Clinical Trials in Degenerative Diseases

: 2017  |  Volume : 2  |  Issue : 3  |  Page : 66--76

An update on clinical trials targeting human tauopathies

Monica Javidnia1, Bahjat T Kurd-Misto2, Charbel E-H Moussa2,  
1 Department of Neurology, The Laboratory for Dementia and Parkinsonism, Translational Neurotherapeutics Program, Georgetown University Medical Center, Washington D.C; Department of Pharmacology & Physiology, Georgetown University Medical Center, Washington D.C., USA
2 Department of Neurology, The Laboratory for Dementia and Parkinsonism, Translational Neurotherapeutics Program, Georgetown University Medical Center, Washington D.C., USA

Correspondence Address:
Charbel E-H Moussa
Department of Neurology, The Laboratory for Dementia and Parkinsonism, Translational Neurotherapeutics Program, Georgetown University Medical Center, Washington D.C.


The microtubule-associated protein 'tau' is primarily expressed within axons in the central nervous system where it stabilizes microtubules and aids in cargo transport. While basal phosphorylation of tau is normal, tau modifications, predominantly hyperphosphorylation, are critical in the pathogenesis of numerous neurodegenerative disorders known as the tauopathies. Over the years, tau has been shown to be a valuable and elusive target for the treatment of neurodegenerative diseases. Targeting tau via genetic, biological, and pharmacological approaches in vitro and in vivo may prevent degenerative pathologies. However, to date none of these approaches have been successful in human studies, albeit some promising studies are currently underway. This review aims to briefly discuss the biology and pathology of tau and summarize current treatment strategies in clinical trials.

How to cite this article:
Javidnia M, Kurd-Misto BT, Moussa CE. An update on clinical trials targeting human tauopathies.Clin Trials Degener Dis 2017;2:66-76

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Javidnia M, Kurd-Misto BT, Moussa CE. An update on clinical trials targeting human tauopathies. Clin Trials Degener Dis [serial online] 2017 [cited 2021 Jan 23 ];2:66-76
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Tau was first characterized in 1975 as a protein responsible for assembling α- and β-tubulin to form microtubules.[1] This protein is encoded by the microtubule-associated protein tau (MAPT) gene on chromosome 17q212 and is divided into four components: an amino-terminal region, a proline-rich domain, a 3 or 4-repeat microtubule-binding domain, and a carboxy-terminal region. Tau has six isoforms, ranging from 352 to 441 amino acids expressed in the adult human brain generated by alternative splicing of exons,[2],[3] and 10.[3],[4] The isoforms are named according to the absence of exons 2 and 3 (0N), presence of exon 2 (1N), or presence of exons 2 and 3 (2N) and whether exon 10 remains in the microtubule-binding domain for a total of 4 repeats (3R or 4R) [Figure 1].{Figure 1}

Tau dysregulation is associated with a group of neurodegenerative diseases known as the tauopathies. These include frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), Alzheimer’s disease (AD), corticobasal degeneration (CBD), argyrophilic grain disease (AgD), among others.[5],[6],[7],[8],[9] Additionally, tau modifications are found in the majority of neurodegenerative diseases, including Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).[10],[11],[12],[13] While the tauopathies share a common pathological protein, they may have a different predominant isoform [Table 1] and exhibit a broad range of symptoms of the scale of Parkinsonism and dementia, largely correlating with the amount and location of the tau burden.{Table 1}

There have been numerous successes modeling tau pathology in transgenic mouse models, some of which are summarized in [Table 2]. Many of the animal models utilized in research express human P301L tau, which is the most common mutation associated with FTDP-17.[14],[15] This tau mutation is very aggressive and a well characterized tau mutation[16],[17],[18] in experimental preclinical models. Other tau mutations including P301S have also been studied, but considering the identified 100 mutations[19] of tau in human pathology and the absence of tau mutations in AD, more research is needed to better understand the effects of tau on human disease. Additionally, the need for further investigation of other tau mutations may render data obtained from pre-clinical models more translatable to human clinical studies. This is important because tau pathology does not seem to be specific to certain diseases, and tau may constitute a common marker of several human diseases as a genetic risk factor[20],[21] that is not necessarily associated with a specific gene mutation. The variability of tau species that are generated from several post-transcriptional (splicing) and post-translational (ubiquitination, phosphorylation etc.) modifications may limit the validity of existing transgenic and preclinical models.{Table 2}

The growing prevalence and cost of tauopathies stresses the need for effective treatments.[22] There are few drugs available to address the symptoms of tauopathies and no disease-modifying drugs or cures. There are, however, FDA-approved treatments for AD: acetylcholinesterase inhibitors, including donepezil, galantamine, rivastigmine and the glutamate receptor NMDA antagonist memantine. Interestingly, these drugs have shown little, no, or negative effects in patients with non-AD tauopathies.[23] Largely, patients with tauopathies receive antidepressants such as selective serotonin reuptake inhibitors (SSRIs) to treat the behavioral symptoms related to the disease. It is of note that these drugs are not FDA approved for FTD, PSP, CBD, etc. and are given off-label.

