Special focus on neuroscience: Neurodegenerative disease

We take a look at some of the latest research on neurodegeneration, beginning with Alzheimer's disease but covering Parkinson's disease and multiple sclerosis as well

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The ‘Tao’ of tau?
In the recurring debate of tau vs. amyloid, we take a look at how anti-tau research is progressing
Jeffrey Bouley
In looking at neurodegenerative diseases for this special focus section on neuroscience, it seemed fitting to check in not just on the consistently hot topic of Alzheimer’s disease, but more specifically the issue of the tau protein and some of the recent insights and progress on the anti-tau front.
Alzheimer’s has already proven to be a particularly complex and challenging disease for life-sciences researchers and pharma/biotech companies. And in a disease where sticky tangles of proteins seems to atrophy the brain and choke off cognition, one of the stickiest areas has been the issue of the amyloid protein vs. the tau protein. The aggregation of the tau protein is a hallmark of Alzheimer’s disease, but traditionally much of the energy and effort has gone toward focusing on ways to reduce the number of amyloid plaques.
As Emily Underwood wrote in a 2016 article in Science, “One of the telltale signs of Alzheimer’s disease (AD) is sticky plaques of ß-amyloid protein, which form around neurons and are thought by a large number of scientists to bog down information processing and kill cells. For more than a decade, however, other researchers have fingered a second protein called tau, found inside brain cells, as a possible culprit.”
The topic Underwood was addressing was an imaging study of 10 people with mild AD that indicated tau deposits, rather than amyloid, are closely linked to memory loss, dementia and other AD symptoms. It wasn’t evidence that actually resolved the amyloid-tau debate—almost certainly both proteins play major roles, and perhaps other factors as well—but the findings did serve as a potential jumping-off point for additional effort on tau-targeting treatments and better diagnostic tools.
And on the subject that tau and amyloid likely represent more of a “pair of culprits” rather than an “either-or” situation, we can go back a couple years to a JAMA Neurology paper by G.S. Bloom that cast ß-amyloid protein and tau in a “trigger and bullet” metaphor. As the author noted in the abstract, “During the past dozen years, a steadily accumulating body of evidence has indicated that soluble forms of Aβ and tau work together, independently of their accumulation into plaques and tangles, to drive healthy neurons into the diseased state and that hallmark toxic properties of Aβ require tau. For instance, acute neuron death, delayed neuron death following ectopic cell cycle reentry, and synaptic dysfunction are triggered by soluble, extracellular Aβ species and depend on soluble, cytoplasmic tau. Therefore, Aβ is upstream of tau in AD pathogenesis and triggers the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau enhances Aβ toxicity via a feedback loop.”
Druggability of tau
So, fast forwarding back to the present day—or June 28, 2018, at least—we see one company continuing the trend toward more focus on tau as news came out of Cantabio Pharmaceuticals Inc. that the preclinical-stage pharmaceutical company, which is working on therapeutics for AD, Parkinson’s disease and related neurological disorders, had seen publication of a peer-reviewed article. Lead authored by Cantabio’s CEO Dr. Gergely Toth, along with collaborators at the Hungarian Academy of Sciences and German Center for Neurodegenerative Diseases (DZNE), the work appeared in the journal ACS Chemical Neuroscience.
The paper was titled “The structural basis of small molecule targetability of monomeric Tau protein” and reported structure-based evidence that native monomeric tau can be a viable target for drug-like small molecules despite its heterogeneous structure.
As the company noted of the news, the aggregation of monomeric tau protein is linked to the onset and progression of Alzheimer’s disease and other tauopathies, and this study and the scientific team’s previous findings provide theoretical and experimental evidence for the ability of monomeric tau to be a receptor of small molecules designed to prevent the aggregation, which leads to toxicity and cell death.
As per Prof. Eckhard Mandelkow, a co-author of the publication and group leader at DZNE in Bonn, this is further evidence that inhibition of tau aggregation by small molecules may be a viable therapeutic approach for tauopathies such as Alzheimer’s disease. He noted that “These molecules are currently being evaluated in animal models of tau-induced pathology.”
