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Non-Aβ, Non-Tau Drugs Tweak Markers, Cognition in Alzheimer’s, Huntington’s

Series - AAT-AD/PD™ 2020 Conference: Advances in Alzheimer's and Parkinson's Therapies:

As the Alzheimer’s field branches out its therapeutics search beyond Aβ and tau, some of those approaches are showing glimmers of promise. The second biannual Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD), held virtually April 2 to 5, featured some new data on therapies that target neuroinflammation, synaptic signaling, epigenetic regulation, and the cortisol stress response. The candidate drugs nudged cognition or biomarkers in small, early stage trials of Alzheimer’s or Huntington’s patients, with larger studies planned. Makers of the nutraceutical drink Souvenaid presented three-year data from a recently concluded trial. Cognitive benefits previously reported at two years had grown, suggesting a sustained effect. Some of these approaches could broaden the therapeutic pipeline for neurodegenerative disease.

  • Souvenaid’s benefits build over time, slowing decline by up to 45 percent.
  • An epigenetic drug suppresses biomarkers of inflammation and degeneration.
  • Anti-inflammatory and synaptic strategies hint at benefit for Huntington’s patients.

Nutrient Drink: Benefit Accrues Over Time
Souvenaid is a medical food formulated as a once-a-day, yogurt-like drink. It contains Fortasyn Connect, a combination of fish oils, vitamins, and other nutrients believed to support synaptic health. The drink is made by Nutricia of Danone Research. Several small trials suggested a possible cognitive benefit when taken early in the course of AD. To evaluate this lead, the LipiDiDiet trial enrolled 311 people with prodromal Alzheimer’s disease and a mean age of 71. After two years, participants who drank Souvenaid performed no better than controls on the primary outcome measure, the Neuropsychological Test Battery, but had declined less on the CDR-SB and their hippocampi had shrunk a little less (Nov 2017 news). An independent analysis confirmed that Souvenaid curbed cognitive decline in these trial participants by a third (Nov 2018 conference news). 

At AAT-AD/PD, LipiDiDiet study coordinator Tobias Hartmann of Saarland University in Homburg, Germany, reported three-year CDR-SB and volumetric data from LipiDiDiet. The third year represented an optional, blinded extension to the initial two-year trial. This far out, 45 participants remained in the treatment and 36 in the placebo group, less than a third of the starting enrollment.

At three years, the cognitive benefit on the CDR-SB widened for those taking Souvenaid, with decline slowing by 45 percent. Likewise, the rate of hippocampal atrophy diverged further between the groups, slowing by 33 percent for those on Souvenaid. The Cohen’s d effect sizes were 0.31 and 0.27, respectively, for CDR-SB and hippocampal atrophy. Both were significant at the 0.01 level or better.

These effect sizes are similar to that seen in the EXPEDITION 1 and 2 studies of solanezumab, where the antibody slowed cognitive decline by a third in the subgroup of participants with mild AD (Jan 2018 news). 

“The benefits observed at the two-year intervention were sustained and amplified over three years, with a remarkable magnitude of slope and effect size,” Hartmann said in his talk. He noted that LipiDiDiet is now the longest intervention trial in prodromal AD, with six years of placebo-controlled data on some participants. The fact that prodromal patients in LipiDiDiet reaped greater benefits than did mild AD patients in earlier trials suggests that Souvenaid is likely to have a better effect the earlier it is given, Hartmann said. Clinicaltrials.gov lists a planned Phase 2 trial that will test the effects of one year of Souvenaid on cognitive aging in 120 cognitively healthy elderly participants.

Calming Astrocytes Aids Huntington’s Brain
Inflammation is a major driver of pathogenesis in Alzheimer’s and other neurodegenerative diseases, and many groups are looking for ways to tweak this complex process. For example, the biotech company Vaccinex in Rochester, New York, is targeting the pro-inflammatory factor semaphorin 4D. First discovered as an axon guidance molecule in the developing nervous system, semaphorin 4D is now known to be released from neurons in response to stress or injury in the adult brain, said Elizabeth Evans of Vaccinex. Secreted Sema4D binds to receptors on glial cells, triggering secretion of inflammatory cytokines and collapse of their cytoskeletons. The net effect is to activate microglia and astrocytes, inhibit myelination, and disrupt the blood-brain barrier (Smith et al., 2015). 

