Clinical Trials Roundup: Broadening the Lines of Attack

Series - Alzheimer's Association International Conference 2013:

This concludes a two-part series. See part 1.

No major clinical trial results were announced at this year’s Alzheimer's Association International Conference (AAIC), held July 13-18 in Boston, Massachusetts. Instead, researchers provided updates on investigational therapies. Some presented phase 3 or 2 data (see part 1 of this series), while others outlined approaches that are just entering the clinical pipeline. Here is a sampling of the latter.

Stimulating Regeneration
Could regenerative approaches preserve cognition in a disease that, after all, is marked by rapid loss of neurons and brain mass? Speaking at an AAIC press briefing, Roberta Brinton from the University of Southern California, Los Angeles, said that the neurosteroid allopregnanolone may do just that. Allopregnanolone is a metabolite of the hormone progesterone. It is made in the brain and spinal cord, and occurs at high levels in the blood of pregnant women. In the triple transgenic mouse model of Alzheimer’s disease (AD), the steroid promotes the birth of new neurons and rescues cognition, while lowering amyloid β pathology and dampening inflammation, Brinton said.

Brinton and Lon Schneider, also at USC, will lead a Phase 1 trial of allopregnanolone in 16 men and 16 women with mild cognitive impairment (MCI) or early AD. Participants will receive intravenous infusions of the drug once per week for three months. To assess safety and tolerability, the trial will test multiple ascending doses of the steroid, with the highest dose sufficient to boost blood levels to those seen during pregnancy. Brinton expects the trial will be funded by the National Institute on Aging and conducted through the USC Alzheimer’s Disease Research Center, and will begin next year. Michael Rogawski and Gerhard Bauer at the University of California, Davis, will supply the drug and placebo control.

As secondary endpoints, the researchers will compare baseline and final MRI scans of hippocampal volume, white matter hyperintensities, and brain connectivity. Participants will also take standard neuropsychological and cognitive tests. If the drug proves safe in Phase 1, Phase 2 studies will look for a slowing of cognitive decline and brain atrophy over 12 or 18 months, Brinton said. In addition, Rogawski is currently testing allopregnanolone in people with traumatic brain injury.

Earlier studies showed that allo, as the drug is known for short, kindles neurogenesis. It opens chloride channels in neural stem cells, leading to depolarization, increased calcium levels, and transcription of neuronal differentiation factors (see ARF related news story; ARF related news story). Treatment once per week appears to be optimal, because more frequent dosing causes a feedback loop that shuts neurogenesis back down, Brinton told Alzforum (see Chen et al., 2011; Brinton et al., 2013). Because the hormone regulates multiple cellular systems, it also affects diverse processes such as inflammation, cholesterol trafficking, and Aβ production. In 3x Tg mice, treatment with this steroid was reported to rescue associative learning and memory deficits, and to increase mitochondrial respiration, resulting in greater energy production, among other effects (see Irwin et al., 2011; Singh et al., 2012).

Prevention With Pioglitazone
With accumulating evidence that the pathogenesis of AD begins twenty years or more before diagnosis, many researchers are interested in identifying healthy populations at high risk for AD and testing interventions that might delay symptoms. At an AAIC press briefing, Kathleen Welsh-Bohmer from Duke University, Durham, North Carolina, described one such approach. The Phase 3 Tommorrow Study (no, that is not a misspelling) will enroll 5,800 cognitively normal people at 50 sites in the U.S., Europe, and Australia. Participants must be at heightened risk for AD based on age and the genetic factors ApoE4 or Tomm40 variant, hence the study’s name (see ARF related news story). Half the participants will receive a low dose of the approved diabetes drug pioglitazone, which will be supplied by the trial’s sponsor, Takeda Pharmaceuticals (see press release). The Tommorrow trial will start in August and run for four years, with the primary outcome measure being conversion to MCI. In that amount of time, the researchers expect to see 410 conversions, which will give them 90 percent power to detect a treatment effect, Welsh-Bohmer said.