“We are excited to publish further scientific evidence that establishes a structural biology basis for Cantabio’s tau small-molecule pharmacological chaperone program, which aims to prevent and reduce aggregation of tau protein as a therapeutic strategy for Alzheimer’s disease and other tauopathies such as concussion-related chronic traumatic encephalopathy,” said Cantabio’s CEO, Dr. Gergely Toth. “The tau protein has long been a major target for Alzheimer’s drug development, but due to the nature of its structure, it has historically proven to be a difficult target for small-molecule drug candidates. Our work at Cantabio represents a significant step forward in developing a therapy that is able to prevent the formation of the toxic protein aggregates that are associated with neurodegeneration in these diseases.”
Tau as a therapeutic and diagnostic target
And, perhaps in a sign of how much tau research remains in the shadow of amyloid research, our next piece of fairly recent news comes from the end of last year, when AC Immune SA, a clinical-stage biopharmaceutical company with a broad pipeline focused on neurodegenerative diseases, shared the top-level insights from a key opinion leader (KOL) luncheon meeting on the importance of tau as a target in Alzheimer’s disease and other neurodegenerative diseases. The meeting featured presentations by KOLs Dr. Khalid Iqbal of the New York State Institute for Basic Research in Developmental Disabilities and Dr. Michael Rafii of the University of California, San Diego, and the University of Southern California.
Iqbal highlighted the critical importance of tau as a therapeutic target in Alzheimer’s disease and other neurodegenerative diseases and how inhibition and prevention of the Tau pathology can potentially rescue the pathology of Alzheimer’s disease and cognitive impairment, commenting: “Neurodegeneration leads to tau pathology, and tau pathology leads to neurodegeneration. Where there is no tau pathology, there is no Alzheimer’s disease. Tau-based therapeutic approaches have significant potential to treat a range of neurodegenerative diseases.”
Rafii discussed tau-mediated pathology and the importance of tau diagnostics in people with Down syndrome, a population with a genetic predisposition to develop Alzheimer’s-related neuropathological changes, including ß-amyloid plaques and tau tangles.
“Biomarkers of Alzheimer’s, including Tau-PET, can be readily studied in adults with Down syndrome as in other preclinical AD populations,” Rafii noted. “By understanding the link between Alzheimer’s and Down syndrome, we may not only be able to help the Down syndrome community, but the broader population as well. People with Down syndrome are an important population to study as we enhance our understanding of early intervention and prevention of Alzheimer’s disease in general.”
Also at the KOL meeting, Dr. Andreas Muhs, chief scientific officer of AC Immune, highlighted the company’s relevant Tau programs:
  • ACI-35, an anti-tau vaccine in Phase 1b and developed in collaboration with Janssen Pharmaceuticals under a 2014 licensing agreement
  • RO7105705, an anti-tau antibody in Phase 2 and developed in collaboration with Genentech under a 2012 licensing agreement
  • Morphomer Tau, a small molecule in preclinical development and developed in-house
  • PI-2620, a Tau-PET imaging agent developed in collaboration with Piramal Imaging under a 2014 licensing agreement.
“We are delighted to share the valuable insights of these world-leading experts with our investors and stakeholders. These types of exchanges are vital so we can all work more effectively together to achieve the common goal of an approved disease-modifying therapeutic and earlier diagnosis of Alzheimer’s disease—one of society’s biggest challenges of the century,” said Prof. Andrea Pfeifer, CEO of AC Immune.
Potential monotherapy?
Also late in 2017, TauRx Therapeutics Ltd. reported the full results from its second Phase 3 clinical study of LMTX, a tau aggregation inhibitor for Alzheimer’s disease, which were published online in the Journal of Alzheimer’s Disease. The company noted that results from this study (TRx-237-005) are consistent with those from the first Phase 3 study, recently published in The Lancet in mild to moderate Alzheimer’s disease, in supporting the hypothesis that LMTX might be effective as monotherapy at a dose as low as 4 mg twice daily.