Evans noted that, once activated, astrocytes retract their processes from synapses. They no longer mop up excess glutamate from the synaptic cleft, which can lead to excitotoxicity and kill those synapses. Activated astrocytes also pull back from blood vessels, and so cannot take up glucose from the bloodstream to feed to neurons.

The researchers generated an antibody, pepinemab (previously known as VX15), that binds Sema4D and blocks its signaling (Fisher et al., 2016). In the YAC128 mouse model of Huntington’s disease, treatment with pepinemab slowed brain atrophy and improved some behaviors (Southwell et al., 2015). 

At AAT-AD/PD, Evans discussed data from a second HD mouse model, Q175, as well as from a clinical trial. Immunostainings of Q175 brains revealed that neurons increasingly turned up Sema4D expression as disease progressed, starting at three months, before symptoms appeared. Adding Sema4D to isolated rat astrocyte cultures caused the cells’ actin cytoskeleton to collapse. They became pro-inflammatory, confirming an effect of Sema4D on these cells.

In sections from human postmortem HD brains, Sema4D was likewise elevated over controls, correlating with disease stage and with neuronal death in multiple cortical regions. Immunostainings of these brain sections showed that, in the presence of high Sema4D expression, astrocytes pulled back their processes and balled up. Together, the data suggested that blocking Sema4D might help preserve normal astrocytic functions and brain glucose metabolism.

To test this, the researchers initiated a Phase 1/2 trial, SIGNAL-HD, of pepinemab in 36 people with the causative CAG expansion. All were in either the late prodromal or early manifest stage of the disease. Half the cohort received a monthly infusion of 20 mg/kg pepinemab for six months, the remainder placebo. This trial met its primary endpoint of safety and tolerability, Evans noted.

A secondary endpoint, FDG PET, measured brain glucose metabolism. A preliminary interim analysis of 11 people on pepinemab and eight people on placebo found consistent differences between the groups. In controls, the FDG signal fell over the course of the study, while in the treatment group, it rose. This was consistent across the whole cohort. It occurred in every brain region, with the largest effects seen in frontal and parietal cortex.

After six months, the placebo group “crossed over” to receive pepinemab. Six months later, their FDG PET signals had risen to the level seen in the treatment group. “We were encouraged by the magnitude and consistency of the change in FDG PET signal in two different cohorts of patients,” Evans said. She said they also saw encouraging trends on brain atrophy, motor skills, and cognition, although she did not show those data.

Based on these findings, Vaccinex has launched a larger Phase 2 study, enrolling 179 people with early manifest HD and 86 with late prodromal disease. The former will receive 18 months of treatment with 20 mg/kg pepinemab, the latter 18 or 36 months. This study is fully enrolled, with the last patient visit scheduled for July 2020 and topline data expected in October. Evans did not say whether the current coronavirus pandemic would affect this timeline.

The researchers will also test pepinemab in AD patients. In postmortem sections from AD brains, Sema4D rises with disease progression just as it does in HD. The Phase 1b trial will enroll 60 people with MCI due to AD or mild AD. Twenty of them will receive monthly infusions of placebo, 20 will get 20 mg/kg pepinemab, and 20 will get 40 mg/kg for 32 weeks. The primary objective is safety and tolerability, with FDG PET as a secondary outcome. Other secondary and exploratory outcomes include cognitive measures such as the ADASCog and CDR, MRI volumetric scans, and fluid biomarkers of Aβ, p-tau, NfL, and cytokines. The trial is slated to start in July.

Epigenetic Drug Nudges Biomarkers of Inflammation and Degeneration
Next up, a drug that targets epigenetic regulation. Researchers at Oryzon Genomics in Barcelona, Spain, developed vafidemstat, also known as ORY-2001, as a selective inhibitor of lysine-specific demethylase 1 (LSD1). This enzyme represses neuronal genes and is the most abundant histone demethylase in the frontal cortex. In unpublished work on animal models, inhibiting LSD1 with vafidemstat boosted learning and memory while lessening neuroinflammation and aggression. Vafidemstat also inhibits monoamine oxidase B (Fang et al., 2019). 

