Positive spin belies uncertain LMTX Phase III findings.
By Maha Elsayed, Analyst
31 July 2016
I am an analyst at Datamonitor Healthcare based at the New York office, where I am part of the CNS and rare disease team...
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On 27 July 2016, TauRx Therapeutics presented the results of a Phase III study evaluating the efficacy and safety of LMTX (leuco-methylthioninium) for Alzheimer’s disease at the Alzheimer’s Association International Conference in Toronto, Canada. The study failed to demonstrate LMTX’s therapeutic benefits in patients with mild to moderate disease. However, when a subgroup analysis was carried out in patients receiving LMTX as a monotherapy, an efficacy signal emerged. While TauRx Therapeutics attempted to position these latter findings as positive and encouraging, the analysis was misleading and raised many unanswered questions. Despite the failure of the Phase III study, TauRx Therapeutics plans to discuss these findings with the regulatory authorities after the readout of the second pivotal Phase III trial evaluating LMTX in mild patients, to decide on the drug’s future development as a treatment for Alzheimer’s disease. TauRx Therapeutics is also conducting another Phase III study in behavioral variant frontotemporal dementia, the results of which will be presented at the 10th International Conference on Frontotemporal Dementias from 31 August to 2 September 2016.
LMTX is a second-generation drug, following its predecessor Rember (methylthioninium chloride, also known as methylene blue), provided in a stable reduced form, thereby permitting higher doses to be absorbed. It is an orally available tau aggregation inhibitor and the most advanced tau-based approach in the clinical pipeline. Alongside amyloid-beta, tau is one of the two proteins thought to be fundamental to the pathogenesis of Alzheimer’s disease, although it is greatly under-represented in the clinical pipeline. In Alzheimer’s disease, intracellular tau tangles destroy nerve cells critical for memory. The aggregation of tau then spreads to other neuronal networks, which face a similar fate. LMTX is believed to block the formation of tau oligomers and dissolve them into short truncated monomers. Once reduced to their constituent monomers, the truncated tau monomers become susceptible to proteases and can be cleared efficiently through the proteasomal clearance pathway.
TauRx conducted a 24-week Phase II study of Rember as a proof-of-concept, which informed trial designs of LMTX’s pivotal program. At the 60mg dose, Rember demonstrated cognitive improvement in patients with moderate Alzheimer’s disease. However, there was no cognitive benefit associated with Rember relative to placebo in mild patients, which was likely due to a lack of cognitive decline in the placebo group over the first 24 weeks, preventing initial efficacy analysis. Furthermore, there was no treatment effect with the higher dose (100mg/day); this was later identified as a formulation defect and led to the study’s suspension. Despite this, the overall results were encouraging and prompted the development of an entirely new form of the molecule, with improved bioavailability and tolerability. This newly formulated drug, LMTX, advanced directly to Phase III trials at an even higher dose.
LMTX fails its first Phase III trial, but TauRx Therapeutics claims the drug yields benefits in a specific patient subset
The first of LMTX’s two Phase III studies was a 15-month, double-blind, placebo-controlled trial in patients with mild to moderate Alzheimer’s disease, defined as having a Mini-Mental State Examination score of 14−26 (TRx-237-015; ClinicalTrials.gov identifier: NCT01689246). The study was global and 85% of participants were receiving the standard of care (ie memantine, or cholinesterase inhibitors). There were three study arms: LMTX 150mg/day, LMTX 250mg/day, and placebo (containing LMTX 8mg/day to maintain blinding). To ensure a thorough analysis, the study was stratified by disease severity, geography, and co-medication. In the full study population, neither of the LMTX treatment arms differed from placebo on the trial’s primary endpoints: Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) and Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL). There were also no effects seen on additional endpoints such as assessment of brain atrophy level. However, when a pre-specified subgroup analysis was carried out on patients receiving LMTX monotherapy versus the control group, a statistically significant treatment benefit emerged on the cognitive outcomes (ADAS-Cog scores of -6.3 and -5.8 for 150mg/day and 250mg/day, respectively; p<0.0001) and functional outcomes (ADCS-ADL scores of 6.5 and 6.9 for 150mg/day and 250mg/day, respectively; p<0.0007). The magnitude of improvement in cognition was impressive considering that the gold-standard therapy, Aricept (donepezil; Eisai/Pfizer), has a cognitive benefit of approximately three points only. Furthermore, there was a significant treatment effect on brain atrophy levels, as measured by magnetic resonance imaging, which supports LMTX’s role as a disease-modifying drug. TauRx carried out an initial analysis of the data from LMTX’s second Phase III trial – TRx-237-005 – in North American patients. The analysis appears to confirm these findings and again suggests the therapeutic benefits of LMTX monotherapy.
