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Treating Tau: Finally, Clinical Candidates Are Stepping into the Ring

Series - AD/PD 2017 Draws Record Number of Scientists To Vienna:

While many of the more advanced Alzheimer’s therapies currently in trials target amyloid, tau-based approaches are stepping up to the plate. At the 13th International Conference on Alzheimer’s and Parkinson’s Diseases, held March 29 to April 2 in Vienna, researchers shared updates on molecules wending their way through early stage trials. AbbVie reported Phase 1 data for its antibody, ABBV-8E12, against aggregated, extracellular tau. This antibody is in Phase 2. Genentech showed preclinical and Phase 1 findings of its pan-tau antibody, RO 7105705. Other therapies are headed to Phase 1. Biogen reported pharmacokinetic and dose-finding data from studies of its anti-tau antibody BIIB076 in non-human primates. Taking a different tack, Asceneuron presented preclinical data on its O-GlcNAcase inhibitor ASN120290 (previously ASN-561), which prevents tau tangles from forming and earlier this month was approved to enter human trials.

Dirk Beher of Asceneuron, Lausanne, Switzerland, applauded the field’s exploration of different ways to target tau, and suggested that approaches such as antibodies and O-GlcNAcylation could be synergistic. “The field had too much focus on β-amyloid in the past. Tau pathology drives clinical symptoms in AD—we need more therapies that target it,” Beher said in Vienna.

Preventing Tangles

Tau model mice treated for 3.5 months with an O-GlcNAcase inhibitor (right) develop few neurofibrillary tangles (black) compared to controls (left). [Courtesy of Dirk Beher.]

 

Researchers are keen to go after tau because imaging studies confirm that the progression of neurofibrillary tangles through the brain correlates with cognitive decline even at pre-dementia stages (see Nov 2013 conference news; Aug 2014 conference news; May 2016 news). This has raised hope that stopping tau pathology might arrest deterioration.

Alas, the protein has been obstreperous. Attempts to block its aggregation with methylene blue derivatives did not pan out; indeed all previous approaches, such as the microtubule stabilizer epothilone D, davunetide, or the GSK-3β inhibitor tideglusib, fell by the wayside (see Feb 2013 news; Apr 2013 conference news; Dec 2016 conference news).

Recently, growing evidence that pathological species of tau travel from cell to cell has sparked interest in halting its march with antibodies (see Mar 2013 conference news; Aug 2013 conference news; Sep 2013 news). 

AbbVie developed ABBV-8E12 in collaboration with C2N Diagnostics, St. Louis. The antibody blocked tau seeding in cell cultures and prevented tangles in tau model mice (see Kfoury et al., 2012; Yanamandra et al., 2013; Yanamandra et al., 2015). In Vienna, Nuno Mendonca at AbbVie, Ludwigshafen, Germany, reported Phase 1 results of a study testing the antibody in 30 people with PSP at 12 clinical sites. Participants received a single IV dose of either 2.5, 7.5, 15, 25, or 50 mg/kg, with about one-fourth of the cohort receiving placebo. Twenty-seven people completed the study. The researchers monitored participants by blood sample and MRI scans for 84 days after dosing, and sampled cerebrospinal fluid at baseline and day 14.

The researchers reported a typical pharmacokinetic profile for an antibody. ABBV-8E12 had a half-life of about 30 days in the blood, with concentrations in CSF running 250 to 500 times lower than in plasma. Researchers are increasingly using a measure called CSF/plasma ratio for this purpose; for this antibody, it ranged from 0.2 to 0.4 percent. The maximum concentration in plasma increased linearly with dose. The treatment appeared safe. Some patients reported headaches, but these did not correlate with antibody dose. One person, who had a history of anxiety during medical procedures, withdrew from the trial due to agitation. The researchers were unable to detect anti-drug antibodies in the plasma of participants.

AbbVie is currently recruiting for two Phase 2 trials of this antibody. The first enrolls 180 people who have had progressive supranuclear palsy (PSP), a pure tauopathy, for less than five years. Most people with this disease survive no more than seven years. Sixty people will receive a low dose of the drug, 60 a high dose, and the remainder placebo. AbbVie did not disclose the doses it picked. After 52 weeks, the researchers will measure motor skills, cognition, and daily function via change on the PSP Rating Scale, and will follow participants for another 16 weeks. The other trial is in AD, and aims to test three different doses against placebo in 400 people with mild cognitive impairment who have a CDR score of 0.5 and a positive amyloid scan. The trial will run for 96 weeks, with the primary outcome being change on the CDR-sum of boxes.