Taken orally, vafidemstat enters blood and brain well, and appeared safe in Phase 1 trials (May 2017 conference news). At AAT-AD/PD, Oryzon’s Michael Ropacki elaborated on these data. He noted that more than 250 people have now taken the drug without ill effects. About 150 of those were on the drug for two months or more, while 40 people took it for more than a year.

Ropacki discussed interim data from the Phase 2a Epigenetic Therapy in Alzheimer’s Disease, or ETHERAL, trial. This one-year trial has a target enrollment of 150 participants with mild to moderate AD confirmed by biomarkers. Currently, it is fully enrolled in Spain, France, and the U.K., with a total of 117 participants from those locations. Enrollment in the U.S. is ongoing, with 21 participants from there so far. Ropacki showed six-month cerebrospinal fluid biomarker data from the European cohort, but cautioned that the analysis is ongoing and findings are preliminary.

The European participants are nearly all white, with an average age of 73. Fifty-five percent of them have mild AD, the remainder moderate. In this cohort, 38 people take 0.6 mg vafidemstat, 34 take 1.2 mg, and 45 take placebo. After six months, the inflammatory biomarker YKL40 dropped statistically significantly in CSF in those on drug. This appeared to be driven by an effect in people with moderate AD, rather than mild. CSF neurogranin, a marker for synaptic damage, trended lower in the treatment group, with the effect reaching significance in the moderate subgroup taking 0.6 mg vafidemstat. CSF NfL, a marker of neurodegeneration, rose in all participants as disease progressed, but its rise was significantly dented in the mild subgroup taking 1.2 mg vafidemstat. As expected from vafidemstat’s mechanism of action, there were no changes in cerebrospinal fluid biomarkers of Aβ and tau after six months. In addition, participants on drug did no better than the placebo group on the ADAS-Cog14. Ropacki noted this trial was not powered to show changes in cognition.

“ETHERAL has produced interesting biomarker data that require further exploration and replication in the larger combined European and U.S. samples,” Ropacki said. The drop in YKL40 is the first evidence in people of the anti-inflammatory effect seen in animal models, he added.

Because vafidemstat treated aggression and apathy in animal models, the researchers are also studying behavioral effects in people. In small trials of people with autism spectrum, borderline personality, and attention-deficit and hyperactivity disorder, the drug significantly calmed agitation and aggression, Ropacki said. This led the researchers to offer an open-label substudy of the ETHERAL trial, dubbed REIMAGINE AD, to examine behavioral change in AD. It enrolled 12 AD patients from a single site in Barcelona. On several measures of aggression, namely the Cohen-Mansfield Agitation Inventory, Neuropsychiatric Inventory Agitation/Aggression subscale, and the Clinical Global Impression Improvement scale, participants improved markedly, with scores dropping by up to 80 percent from baseline. The findings were significant at the 0.05 level. On two caregiver measures, the Zarit Caregiver Burden Interview and NPI emotional distress scale, scores dropped similarly. However, the benefits took longer to show up in these AD patients than they had in cohorts of younger people, Ropacki noted.

Could Suppressing Cortisol Boost Cognition in AD?
Stress has also been implicated in AD, with evidence that high levels of glucocorticoids such as cortisol can worsen pathology (Dec 2011 news; Jun 2007 news). Cortisol has numerous harmful effects, including raising Aβ levels, boosting excitatory signaling and neurotoxicity, and dampening long-term potentiation. However, few groups have tried to target this mechanism in AD.

At AAT-AD/PD, Craig Ritchie of the University of Edinburgh described an approach being pursued by the biotechnology company Actinogen, based in Sydney. Ritchie noted that he is a paid consultant for Actinogen. The company developed a small molecule, Xanamem, that reversibly binds to the enzyme 11beta-HSD1 and inhibits it. Because this enzyme converts inactive cortisone to active cortisol, the inhibitor suppresses cortisol production (Webster et al., 2017). 

