The Bright Lights: Will New AD Therapy Really Shine?

Investigational drug studies are being hyped with promising results in dementia. Can the therapies live up to lofty expectations?

By Zac Haughn, Senior Associate Editor

A global Phase III clinical trial in a type of Frontotemporal Dementia (FTD) also known as Pick’s Disease has been initiated. The study drug, LMTX, a second-generation Tau Aggregation Inhibitor (TAI), targets a process in the brain whereby a normal form of tau protein begins to self-aggregate due to binding neuronal waste-products, according to TauRx Therapeutics, the company behind the drug.

A drug entering a Phase III isn’t normally headline-grabbing news, but this agent is noteworthy because of the headlines that the developing company grabbed with a previous treatment. “Daily pill that halts Alzheimer’s is hailed as ‘biggest breakthrough against disease for 100 years’,” The Daily Mail in the UK blasted to its readers in 2008. “New Alzheimer’s drug shows early promise,” wrote optimistically.

That drug, Rember, was featured in a clinical trial reported at the International Conference on Alzheimer’s Disease (ICAD) held July 2008 in Chicago. A press release from the company at that time said: “A major breakthrough in the treatment of Alzheimer’s disease is revealed today by scientists at the Alzheimer’s Association ICAD 2008. Their pioneering research points to a new treatment that appears to slow the progress of the disorder by 81 percent over a year, and could offer hope to millions worldwide. The product—Rember—is the first drug to act on the tangles discovered by Alois Alzheimer over a century ago.”

It should be noted that the reaction from the conference attendees ranged from “puzzled to intensely skeptical,” according to the Alzheimer’s Research Forum. But TauRx has taken what they learned from Rember and thrown that focus on LMTX, which it calls “an improved form of the first generation compound, Rember.”

In a pilot series of cases, LMTX was found to arrest the progression of FTD. LMTX has been found to act in a similar way on the aggregation of TDP-43 protein, according to the company. Tau or TDP-43 aggregates each account for about 50 percent of patients with this early form of dementia, they note.

The Phase III double-blind placebo-controlled study is intended to assess the safety and efficacy of LMTX. The study aims to confirm the results first seen in the pilot cases in a larger controlled clinical trial in bvFTD patients over a 52-week timeframe. Due to the relative rarity of the disease, TauRx was granted Orphan Designation by the FDA in 2010, which could provide a basis for a more rapid review process and approval for marketing if the trials are successful.

The study focuses on a type of FTD known as behavioral-variant, or bvFTD, which can cause early changes in personality and loss of empathy. A large number of these patients have a specific pathology that involves abnormal collections of tau protein in the brain.

Once the process has started, the aggregates are able to propagate themselves indefinitely, using up normal tau protein and converting it into the toxic aggregates. After destroying the nerve cells where they are initially formed, the aggregates go on to infect nearby healthy neurons, progressively spreading and accelerating the destruction throughout the brain. TauRx says LMTX stops this aggregation process and releases the trapped tau protein in a form, which can be easily cleared by nerve cells.

The Singapore-based company, spun out of the University of Aberdeen, says they developed the novel treatment “based on a new approach that targets aggregates of abnormal fibres of tau protein that form inside nerve cells in the brain.” They believe that LMTX could also have beneficial effects on other proteins that aggregate abnormally, including TDP-43 in FTD and synuclein in Parkinson’s disease.

Below, Claude Wischik, MD, PhD, Chairman of TauRx and Professor of Old Age Psychiatry at the University of Aberdeen, discusses the investigational agent and its potential uses.

What should neurologists take away from the earlier studies in oral AD therapy?

Dr. Wischik: With the continuing failure of Phase II and Phase III studies with agents targeting various aspects of the beta-amyloid pathway, there is increasing interest in a treatment targeting the Tau pathology of AD. Numerous studies have confirmed a high correlation between the Tau pathology and clinical dementia, from the earliest detectable stages of AD. Indeed, Tau pathology begins in the brain 20–30 years prior to the appearance of clinical features.