Right behind ABBV-8E12 in terms of development is Genentech’s RO 7105705, now in Phase 1. In Vienna, Gai Ayalon of Genentech, South San Francisco, laid out preclinical evidence for this antibody. Developed in collaboration with AC Immune, Lausanne, Switzerland, RO 7105705 recognizes tau’s N-terminus and reacts with all six isoforms of human and primate tau, but not mouse tau. The antibody is indifferent to whether tau is monomeric or oligomeric, phosphorylated or not. Despite this promiscuity, the researchers believe it will act primarily on pathological tau because it targets extracellular forms of the protein. In P301L mice, which carry human mutant tau, 13 weeks of treatment with either 3, 10, or 30 mg/kg RO 7105705 curtailed brain pathology in a dose-dependent fashion, Ayalon reported.

At the same time, RO 7105705 treatment boosted tau levels in blood, Ayalon noted. This phenomenon has been seen with other anti-tau antibodies as well, and has been hypothesized to reflect stabilization of the protein in the periphery (see Apr 2017 news). To some researchers, this raises concerns that high plasma tau levels could interfere with brain clearance, given that a similar effect may have limited solanezumab’s ability to clear Aβ (see Jan 2017 news). Ayalon believes this is unlikely to be a problem for anti-tau therapy. “The proposed mechanisms of action for solanezumab and anti-tau antibodies are different,” he wrote to Alzforum. The latter attempt to stop the spread of misfolded tau through the brain, rather than clearing deposits.

To derive the RO 7105705 clinical candidate, Genentech researchers used an IgG4 backbone, which only weakly activates microglial Fcγ receptors. They did this because this type of microglial activation worsens inflammation in the brain, the researchers believe. In neuron-microglia co-cultures, the IgG4 version, as well as an “effectorless” version of the antibody lacking the Fcγ binding site, both protected neurons from toxicity better than the unmodified version did, suggesting that proinflammatory microglial activation in this case did harm neurons. In mouse brain, the effectorless antibody cleaned up tau aggregates as well as the normal antibody did (see Lee et al., 2016).  Chronic dosing with RO 7105705 caused no adverse effects in mice or cynomolgus monkeys.

Genentech’s Geoff Kerchner reported Phase 1 data to date. The trial is fully enrolled but ongoing, comprising 55 healthy volunteers from 18 to 80 years old. They receive single IV doses of RO 7105705 ranging from 225 mg to a whopping 16.8 grams. Participants thus far have tolerated all doses well, Kerchner reported. Some complained of headaches or nausea, but as with the AbbVie antibody, it was unclear if this related to treatment. Some participants got a bruise at the injection site. The antibody’s half-life is 30 days, and it was detectable in CSF, with pharmacokinetic parameters as expected, Kerchner said. Genentech also tested subcutaneous administration of 1,200 mg of RO 7105705, and found that 70 percent of it became bioavailable.

The ongoing Phase 1 trial is now evaluating multiple once-weekly 8,400 mg doses of the antibody in healthy controls and AD patients. The latter meet NIA-AA criteria for AD, with CDR of 0.5-2 and a positive amyloid scan. In future trials, the researchers plan to use their in-house tau PET tracer, GTP1, to determine baseline tau pathology and any changes due to treatment, Kerchner said (see Apr 2017 conference news).

Meanwhile, Biogen in Cambridge, Massachusetts, now has two antibody candidates. Biogen recently licensed an antibody directed against fragmented extracellular tau, BMS-986168, from Bristol-Myers Squibb, and has announced plans to take it into Phase 2 trials in PSP and AD (see press release). BMS-986168 is currently completing a multiple ascending dose Phase 1 study in PSP.

Biogen has also developed its own antibody, BIIB076, which is still in preclincial testing. In Vienna, Danielle Graham reported that BIIB076 recognizes both monomeric and fibrillar human and primate tau, binding to the protein with subnanomolar affinity. In 3-year-old cynomolgus monkeys, a single 100 mg/kg dose of the antibody had a half-life of eight to 11 days in blood. It reached maximum CSF concentration within 24-48 hours. As with other antibodies, its concentration in CSF was 1,000 times less than in plasma. The researchers also measured tau concentrations in blood and CSF using ultrasensitive single-molecule array (Simoa) assays. In some animals, plasma total tau rose after antibody administration, as happens with other antibodies. In CSF, total tau did not change, but free tau (i.e., that not bound by the antibody) dropped by three-quarters after 24 hours, taking three weeks to return to baseline. This indicated target engagement in the central nervous system. The pharmacokinetic data will be used to select the doses and sampling times for human trials, Graham noted.