In the Tg2576 mouse model of amyloidosis, nine to 12 months of Xanamem lowered cortical plaque load and improved memory in the Morris water maze. When started early, it prevented cognitive decline (Sooy et al., 2015). In healthy or diabetic old people, a different 11beta-HSD1 inhibitor was shown to improve verbal fluency or memory, respectively, after four or six weeks of treatment (Sandeep et al., 2004). 

Based on these data, the researchers took Xanamem into human trials. In the XanADu Phase 2 study, they gave 10 mg Xanamem daily for 12 weeks to 186 people with mild AD at 25 sites in Australia, the U.S., and the U.K. This did not affect cognition, but did alter levels of stress hormones, including boosting the inactive form, cortisone, as expected. Analysis of these data suggested the dose had been too low, so the researchers doubled it. In the XanaHES Phase 1 study in Perth, Australia, 30 healthy old people took 20 mg daily, while 12 took placebo for 12 weeks. After four weeks, participants on drug did better than the placebo group in CogState tests of working memory, visual attention, and psychomotor function. These improvements were sustained for the rest of the study, and had large effect sizes, with Cohen’s ds of around 0.6 to 0.8, Ritchie noted.

Because 20 mg Xanamem appeared to benefit cognition in healthy aging, but 10 mg did not help cognition in mild AD, the researchers decided to next test 20 mg in prodromal AD. They are also planning trials in schizophrenia and Type 2 diabetes, conditions marked by high cortisol and cognitive impairment. “11beta-HSD1 inhibition with Xanamem is a targetable and rational approach to therapy in AD, with a range of additional potential therapeutic applications,” Ritchie noted.

Will Making Synapses More Plastic Sharpen Memory in HD?
Synapses falter in Alzheimer’s and other neurodegenerative diseases. Could propping them up slow decline? Aaron Koenig of Sage Therapeutics in Boston described SAGE-718, a derivative of the endogenous steroid 24(S)-hydroxycholesterol. SAGE-718 binds to the NMDA receptor and enhances its function. The steroid does not directly activate the receptor, but acts as a positive allosteric modulator, or PAM. NMDA receptor activity induces long-term potentiation of synapses, and thus is essential for learning and memory.

Notably, in the observational TRACK-HD study, which follows biomarker and clinical change in Huntington’s patients, plasma 24(S)-hydroxycholesterol levels waned as symptoms appeared, correlating with worse performance on tests of executive function and emotional processing (ACNP poster presentation M-147; Tabrizi et al., 2012). An older study also reported a drop in 24(S)-hydroxycholesterol in symptomatic HD (Leoni et al., 2008). The findings suggested SAGE-718 might help HD patients.

The researchers first tested SAGE-718 in several small Phase 1 studies of healthy volunteers, who took either the steroid or a placebo pill, and then a low dose of ketamine to inactivate their NMDA receptors. Electrophysiology and fMRI measures showed that SAGE-718 counteracted ketamine, normalizing synaptic activity. In the largest study, 19 participants took SAGE-718 for 11 days, 21 placebo. Every other day, they took CogState card-playing tests designed to evaluate working memory, attention, spatial learning, and executive function. On the simpler tasks, treatment and placebo groups performed equally well, but a difference emerged on more demanding tasks. In the “two back” card test of working memory, where participants need to recall the card they saw two card flips ago, those taking SAGE-718 outperformed the placebo group at every time point. On the Groton maze learning test of executive function, participants on SAGE-718 did better starting at day six. They also trended toward better performance on a test of spatial learning.

Based on these results, the researchers launched a pilot study of SAGE-718 in Huntington’s disease, which is characterized by executive dysfunction in addition to the signature motor problems. Six people with mild to moderate HD took SAGE-718 every other day for two weeks, with repeated testing on the Cogstate tasks. After one week, their performance on the “two back” card test improved, and remained high for the rest of the study. Koenig noted that the magnitude of improvement was greater than that seen in healthy controls in the previous study. There was no control group in this study.