Our large Phase II study in 321 subjects represented the first trial of an agent targeting the Tau pathology of AD. The results were reported at the ICAD 2008 meeting. In essence, treatment with methylthionine (MT) at 138mg MT/day (given as methylthioninium chloride, MTC) reduced the rate of cognitive decline over 12–18 months by about 90 percent in pooled mild/moderate AD, separately in mild and moderate AD on the ADAS-cog and MMSE scales. Now that the TauRx Phase III program has been approved to proceed by the FDA and the EMA, we plan to publish the Phase II findings during the course of 2013 while the AD studies are recruiting.

The conclusions in 2008 have been supported in a recent re-analyses using the statistical methodology requested by the FDA for TauRx’s Phase III program in AD, but applied to the Phase II data set (linear mixed effects, modified Intent-to-Treat, no imputation). Using this analysis on the ADAS-cog scale data, the control arm decline seen in mild/moderate AD over 12 months was 4.26 ± 0.94 units, the effect size was 3.63 ± 1.29 units, p = 0.0053. Therefore the reduction in the rate of decline was 85.1% ± 30.3%. In mild AD over 18 months, the control arm decline was 6.46 ± 1.68 units, the effect size was 6.02 ± 2.47 units, p = 0.015, with reduction in rate of decline 93.2% ± 38.2%. Examining a range of different severity definitions and durations, with different analysis and imputation methodologies, the treatment effect was found to be robust. Although the absolute effect size was found to vary considerably according to analysis methodology, duration and severity examined, effect size was found to be a constant proportion of placebo decline (92.5% ± 10.0%). This indicates that the effect of treatment is multiplicative (as would be expected for a disease-modifying treatment) and not additive (as would be expected for a symptomatic treatment).

These clinical findings indicating arrest of clinical progression of AD were supported by functional neuroimaging studies in a nested sub-study in 135 subjects using HMPAO-SPECT (also reported at ICAD 2008). The imaging study showed complete arrest of decline over the six-month period that was studied in pooled mild/moderate subjects, with a particularly strong effect in mild AD, using either Statistical Parametric Mapping (SPM) and Region of Interest (ROI) analyses. The SPM analysis showed that the greatest difference relative to placebo was seen in the regions of the brain (medial temporal lobe structures) where the Tau pathology of AD begins and is most severe according to the Braak staging system.

These results support the potential utility of Tau Aggregation Inhbitor (TAI) treatment using MT as a disease-modifying treatment for AD of mild or moderate severity, and potentially also as a preventative treatment at preclinical stages of AD. The regional distribution of benefit in the imaging study confirmed preclinical studies indicating that MT acts primarily as a TAI.

What do you hope to learn from the Phase III study?

Dr. Wischik: The purpose of the Phase III program is to confirm the findings seen in the Phase II study. Specifically, we hope to confirm that MT at doses 150mg MT/day or 250mg MT/day (given as LMTX in divided twice- daily doses) can arrest disease progression as measured on the ADAS-cog scale over 12 months in mild/moderate AD. Furthermore, we hope to confirm that MT at a dose of 200mg MT/day can arrest disease progression on the ADAS-cog scale over 18 months in mild AD. The latter study incorporates a functional neuroimaging endpoint (FDG-PET) in all subjects at nine and 18 months. The purpose of this is to provide objective neuroimaging evidence that LMTX arrests or reduces disease progression and that therefore LMTX impacts the underlying pathobiology of AD. These two studies have been confirmed by FDA and EMA as providing an adequate basis for product licensure if successful.

Is the mechanism of action known? If not, are there any theories?

Dr. Wischik: The mechanism of action has been well studied in a range of in vitro and in vivo preclinical studies. The in vitro studies include inhibition of Tau aggregation using recombinant Tau species corresponding to the repeat-domain core of the Tau tangle filament (Paired Helical Filaments, PHF), dissolution and conversion of PHFs isolated from AD brain from proteolytically stable to proteolytically susceptible and prevention of Tau aggregation and aggregation-dependent proteolyic processing of Tau in a cellular model. In vivo, MT treatment has been shown to reduce Tau pathology and pathology-associated behavioral deficits in two different Tau-transgenic mouse models. Finally, as indicated above, the neuroimaging disease-arrest effect was seen to be greatest in the brain regions known most severely affected by Tau aggregation pathology. The case that MT acts primarily as a TAI is therefore robust. MT has no effect on Tau phosphorylation.