The results of the earlier study showed significant differences in favor of two higher doses of LMTX (75 mg and 125 mg twice daily) when taken as monotherapy compared with the intended 4 mg control dose taken as monotherapy or as add-on therapy to currently approved treatments for AD in prespecified post-hoc analyses. In a further analysis, the same difference in favor of monotherapy compared with add-on treatment was found in patients taking the 4 mg twice-daily dose.
According to TauRx, in both the LMTX monotherapy and add-on therapy groups, whole brain atrophy (measured via MRI scans) initially progressed as expected for patients with mild Alzheimer’s disease. However, after nine months of treatment, the annualized rate of whole brain atrophy in monotherapy patients reduced significantly and became typical of that reported in normal elderly controls without Alzheimer’s disease. The comparable rate seen in the add-on therapy group progressed as reported for patients with mild Alzheimer’s disease.
And early this year, the company reported preclinical study results, published online in Frontiers in Molecular Neuroscience, showing that LMTM, the active pharmaceutical ingredient in the LMTX product developed for the treatment of Alzheimer’s disease, may also be useful for the treatment of Parkinson’s disease.
It is worth noting that in 2016, there was some significant disagreement regarding LMTM when Phase 3 results were presented showing that the drug missed its co-primary endpoints of slowing cognitive and functional decline in mild to moderate AD. Some had argued that the placebo and drug results were nearly identical and, as a commentator on the Alzforum website argued, a scientist involved in the trial presented “a subgroup analysis that held no statistical credence yet purported to show a strong benefit on cognition and brain atrophy.”
Some other takes around the same time contended that LMTM might not benefit AD patients who are receiving standard of care but, as a monotherapy, the drug might stabilize cognition and reduce brain atrophy.

Neuroscientists discover roles of AD-linked gene
Study may reveal why people with the APOE4 gene have higher risk of the disease
By Anne Trafton, MIT News Office
CAMBRIDGE, Mass.—People with a gene variant called APOE4 have a higher risk of developing late-onset Alzheimer’s disease; in fact, APOE4 is three times more common among Alzheimer’s patients than it is among the general population. However, little is known about why this version of the APOE gene, which is normally involved in metabolism and transport of fatty molecules such as cholesterol, confers higher risk for Alzheimer’s.
To shed light on this question, MIT neuroscientists have performed a comprehensive study of APOE4 and the more common form of the gene, APOE3. Studying brain cells derived from a type of induced human stem cells, the researchers found that APOE4 promotes the accumulation of the beta amyloid proteins that cause the characteristic plaques seen in the brains of Alzheimer’s patients.
“APOE4 influences every cell type that we studied, to facilitate the development of Alzheimer’s pathology, especially amyloid accumulation,” says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the senior author of the study.
The researchers also found that they could eliminate the signs of Alzheimer’s in brain cells with APOE4 by editing the gene to turn it into the APOE3 variant.
Picower Institute Research Scientist Yuan-Ta Lin and former postdoc Jinsoo Seo are the lead authors of the paper, which appears in the May 31 online edition of Neuron.
Amyloid accumulation
APOE, also called apolipoprotein E, comes in three variants, known as 2, 3 and 4. APOE binds to cholesterol and lipids in cells’ environments, enabling the cells to absorb the lipids. In the brain, cells known as astrocytes produce lipids, which are then secreted and taken up by neurons with the help of APOE.
Among the general population, about 8 percent of people have APOE2, 78 percent have APOE3 and 14 percent have APOE4. However, among people with late-onset, nonfamilial Alzheimer’s, which accounts for 95 percent of all cases, the profile is very different: only 4 percent have APOE2, and the percentage with APOE3 drops to 60 percent. APOE4 shows a dramatic increase—37 percent of late-onset Alzheimer’s patients carry this version of the gene.