“We believe this early signal holds promise for showing effects that would ultimately be meaningful for patients with Huntington’s-related cognitive impairment,” Koenig said. Further investigation of SAGE-718 is warranted for conditions associated with NMDA hypofunction, including cognitive deficits in early HD, he added.—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. Souvenaid
  2. Solanezumab

News Citations

  1. LipiDiDiet Data Published
  2. Which Are the Right Tests to Satisfy New FDA Guidance?
  3. End of the EXPEDITION: Solanezumab Results Published
  4. Non-Amyloid Treatments: Inflammation, Epigenetics, Regeneration
  5. Stress and AD: Glucocorticoids Accelerate Neuropathology in Animals
  6. Stress and Aβ—A Fluid Connection in Mice

Paper Citations

  1. Smith ES, Jonason A, Reilly C, Veeraraghavan J, Fisher T, Doherty M, Klimatcheva E, Mallow C, Cornelius C, Leonard JE, Marchi N, Janigro D, Argaw AT, Pham T, Seils J, Bussler H, Torno S, Kirk R, Howell A, Evans EE, Paris M, Bowers WJ, John G, Zauderer M. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiol Dis. 2015 Jan;73:254-68. Epub 2014 Oct 18 PubMed.
  2. Fisher TL, Reilly CA, Winter LA, Pandina T, Jonason A, Scrivens M, Balch L, Bussler H, Torno S, Seils J, Mueller L, Huang H, Klimatcheva E, Howell A, Kirk R, Evans E, Paris M, Leonard JE, Smith ES, Zauderer M. Generation and preclinical characterization of an antibody specific for SEMA4D. MAbs. 2016;8(1):150-62. Epub 2015 Oct 2 PubMed.
  3. Southwell AL, Franciosi S, Villanueva EB, Xie Y, Winter LA, Veeraraghavan J, Jonason A, Felczak B, Zhang W, Kovalik V, Waltl S, Hall G, Pouladi MA, Smith ES, Bowers WJ, Zauderer M, Hayden MR. Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease. Neurobiol Dis. 2015 Apr;76:46-56. Epub 2015 Feb 3 PubMed.
  4. Fang Y, Liao G, Yu B. LSD1/KDM1A inhibitors in clinical trials: advances and prospects. J Hematol Oncol. 2019 Dec 4;12(1):129. PubMed.
  5. Webster SP, McBride A, Binnie M, Sooy K, Seckl JR, Andrew R, Pallin TD, Hunt HJ, Perrior TR, Ruffles VS, Ketelbey JW, Boyd A, Walker BR. Selection and early clinical evaluation of the brain-penetrant 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor UE2343 (Xanamem™). Br J Pharmacol. 2017 Mar;174(5):396-408. Epub 2017 Jan 25 PubMed.
  6. Sooy K, Noble J, McBride A, Binnie M, Yau JL, Seckl JR, Walker BR, Webster SP. Cognitive and Disease-Modifying Effects of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition in Male Tg2576 Mice, a Model of Alzheimer's Disease. Endocrinology. 2015 Dec;156(12):4592-603. Epub 2015 Aug 25 PubMed.
  7. Sandeep TC, Yau JL, Maclullich AM, Noble J, Deary IJ, Walker BR, Seckl JR. 11Beta-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6734-9. PubMed.
  8. Tabrizi SJ, Reilmann R, Roos RA, Durr A, Leavitt B, Owen G, Jones R, Johnson H, Craufurd D, Hicks SL, Kennard C, Landwehrmeyer B, Stout JC, Borowsky B, Scahill RI, Frost C, Langbehn DR, . Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurol. 2012 Jan;11(1):42-53. PubMed.
  9. Leoni V, Mariotti C, Tabrizi SJ, Valenza M, Wild EJ, Henley SM, Hobbs NZ, Mandelli ML, Grisoli M, Björkhem I, Cattaneo E, Di Donato S. Plasma 24S-hydroxycholesterol and caudate MRI in pre-manifest and early Huntington's disease. Brain. 2008 Nov;131(Pt 11):2851-9. PubMed.

Other Citations

  1. Xanamem

External Citations

  1. Phase 2 trial
  2. YAC128
  3. Q175
  4. Phase 2 study
  5. inhibits monoamine oxidase B
  6. ETHERAL
  7. XanADu 
  8. XanaHES
  9. ACNP poster presentation M-147

Further Reading

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