TauRx’s claims about the benefits of LMTX monotherapy might be too optimistic
While the findings on the therapeutic benefits of LMTX monotherapy may seem encouraging at first, upon closer examination, the data are found to be ambiguous and misleading. The pre-specified analysis of the LMTX monotherapy group was performed using a very small sample size, and only 15% of the patients enrolled in the study were not taking traditional Alzheimer’s disease therapy (ie cholinesterase inhibitors or memantine). In addition, the therapeutic benefits of LMTX monotherapy were concluded by making comparisons to a pooled control group that entailed both patients on, and off, traditional therapy. These findings should therefore be viewed with caution, as an appropriate control is necessary before any conclusions can be drawn.
One point raised during the presentation of the Phase III LMTX trial data was that patients enrolling in Alzheimer’s disease clinical trials, and who are receiving pharmacological therapy, tend to exhibit faster cognitive decline than patients not receiving any treatment. The reasoning behind this is that patients not receiving pharmacotherapy may present with slower cognitive decline symptoms, meaning they are less likely to be interested in seeking treatment. If such was the case in this study, this may raise the possibility of the LMTX monotherapy cognitive and functional results being a fluke. This is one hypothetical example demonstrating the need for an appropriate placebo arm.
In addition to the questionable treatment benefits of LMTX monotherapy, regulators are unlikely to approve a drug that fails to demonstrate added benefits when used as an adjunctive therapy, especially when there is no explanation as to why this is the case. While one possible explanation for this lack of added benefit is that LMTX could be counteracting acetylcholinesterase inhibitor activity in the brain, this, along with other possibilities, would need to be explored. TauRx may attempt to convince the US Food and Drug Administration (FDA) that LMTX’s added benefit over traditional therapy results from its disease-modifying properties. However, there was no indication of such effects on brain atrophy levels when comparing LMTX to controls in the overall study population. Furthermore, the disease-modifying effects of LMTX monotherapy would still need to be demonstrated using the appropriate controls.
LMTX’s Phase III failure will threaten its future prospects, and could impact the prospects of other tau candidates as well
While previous development efforts have heavily focused on drugs targeting amyloid-beta, the development of LMTX was the first attempt at bringing a disease-modifying therapy to the market that targets an overlooked key pathology in Alzheimer’s disease. The pipeline for other tau candidates is currently scarce, with few in early-stage development, placing LMTX in a leading position. As an oral molecule with a differentiated mechanism, thought to halt and theoretically reverse the disease, LMTX had the potential to be the first drug to address the biggest unmet need for Alzheimer’s disease patients. However, the failure of its Phase III study to demonstrate therapeutic benefits is likely to negatively impact the prospects of other tau candidates, as well as the future of pursuing therapies targeting tau only. While TauRx plans to approach the FDA with data from both studies, there is a good chance that the meeting will not be in the company’s favor, with the FDA potentially requesting additional trials. However, carrying out supplementary trials may be another hurdle for TauRx; given that the company is privately held, it may face difficulties garnering enough financial support to carry LMTX through another Phase III trial – unless it decides to partner up with a larger pharmaceutical company.
Don’t miss our free Post Alzheimer’s Association International Conference webinar on 11th August, hosted by Maha Elsayed.