 Amyloid Beta

In addition to intracellular tau pathology, AD patients exhibit extracellular plaques composed of amyloid beta, a cleavage product of the amyloid precursor protein (APP).[24] APP cleavage by β- (BACE1) and γ-secretases promote formation of amyloid beta, and α- and β-secretases are involved in the non-amyloidogenic pathway. Many clinical trials for AD thus far have been targeting Aβ production or destruction, largely by inhibiting enzymes which cleave APP or reducing Aβ with Aβ-vaccines. Eli Lilly and Biogen were among the first to introduce anti-Aβ vaccines or BACE1 inhibitors to clinical trials. These Aβ-directed treatments are not without side effects, and most have been discontinued for a variety of reasons. For example, the antibody bapineuzumab led to reversible vasogenic edema in 12 of 124 patients,[25] a side effect now under the umbrella term of ARIA or amyloid-related imaging abnormalities.[26] Semagacestat, a γ-secretase-inhibitor trial was halted due to worsening of cognition and increased risk of infections and skin cancer, among other concerns.[27] The β-secretase inhibitor verubecestat was also terminated, following conclusions from the study’s data monitoring committee.[28] Aβ therapies are still currently under investigation, though tau-based treatments are an emerging new paradigm. [Table 3] provides a summary of clinical trials targeting tauopathies which will be discussed below.{Table 3}

 Tau Phosphorylation

Tau protein undergoes numerous post-translational modifications, with phosphorylation being arguably the most prominent and significant change. Tau is primarily a serine/threonine phosphoprotein with 45 serine residues, [35] threonine residues, and 5 tyrosine residues in the longest isoform (2N4R).[29] Tau is phosphorylated and dephosphorylated by numerous kinases, divided into three groups: proline-directed protein kinases, non-proline-directed protein kinases, and tyrosine protein kinases. Kinases include glycogen synthase kinases 3 alpha and beta (GSK3α, GSK3β),[30],[31],[32],[33],[34] cyclin dependent kinase 5 (cdk5),[35],[36] the mitogen-activated protein kinase family (MAPKs),[37],[38],[39] leucine-rich repeat kinase 2 (LRRK2),[40],[41],[42] Akt (protein kinase B),[43] c-Abelson (c-Abl),[44] Fyn,[45] and many others. Individual kinases are capable of phosphorylating tau on numerous sites.[37],[46] Phosphorylation leads to a decrease in the ability of tau to bind and stabilize microtubules,[47],[48],[49],[50] therefore normal tau function is critical to microtubule role and integrity. Tau has been reported to be dephosphorylated by several phosphatases such as protein phosphatases 1, 2A, 2B, 5[51],[52],[53],[54],[55],[56] and phosphatase and tensin homolog (PTEN).[57] In addition to their own roles, kinases and phosphatases interact to regulate each other’s functions.[54],[58],[59]

A balance of phosphorylation and dephosphorylation is required for tau to properly support the function and structural integrity of neurons.[60],[61] Phosphorylated tau is unable to promote microtubule assembly,[62],[63] and in more pathological states, tau is hyperphosphorylated and forms intracellular protein aggregates.[31] Thus, the stabilization of microtubules is a target for tauopathy treatment. Microtubule (MT) stabilizers are often used for cancer, though studies suggest they may be useful in tauopathies to support the axons after tau dissociates from MTs and aggregates. Dictyostatin is a MT-stabilizing agent which was found to promote neuronal survival and MT density in PS19 mice.[64] BMS-241027 (Epothilone D, Bristol-Myers Squibb) is a MT-stabilizing drug which decreased tau pathology in rTg4510 mice[65] and PS19 mice.[66] A Phase 1 clinical trial with BMS-241027 for mild AD (NCT01492374) was completed in October 2013, and there are no current trials with the drug.