While antibody strategies currently hog the tau airwaves, some groups are trying to create buzz with fresh alternatives. Asceneuron’s Beher discussed preclinical data for ASN120290, a small molecule that inhibits O-GlcNAcase, the enzyme that strips sugars from tau. Tau decorated with sugar molecules is less likely to aggregate, though it is unclear why that is. Some believe that O-GlcNAcylation competes with phosphorylation for the same serine/threonine residues (see Liu et al., 2009; for review, Hart et al., 2011). Others think the sugar moieties simply prevent tau molecules from cozying up to one another. At any rate, in animal studies, O-GlcNAcase inhibitors suppress tau phosphorylation, prevent tangles, and boost neuronal survival (see Jul 2008 news; Mar 2012 news). 

Asceneuron identified an inhibitor with favorable drug properties that enters the brain well. In JNPL3 tau mice, ASN120290 bumped up O-GlcNAcated tau 12-fold (see Aug 2014 conference news). 

In Vienna, Beher presented new data on how ASN120290 affects tau. In young P301S mice fed ASN120290 for 3.5 months, 100 mg/kg of it boosted tau O-GlcNAcylation, whereas 30 mg/kg did not. At the higher dose, treated mice had less phosphorylated tau than controls, and developed 40 percent fewer paired helical filaments in cortex. This amount of reduction is similar to that seen with tau antibodies, Beher noted. Strikingly, 80 percent fewer neurofibrillary tangles formed.

“O-GlcNAcase inhibitors have a profound effect on tangle formation,” Beher said. Tangles never contain tau modified with sugars, he added. The data suggest that tau O-GlcNAcylation and PHF formation are mutually exclusive. “This is a druggable pathway,” Beher claims.

The first Phase 1 trial has gotten underway. It will include a placebo group and will test single and multiple doses of oral ASN120290 in healthy volunteers. Tau O-GlcNAcylation will be measured in peripheral blood mononuclear cells (PBMCs). In mice, this biomarker has been found to correlate well with levels of brain tau O-GlcNAcylation, as well as with levels of drug, Beher noted. Importantly, this biomarker translates well between rats and humans, and ASN120290 shows comparable potencies in the two species by this measure. In Phase 1, the researchers will not use any other measures of CNS target engagement, Beher said. The biomarker readings will help select the dose to take forward into a Phase 2 study in people with PSP, planned for 2018.

How about tau PET in later trials? Beher noted that, at present, most tracers have not been studied much in PSP, and the off-target binding in the midbrain seen with some current tracers could become a problem (see Sep 2016 conference news). Newer PET tracers may work better for PSP (see Apr 2017 conference news).—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. Tilavonemab
  2. Epothilone D
  3. Davunetide
  4. Tideglusib
  5. Solanezumab

News Citations

  1. Do Tau Tracers Track Cognitive Decline in Disease?
  2. Scan by Scan, Growing Tau PET Data Picks Up Early Memory Deficits
  3. On Multiple Marker Analysis, Tangles Track Best With Functional Decline
  4. Truncated Tau Triggers Tangles, Transmits Pathology
  5. Drug Data Dash at AAN Annual Conference
  6. Tau Inhibitor Fails Again—Subgroup Analysis Irks Clinicians at CTAD
  7. Tau, α-Synuclein Spread: Crazy Stuff—How Might It Work?
  8. Tales of Traveling Tau: Is Transfer Between Neurons Normal?
  9. Antibodies Stop Toxic Tau in Its Extracellular Tracks
  10. Nice Catch? Antibodies Stabilize Tau in the Blood; Mark Levels in Brain
  11. Solanezumab: Did Aβ ‘Reflux’ From Blood Confound Target Engagement in CSF?
  12. Next-Generation Tau PET Tracers Strut Their Stuff
  13. Target Practice: A Trio of Papers to Ponder for Potential Therapies
  14. Can a Little Sugar Keep Tau From Souring Neurons?
  15. Therapies Take Aim at Tau
  16. Fluid NfL Shines, Tau PET Dims, in the Hunt for FTD Biomarkers

Research Models Citations

  1. JNPL3(P301L)

Paper Citations

  1. Kfoury N, Holmes BB, Jiang H, Holtzman DM, Diamond MI. Trans-cellular propagation of Tau aggregation by fibrillar species. J Biol Chem. 2012 Jun 1;287(23):19440-51. Epub 2012 Mar 29 PubMed.
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  5. Liu F, Shi J, Tanimukai H, Gu J, Grundke-Iqbal I, Iqbal K, Gong CX. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain. 2009 Jul;132(Pt 7):1820-32. PubMed.
  6. Hart GW, Slawson C, Ramirez-Correa G, Lagerlof O. Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu Rev Biochem. 2011;80:825-58. PubMed.

Other Citations

  1. RO 7105705

External Citations

  1. first
  2. trial 
  3. Phase 1
  4. Phase 2 trials in PSP
  5. press release
  6. Phase 1 

Further Reading

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