“APOE4 is by far the most significant risk gene for late-onset, sporadic Alzheimer’s disease,” Tsai says. “However, despite that, there really has not been a whole lot of research done on it. We still don’t have a very good idea of why APOE4 increases the disease risk.”
Previous studies have shown that people with the APOE4 gene have higher levels of amyloid proteins, but little is known about why that is.
In this study, the MIT team set out to answer that question using human induced pluripotent stem cells—stem cells derived from skin or other cell types. They were able to stimulate those stem cells to differentiate into three different types of brain cells: neurons, astrocytes and microglia.
Using the gene-editing system CRISPR/Cas9, the researchers genetically converted APOE3 in stem cells derived from a healthy subject to APOE4. Because the cells were genetically identical except for the APOE gene, any differences seen between them could be attributed to that gene.
In neurons, the researchers found that cells expressing APOE3 and APOE4 differed in the expression of hundreds of genes—about 250 genes went down and 190 went up in cells with APOE4. In astrocytes, the numbers were even higher, and they were highest of all in microglia: in APOE4 microglia, more than 1,100 genes showed reduced activity, while 300 became more active.
These genetic changes also translated to differences in cell behavior. Neurons with APOE4 formed more synapses, and they secreted higher levels of amyloid protein.
In APOE4 astrocytes, the researchers found that cholesterol metabolism was highly dysregulated. The cells produced twice as much cholesterol as APOE3 astrocytes, and their ability to remove amyloid proteins from their surroundings was dramatically impaired.
Microglia were similarly affected. These cells, whose normal function is to help remove foreign matter, including amyloid proteins and pathogens such as bacteria, became much slower at this task when they had the APOE4 gene.
The researchers also found that they could reverse most of these effects by using CRISPR/Cas9 to convert the APOE4 gene to APOE3 in brain cells derived from induced stem cells from a patient with late-onset Alzheimer’s disease.
Disrupting cell behavior
In another experiment, the researchers created three-dimensional “organoids,” or miniature brains, from cells with genes that are known to cause early-onset Alzheimer’s. These organoids had high levels of amyloid aggregates, but when they were exposed to APOE3 microglia, most of the aggregates were cleared away. In contrast, APOE4 microglia did not efficiently clear the aggregates.
Tsai said she believes that APOE4 may disrupt specific signaling pathways within brain cells, leading to the changes in behavior that the researchers saw in this study.
“From this gene expression profiling, we can narrow down to certain signaling pathways that are dysregulated by APOE4,” she says. “I think that this definitely can reveal potential targets for therapeutic intervention.”
The findings also suggest that if gene-editing technology could be made to work in humans, which many biotechnology companies are now trying to achieve, it could offer a way to treat Alzheimer’s patients who carry the APOE4 gene.
“If you can convert the gene from E4 to E3, a lot of the Alzheimer’s-associated characteristics can be diminished,” Tsai says.

Picking apart PD
A roundup of recent news on R&D related to Parkinson’s disease
By Jeffrey Bouley
NEW YORK—A recent study from researchers at the Icahn School of Medicine at Mount Sinai provides new insights into a link between inflammatory bowel disease (IBD) and Parkinson’s disease (PD), and may have significant implications for the treatment and prevention of PD.
The study, published in JAMA Neurology, shows that individuals with IBD are at a 28-percent higher risk of developing PD than those without IBD. However, if they are treated with anti-tumor necrosis factor alpha (anti-TNFα) therapy, a monoclonal antibody that is commonly used to control inflammation in IBD patients, then their risk of developing Parkinson’s goes down significantly, and becomes even lower than that in the general population.
These new insights may allow for better screening of IBD patients for Parkinson’s disease, given that IBD onset usually precedes that of PD by decades, and they also offer evidence to support exploring anti-TNFα therapy to prevent PD in at-risk individuals.
