibitor in vitro and in transgenic mouse models  The present 15-month double-blind, placebo-controlled trial (NCT01689246) was performed in patients with probable AD, MMSE score in the range 14-26, Clinical Dementia Rating 1-2 and age < 90 years. Patients were randomized 3:3:4 to receive oral LMTM at doses of 150 or 250 mg/day or placebo (containing 8 mg/day, to maintain blinding) respectively. Primary efficacy outcomes were change from baseline on cognitive (ADAS-Cog) and functional (ADCS-ADL) scores. Three-monthly assessment included magnetic resonance imaging (MRI) as a disease modifying outcome. Other secondary outcomes included ADCS-CGIC and MMSE. Results: A total of 891 patients were randomized, of whom 62% were female. Approved AD treatments were being taken in 85%. The mean age was 70.6 (SD 9.0) years and baseline MMSE score was 18.7 (SD 3.4). ... The study efficacy and safety outcomes will be reported. The outcomes of this phase 3 trial will highlight the potential therapeutic value of tau aggregation inhibitor therapy in AD. A second phase 3 trial of LMTM for AD will be completed and reported later in 2016.

[The entire abstract with authors and affiliations is at the end of this post.]

The 15% who benefited from LMTX® were the patients who were not taking any other medications for dementia (e.g., acetylcholinesterase inhibitors). This monotherapy subgroup was compared to the entire placebo group, not to the subgroup of placebo patients not on any other dementia meds (as pointed out by @bengoldacre). It was nice to read critical coverage of the TauRx spin (and media reporting) at Forbes, BuzzFeed, and Quartz.


Meanwhile, New Scientist updated their headline (and url) to more accurately reflect reality.




Is it worthwhile for TauRx to pursue a proper clinical trial of LMTX as a monotherapy?  Maybe. The big mystery is why LMTX didn't work in patients taking the usual medications for dementia. There's no convincing mechanism to explain that odd result (Wischik: “other Alzheimer’s treatments help to clear toxic material out of the brain, and may also clear away LMTX too”). Or it could be a p-hacked false positive, or a function of milder severity or diagnostic issues or study site in the 15%. If TauRx is truly confident that LMTX taken alone can slow the progression of AD by 80%, then run another randomized controlled study where LMTX + no AD meds is compared to placebo + no AD meds.

Meanwhile, exaggerated reporting on “the first drug to halt Alzheimer’s” is highly unethical.


ADDENDUM (Aug 2 2016): A damning article at Alzforum says, In First Phase 3 Trial, the Tau Drug LMTM Did Not Work. Period.
On the main primary results slide, disease progression curves for both doses of drug and the placebo were practically identical. Scientists’ disappointment at this finding soon turned into disbelief when Gauthier went on to present a subgroup analysis that held no statistical credence yet purported to show a strong benefit on cognition and brain atrophy.
 
Thanks to @MaikWallas for the link.


AAIC Conference Abstract

Phase 3 Trial of the Tau Aggregation Inhibitor Leuco-Methylthioninium-Bis(hydromethanesulfonate) (LMTM) in Mild to Moderate Alzheimer's Disease

Serge Gauthier, MD1; Howard H Feldman, MD2; Lon S Schneider, MD, MS3; Gordon Wilcock, MD4; Giovanni B Frisoni, MD5; Jiri Hardlund, MD6; Karin Kook, PhD7; Damon J Wischik, PhD6; Bjoern O Schelter, PhD8; John M Storey, PhD6,8; Charles R Harrington, PhD6,8 and Claude M Wischik, MD, PhD6,8, (1)McGill University Research Centre for Studies in Aging, Verdun, QC, Canada, (2)University of British Columbia, Vancouver, BC, Canada, (3)Keck School of Medicine of USC, Los Angeles, CA, USA, (4)Oxford University, Oxford, United Kingdom, (5)Universite de Geneve, Geneve, Switzerland, (6)TauRx Therapeutics Ltd, Aberdeen, United Kingdom, (7)Salamandra LLC, Bethesda, MD, USA, (8)University of Aberdeen, Aberdeen, United Kingdom

Background: Leuco-methylthioninium-bis(hydromethanesulfonate) (LMTM; TRx-0237) is a novel stabilized reduced form of the methylthioninium (MT) moiety (Harrington et al. J Biol Chem 2015;290:10862) with potential for efficacy in treatment of Alzheimer's disease (AD). A previous trial using the oxidized form of MT identified dose dependent absorption limitations (Wischik et al. J Alzheimers Dis 2015;44:705). LMTM is better absorbed and tolerated (Baddeley et al. J Pharmacol Exptl Therapeutics 2015;352:110) permitting higher doses to be tested. It acts as a selective tau aggregation inhibitor in vitro (Harrington et al. J Biol Chem 2015;290:10862) and in transgenic mouse models (Melis et al. Behav Pharmacol 2015;26:353). Methods: The present 15-month double-blind, placebo-controlled trial (NCT01689246) was performed in patients with probable AD, Mini-Mental State Examination (MMSE) score in the range 14-26, Clinical Dementia Rating (CDR) 1-2 and age < 90 years. Patients were randomized 3:3:4 to receive oral LMTM at doses of 150 or 250 mg/day or placebo (containing 8 mg/day, to maintain blinding) respectively. Primary efficacy outcomes were change from baseline on cognitive (Alzheimer's Disease Assessment Scale cognitive subscale; ADAS-Cog) and functional (Alzheimer's Disease Cooperative Study Activities of Daily Living; ADCS-ADL) scores. Three-monthly assessment included magnetic resonance imaging (MRI) as a disease modifying outcome. Other secondary outcomes included ADCS-CGIC and MMSE. Results: A total of 891 patients were randomized, of whom 62% were female. Approved AD treatments were being taken in 85%. The mean age was 70.6 (SD 9.0) years and baseline MMSE score was 18.7 (SD 3.4). Dementia was of moderate severity (MMSE score 14-19) in 61%. The study efficacy and safety outcomes will be reported. Conclusions: The outcomes of this phase 3 trial will highlight the potential therapeutic value of tau aggregation inhibitor therapy in AD. A second phase 3 trial of LMTM for AD will be completed and reported later in 2016.

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1 Comments:

At August 10, 2016 7:30 AM, Anonymous NeuroSéance said...

Unprecedented. The placebo effect suggested by Team Amyloid is hardly likely to result in preservation of brain volume.*

This is sort of like the allegory of the blind men and the elephant. I'm trying to piece it together. This is somewhat mysterious...In the Alzforum critique, it said
"On the main primary results slide, disease progression curves for both doses of drug and the placebo were practically identical."

I drew a table:
http://pasteboard.co/6WJDM0crK.png

Does the quoted material refer to my columns #2 and #3, for both doses of drug, and column #1 for placebo? If so, there's no main effect. That doesn't mean the drug is ineffective or that the trial failed. In this case there could be an interaction. The fact that the researchers "spent their alpha" doesn't mean there's no effect outside of the planned analyses. It's a fallacy to think the planned analysis finds legit effects and any later analyses can only find flukes. The data are what they are, independent of the order in which you test relationships.

Back to my table...
http://pasteboard.co/6WJDM0crK.png

The much-disparaged comparison (TaurX drug only vs The Wrong Control Group) was of my cells 2 and 3, and ...1, 4, 5 and 6? Or a subset of those four cells? I'd love to know.

Your post was more even-handed than most.

*The treatment-as-usual might cause volume loss.

 

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