Hyperphosphorylated tau (p-tau) has been shown to affect the function of normal tau and sequester it into a pathological form.[67],[68] Homogenates from human brain tauopathies can induce tau pathology in mice,[69] demonstrating pathological effects of human p-tau. There is some debate as to which forms of tau may be pathological[70],[71],[72],[73] as well as the route by which soluble tau becomes filamentous or associated into paired helical filaments (PHF). It is believed that tau dimerization is a critical step in the formation of filamentous tau.[74],[75] The traditional thought is that tau monomers follow a single pathway toward the formation of neurofibrillary tangles (NFTs); tau assembles into higher forms such as dimers and oligomers[76] which can then give rise to PHFs.[77],[78],[79],[80] PHFs are the primary component of NFTs,[81],[82],[83] along with ubiquitin[84],[85] and high molecular weight, phosphorylated neurofilament,[86] as well as other proteins.[87],[88] Less is known about straight filaments (SFs), though they are similar to PHFs[89],[90] and both can form neuropil threads, presumably replacing neurofilaments in neuritis.[91] Studies have shown dephosphorylation of PHFs can help restore tau function and shift PHFs into a lower confirmation.[92],[93] In addition to NFTs, tau is a component of other disease-related inclusions such as Lewy bodies[94],[95],[96] in dementia with Lewy bodies (DLB) and Pick bodies[97] in Pick’s disease, which are variable forms of dementia.

Davunetide, developed by Allon Therapeutics, is a peptide composed of eight amino acids (NAPVSIPQ) delivered intranasally. The peptide showed promise in in vivo studies using a K257T/P301S mouse model, decreasing levels of p-tau, increasing levels of soluble tau, and improving cognition on the Morris water maze (MWM).[98] In a Phase 2/3 study in patients with PSP (NCT01110720), davunetide was shown to be well tolerated but had no efficacy for PSP.[99] Another Phase 2/3 study in MCI (NCT00422981) also showed the drug to be safe but provided no significant differences in composite cognitive memory score.[100] A Phase 2 study in patients with predicted tauopathies (NCT01056965) was completed in July 2017.

 Tau Clearance

In addition to phosphorylation and microtubule stabilizing, tau clearance is a promising target. The buildup of toxic proteins is a common feature among most neurodegenerative diseases. These proteins, including tau, can be cleared in several ways such as the ubiquitin-proteasome system (UPS) or autophagy.[101],[102],[103],[104] A study with R406W mutant tau drosophila showed 1 µm rapamycin food treatment cleared aggregate-prone tau.[105] Trehalose was shown to promote tau degradation,[106] and another study with P301S mice treated with water containing 2% trehalose prevented cell death and reduced p-tau levels.[107] Methylthioninium chloride (methylene blue, MB) was shown to decrease tau aggregation and stimulate autophagy.[108],[109],[110],[111],[112],[113],[114],[115] One group found 0.02 mg/kg MB stimulates autophagy and decreases both total tau and p-tau in JNPL3 (P301L) mice after two weeks of treatment via oral gavage.[108] Another group showed a 5 month treatment with water containing 6 µg/mL MB reduced p-tau in the sarkosyl-insoluble fractions without affecting total tau in JNPL3 mice. TauRx Therapeutics Ltd performed several studies with the MB formulation TRx0014 (Rember®), showing some beneficial effects.[116] There is growing evidence of possible relation between Abelson (Abl) and tau pathology,[44],[117],[118] and treatment with tyrosine kinase inhibitors (TKIs) targeting Abl such as nilotinib (Tasigna®, Novartis) or bosutinib (Bosulif®, Pfizer) reduces p-tau levels in different models of neurodegenerative diseases[119],[120],[121],[122] by stimulating autophagy rather than reducing phosphorylation. Imatinib (Gleevec®, Novartis), another Abl inhibitor, was also shown to reduce p-tau levels.[123]

As with the amyloid beta vaccines, clearance via immunization is of interest. Numerous animal studies have been performed with liposome-based, passive, or active immunization to determine safety and efficacy of these biologics,[124],[125],[126],[127],[128],[129],[130],[131],[132],[133] leading to a number of anti-tau vaccines developed for humans. RG7345 (Roche) is a passive vaccine against tau 416-430, following preclinical evidence showing value in targeting serine 422.[127],[134] RG7345 was tested in a Phase 1 trial with healthy volunteers (NCT02281786) and was listed as removed from Phase 1 on the company website. Another vaccine, ACI-35 (AC Immune), a liposome-based vaccine which targets tau 393-408,[124] completed clinical trials for mild-to-moderate AD (ISRCTN13033912) and was licensed to Janssen Pharmaceuticals in 2015.

 Current Clinical Trials

TRx0237 (LMTX™) is a newer MB formulation from TauRx Therapeutics Ltd, intended to have greater bioavailability than TRx0014. It was tested in Phase 3 trials for mild AD (NCT01689233), mild-to-moderate AD (NCT01689246), and behavioral variant of FTD (bv-FTD) (NCT01626378). TRx0237 did not show effects on the primary or secondary outcome measures in mild-to-moderate AD,[135] though post-hoc analyses revealed some benefits of TRx0237 monotherapy. There is one ongoing, Phase 3 extension study (NCT02245568) of TRx0237 in AD and bv-FTD with patients enrolled in previous Phase 2 or 3 TRx0237 trials. TPI-287 (Cortice Biosciences) is an MT-stabilizing drug being tested for various cancers in addition to neurodegenerative diseases. It is currently in Phase 1 clinical trials for AD (NCT01966666) and PSP, CBD, and primary four repeat tauopathies (4RT) (NCT02133846).