While previous research had shown genetic and functional connections between IBD and Parkinson’s disease, clinical evidence linking the two has been scarce. The authors of the study previously identified a number of genetic variants that contributed to either an increased risk of both PD and of Crohn’s disease, a type of IBD, or a decreased risk of both diseases, which prompted them to further study the co-occurrence of the two diseases.
“Systemic inflammation is a major component of IBD, and it’s also thought to contribute to the neuronal inflammation found in Parkinson’s disease,” explained Inga Peter, a professor in the Department of Genetics and Genomic Sciences at Mount Sinai and lead investigator in the study. “We wanted to determine if anti-TNFα therapy, could mitigate a patient’s risk in developing Parkinson’s disease.”
The Mount Sinai team found a 78-percent reduction in the incidence of Parkinson’s disease among IBD patients who were treated with anti-TNFα therapy when compared to those who were not.
It was previously thought that anti-TNFα therapies had limited effects on the central nervous system, the site where molecular mechanisms of PD are found, because the large molecules in the anti-TNFα compounds cannot independently pass through the blood-brain barrier. The outcomes of this study suggest that it may not be necessary for the drug to pass through the blood-brain barrier to treat or prevent inflammation within the central nervous system, or that the blood-brain barrier in patients with IBD may be compromised, allowing the large molecules of the compound to pass through.
Preclinical evidence for DJ-1 protein targeting
SAN FRANCISCO—Cantabio Pharmaceuticals Inc. recently presented results of the company’s DJ-1 protein-targeting small-molecule pharmacological chaperone therapeutic program at the Neuro4D Conference (Advances in Drug Discovery for Proteopathic Neurodegenerative Diseases) in Mainz, Germany.
Loss of DJ-1 protein function has been linked to the onset of a variety of diseases, such as Parkinson’s disease, Alzheimer’s disease, stroke, amyotrophic lateral sclerosis, chronic obstructive pulmonary disease and type 2 diabetes. The DJ-1 protein is considered to be one of the primary therapeutic targets for Parkinson’s disease, as it is genetically linked to the onset of familial PD.
The presentations described the positive therapeutic activity in cellular models and in an MPTP mouse model of PD of Cantabio’s novel DJ-1 candidates.
“We are excited to present positive in-vivo efficacy results of one of our orally bioavailable DJ-1 protein targeting small-molecule pharmacological chaperones. This drug candidate has shown excellent drug-like characteristics and its significant protective function in a recognized mammalian disease model for Parkinson’s disease is a major step forward for Cantabio’s drug development programs,” said Cantabio’s CEO, Dr. Gergely Toth. “We are looking forward to testing this molecule in further disease models of Parkinson’s and Alzheimer’s disease and to the further development of multiple candidates from our other programs. These results also provide excellent validation of our in-house DJ-1 drug discovery platform’s ability to generate prospective drug candidates and for our DJ-1 targeting therapeutic program’s potential for becoming a disease-modifying therapeutic for Parkinson’s and Alzheimer’s disease.”
Axovant licenses investigational gene therapy
BASEL, Switzerland—Axovant Sciences in early June announced that it had licensed the exclusive worldwide rights to develop and commercialize OXB-102, now AXO-Lenti-PD, from Oxford BioMedica. AXO-Lenti-PD is an investigational gene therapy for Parkinson’s disease that delivers three genes encoding a critical set of enzymes required for dopamine synthesis in the brain. Oxford BioMedica is a world leader in lentiviral vector product development and manufacturing, and will be the clinical and commercial supplier of AXO-Lenti-PD. Axovant expects to initiate a Phase 1/2 dose escalation study of AXO-Lenti-PD in patients with advanced PD by the end of 2018.
Under the terms of the license agreement with Oxford BioMedica, Axovant obtained rights to AXO-Lenti-PD, as well as its predecessor product ProSavin, for an initial payment of $30 million in cash, $5 million of which will be applied as a credit against the process development work and clinical supply that Oxford BioMedica will provide to Axovant. Oxford BioMedica is also eligible to receive additional development, regulatory and commercial milestone payments potentially in excess of $812 million, and tiered royalties on net sales of AXO-Lenti-PD, if approved. Roivant has agreed to purchase $25 million of Axovant common shares, which will support the clinical development of AXO-Lenti-PD and additional business development activities.