What side effects have you witnessed?

Dr. Wischik: The top five clinical side effects seen in the Phase II trial were related GI intolerance (mainly diarrhea and nausea), urinary difficulties (primarily variants of urgency) and falls (linked statistically to diarrhea). In addition MT produced a mild methaemoglobinaemia (mean levels raised from a mean of 0.4% to 0.8% of haemoglobin, upper limit of normal 3.5%) and a minor reduction in haemoglobin that remained generally in the normal reference range.

In the Phase I studies bridging MTC to LMTX, LMTX has been found to have much better GI tolerability and reduced haematological effects.

Can you talk about the genesis of the agent? LMTX is base on Rember–where did that drug fail and why do you think LMTX has a better shot?

Dr. Wischik: I first found by serendipity that MTC dissolves PHFs isolated from AD brain when working on the characterization of the PHF leading to the first identification of Tau protein as a structural constituent of the PHF. A Tau-Tau binding assay was then developed to show that this effect is due to inhibition of the critical binding interaction through the repeat domain which determines the proteolytic stability of the Tau oligomers and PHFs formed in the AD brain. The inhibitory effect was shown not to affect the normal Tau-Tubulin binding interaction, which is essential for Tau to function as a microtubule stabilizing protein, even though both interactions occur through the repeat-domain of the Tau molecule. These discoveries formed the basis of the first patent filing in 1995 demonstrating the feasibility of developing pharmaceutical agents of the MT class as selective Tau Aggregation Inhibitors.

The reasons for the failure of the 228mg MT/day dose in the Phase II study are discussed in detail in the abstract to be presented at the next CTAD meeting in Monte Carlo. The Phase I bridging studies demonstrate good tolerability up to 80mg single dose in the fasted state and no interference with absorption in the presence of food, and no dose-dependent limitations in absorption.

Why do you think it’s been so difficult to develop a promising agent for FTD? What makes you excited about its prospects?

Dr. Wischik: About 15 percent of cases with early onset dementia (ie <65 years) have some form of FTD. The peak age of onset is in the range 50-69. There are several different forms of FTD now referred to collectively as Fronto- Temporal Lobar Degeneration (FTLD). In a specialist clinic 57 percent can be expected to have the behavioral variant of FTD (bvFTD), 24 percent have progressive non-fluent aphasia, and 19 percent have semantic dementia. However, in general clinics about 80 percent have bvFTD. For bvFTD, about half the cases are due to aggregation of Tau protein and the other half due to aggregation of a protein called TDP-43. What makes FTLD and FTD so challenging is that the diagnosis is quite difficult, particularly in the absence of availability of functional or structural brain scan to demonstrate the characteristic pattern of lobar atrophy or dysfunction.

Furthermore, even if the diagnosis is correctly made clinically, there is no way at present to distinguish during life between cases of Tau or TDP-43 aggregation. They are phenotypically identical. Therefore, there is no basis for defining the biological substrate of the disease during life except in the rare cases where there is a mutation either in the Tau gene or the progranulin (GRN) gene that leads to TDP-43 aggregation (about 15 percent overall). Furthermore, given the phenotypic heterogeneity of the different kinds of FTLD, it is not possible to conduct a trial with a clear single endpoint across the FTLD spectrum. Therefore a viable treatment can only be tested on a single clinical subtype, the most appropriate in terms of recruitment and rate of decline being bvFTD. However, even narrowing to bvFTD we are still left with heterogeneity at the biological level.

What makes treatment with LMTX particularly interesting is that it should not matter whether the pathology is of the Tau or TDP-43 type. Yamashita et al. have shown that MT is quite potent at inhibiting aggregation of TDP-43 in two difference cell models, with an EC50 of about 0.025 μM. We already know that MT is a potent TAI. Therefore it is in principle possible to treat the bulk of bvFTD (and indeed FTLD) spectrum with LMTX. This is what makes the trial in bvFTD viable in terms of recruitment timeline, rate of decline, measurement of defined clinical assessment endpoints, and rational determination of power for the study.


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