Nilotinib is currently in clinical trials II for mild-to-moderate AD (NCT02947893) after an intriguing, open-label Phase 1 study (NCT02281474) in patients with PD with and DLB[136] showed some preliminary positive effects on cognition in advanced patients. In addition to PD and DLB, Nilotinib has recently been tested in patients with chronic cerebellar ataxia and was found to be beneficial.[137] Another TKI, AZD0530 (saracatinib, AstraZeneca), is a Fyn-targeting drug originally developed as a potential cancer therapeutic. A Phase 1b trial (NCT01864655) showed AZD0530 was well tolerated,[138] and an ongoing Phase 2a trial for AD (NCT02167256) is set to be completed in December 2017.

Bristol-Myers Squibb recently licensed their N-terminalfragment-targeting antibody BMS-986168 to Biogen. BMS-986168 has been evaluated in healthy volunteers (NCT02294851) and is currently being tested in a Phase 1 trial with PSP patients (NCT02460094), in an extension study (NCT02658916), as well as a Phase 2 trial (NCT03068468) also for PSP. C2N-8E12/ABBV-8E12 (C2N Diagnostics, AbbVie) is another passive vaccine targeting the N-terminus. This is being tested in a Phase 1 trial with PSP patients (NCT02494024), Phase 2 trials in PSP (NCT02985879), and early AD (NCT02880956). Preclinical work with the monoclonal antibody DC8E8 led to the active tau vaccine AADvac1 (Axon Neuroscience SE) based on the tau 294-305 peptide.[139],[140] A Phase 1 trial (NCT01850238) with AADvac1 showed both safety and immunogenicity,[141] and an 18-month follow up study (NCT02031198) was completed in December 2016. A Phase 2 trial in patients with mild AD is currently underway (NCT02579252) in addition to a Phase 1 trial for non-fluent primary progressive aphasia (PPA) (NCT03174886) in the works.


As the field of neurodegenerative disease research expands, tau remains useful to study the pathogenesis and progression of human tauopathy as well as for drug development with countless successes on the bench and promising trials underway. There are areas to improve preclinically that may lead to drugs and biologics with better efficacy entering clinical trials. The physiological relevance and translatability of cell culture results and animal models to human disease represent a fundamental challenge to tau research. With regard to current trials, it appears that two hypotheses are currently at the forefront on neurotherapeutic research to reduce tau pathology: the concept of neuronal clearance of tau via autophagy and second, the hypothesis that anti-tau vaccines can capture secreted tau en route from one neuron to another.

Experimental evidence supports the autophagy concept. Normal tau and microtubule function appear to be critical to baseline autophagy that can mediate clearance of multiple toxic proteins such Aβ, tau, and alpha-synuclein.[142],[143] Pathological tau can sequester and convert normal tau, so the ability to degrade p-tau would not only restore neuronal function but also prevent further propagation. In addition to nilotinib and AZD0530, other TKIs are also being explored as treatment options. Anti-angiogenic TKIs such as pazopanib are in preclinical studies for AD by our group as well as others.[144] Masitinib is a mast/stem cell growth factor receptor (c-KIT) inhibitor tested in patients with mild to moderate AD as an adjunct therapy (NCT00976118).[145],[146],[147] With the number of FDA-approved TKIs that are able to modulate autophagy with extensive preclinical and clinical research already available and a diverse set of targets, this is an area of growing interest.

Meanwhile, anti-tau vaccines still have to be tested for safety, as anti-Aβ vaccines have not been devoid of safety concerns. In humans, little is known about what constitutes a normal level of tau in the interstitial fluid (ISF), cerebrospinal fluid (CSF), and within neurons. Some work has been done in P301S mice, demonstrating a decrease in normal tau in the ISF and an increase in CSF tau as it aggregates in neurons.[148] It is unclear whether vaccines that reduce extracellular tau levels may alter the stoichiometry between CSF, ISF, and neuronal tau, and if antibody therapy reaching portions of the brain unaffected by disease could have negative consequences. It is possible that accelerating p-tau clearance inside the neuron by stimulating autophagy is more plausible than vaccines which target secreted tau that has already damaged the neuron. Taken together, the shift from amyloid beta to tau-focused research in addition to an increase in trials testing repurposed TKIs and antibodies shows a directional change in the field.[164]


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