TG Therapeutics shares data on ublituximab for MS
NEW YORK—TG Therapeutics Inc. reently updated results from the Phase 2 multicenter trial of ublituximab (TG-1101), the company’s novel glycoengineered anti-CD20 monoclonal antibody, in relapsing forms of multiple sclerosis (RMS).
Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer, stated, “We are extremely pleased to see that the preliminary week 48 data presented today from this Phase 2 trial supports the week 24 data presented earlier this year at the AAN meeting. While only an early look at the week 48 timepoint, the data continue to be impressive and suggestive of a highly efficacious anti-CD20 monoclonal antibody with a manageable safety profile that can be administered in a convenient one-hour infusion.”
Highlights included:
  • An annualized relapse rate of 0.07, calculated cumulatively, based on 48 subjects with a mean follow-up of approximately 11 months
  • 99-perent median B cell depletion was observed at week 4 and maintained at week 24
  • Ublituximab completely eliminated all of T1 Gd-enhancing lesions at week 24 and at week 48
  • 7.67-percent reduction in T2 lesion volume at week 24 from baseline and a 10.5-percent reduction in T2 lesion volume at week 48 from baseline
  • Ublituximab was well tolerated across all patients including those receiving rapid infusions, as low as a one hour for the 450 mg Phase 3 dose
These data support the international Phase 3 ULTIMATE program evaluating ublituximab for the treatment of RMS. The Phase 3 trials, entitled ULTIMATE I and ULTIMATE II, are being conducted under Special Protocol Assessment agreement with the U.S. Food and Drug Administration and are being led by Dr. Lawrence Steinman of Stanford University. The ULTIMATE trials are currently enrolling and complete enrollment is expected by the end of 2018.

Elenbecestat demonstrates safety and tolerability in MCI and AD
TOKYO—Eisai Co. Ltd. and Biogen Inc. announced recently that elenbecestat was generally safe and well tolerated in a Phase 2 clinical study (Study 202) of the oral BACE (beta amyloid cleaving enzyme) inhibitor elenbecestat conducted in the United States, and the results demonstrated a statistically significant difference in amyloid beta (AB) levels in the brain measured by amyloid-PET (positron emission tomography). A numerical slowing of decline in functional clinical scales of a potentially clinically important difference was also observed, although this effect was not statistically significant. This study, a Phase 2 study of 70 patients, is the first study of a BACE inhibitor to show a statistically significant difference in amyloid beta in the brain while also suggesting a delay of clinical symptom decline in exploratory endpoints.
Study 202  is a multicenter, randomized, double-blind, placebocontrolled parallel-group 18-month clinical study in patients with mild cognitive impairment (MCI) due to Alzheimer’s disease, or mild to moderate dementia due to Alzheimer’s disease with confirmed amyloid pathology by PET screening.
Elenbecestat demonstrated acceptable safety and tolerability profile through 18 months of study drug administration. In the elenbecestat 50 mg total arm, the six most common adverse events observed were contact dermatitis, upper respiratory infection, headache, diarrhea, fall, and dermatitis. No serious adverse reactions suggestive of hepatic toxicity were observed in this study.
In addition to the safety objectives, the study assessed AB in the brain at 18 months as measured by amyloid PET as well as efficacy in terms of clinical symptoms, which were exploratory objectives in this study. The elenbecestat 50 mg total arm demonstrated a statistically significant difference in AB levels in the brain as measured by amyloid PET compared with placebo (35 subjects participated in this longitudinal amyloid PET assessment). This is the first time in which a significant effect in AB in the brain using a BACE inhibitor was confirmed in a clinical study of patients with MCI through moderate Alzheimer’s dementia.
Eisai plans to present detailed results of the study at a future medical meeting.

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