Why pioglitazone? This PPAR-γ agonist improves cognition in AD mice, but had mixed results in prior human trials (see Miller et al., 2011). Researchers involved in this and other human trials noted that pioglitazone and related thiazolidinediones seem to improve brain metabolism, and suggested they might help patients in early stages of the disease (see ARF related news story). Meanwhile, animal studies continue to turn up novel mechanisms for how these drugs might restore cognition and lower pathology (see ARF related news story). Collaborator Allen Roses at Duke told Alzforum that the choice of pioglitazone was guided by the drug’s excellent safety track record, as well as human and animal trial data suggesting that the drug dampens inflammation, curbs amyloid pathology, and improves brain blood flow and use of oxygen and glucose (see, e.g., Sato et al., 2011).

Welsh-Bohmer noted challenges in designing a global preventative study. For one thing, the researchers needed to find cognitive tests that are valid worldwide and are sensitive to changes in the MCI population. Welsh-Bohmer, working with a group of international AD clinical trial experts, selected an outcome battery that includes tests of episodic memory, executive function, language, attention, and visuospatial skills. The researchers are currently validating the test battery in 200 cognitively normal people 65 to 88 years old in Italy, Russia, and Switzerland. They will compare this group’s performance against that of 25 people with Alzheimer’s disease. The goal is to determine what constitutes normal performance across different cultures and a range of ages. The researchers also had to define criteria for MCI. They chose a clinical dementia rating (CDR) of 0.5, plus failing two of 12 measures on the test battery on two consecutive exams taken six months apart. Designing the trial took two years of literature reviews and modeling, Welsh-Bohmer said. She suggested that this work could lay the groundwork for future trials in preclinical AD populations.

Prevention Through Improved Health
Another prevention study takes a different tack. Speaking in an AAIC plenary session, Karen Ritchie from the public research institution INSERM in Paris, France, discussed epidemiological factors that increase risk for AD. The Esprit Project in Montpellier, France, enrolled almost 2,000 cognitively normal people over age 65 and followed them for 12 years, tracking cognitive scores and conversion to MCI or AD (see ARF related news story). The goal was to quantify the contribution of various environmental or behavioral risk factors to AD risk. The data suggested that increasing education could lower AD incidence by about a quarter, while controlling conditions such as diabetes, depression, and stroke could cut another quarter of new cases. Exposure to these risk factors occurs mostly in middle age, Ritchie emphasized. “AD is a disease of middle age that leads to a terminal dementia stage in old age,” she said.

Based on this data, the U.K. Alzheimer’s Association is conducting the PREVENT study, which will investigate whether lowering these risk factors can in fact delay the onset of AD (see also Ritchie and Ritchie, 2012). PREVENT will enroll 600 middle-aged children of people with AD, who are assumed to be at increased risk of developing the disease as they age. In a randomized controlled trial, half the participants will receive an intervention consisting of improved diet and physical exercise as well as computer tasks to increase cognitive reserve. The researchers will track markers of insulin resistance, inflammation, and depression in this group, so that the participants can receive preventative medical treatment at the earliest stage of these disorders. The control group will receive annual checkups and standard medical care from their family practitioner.

The researchers will use cognitive tests and CSF biomarkers to detect the development of preclinical AD or MCI. They will also compare the treatment group to an observational cohort of people at low risk for AD, who do not carry the ApoE4 risk factor or have an affected parent. The hope is that the interventions might lower AD incidence in participants to levels seen in the low-risk group. At the earliest sign of benefit, all participants will be switched to the active prevention group, Ritchie told Alzforum. Several other large European studies are also investigating whether lifestyle changes can reduce AD risk (see ARF related news story).

Epigenetics and Gene Expression
The aging brain undergoes many changes. In primates, genes involved in neural plasticity become less active with age. This is due to changes in chromatin structure that pack DNA more tightly and prevent these genes from being transcribed, said Li-Huei Tsai from MIT in an AAIC plenary session. In animal studies, Tsai identified the enzyme histone deacetylase 2 (HDAC2) as a key regulator to silence genes involved in synaptic plasticity and learning (see ARF related news story; ARF related news story). HDAC2 levels are elevated in AD brains, and neurotoxins such as Aβ induce its expression, Tsai found (see ARF related news story).

Blocking HDAC2 might therefore help restore cognitive function in people with AD, Tsai suggested. She and colleagues have identified a small molecule, SC-027, that inhibits class I HDACs including HDAC2 in a long-acting fashion. The patent on this compound has expired, Tsai said. After 10 days of treatment with SC-027, CK-p25 AD mice have better memory and more synapses than untreated controls, Tsai reported. Three-month-old >5xFAD mice treated for one month have less amyloid pathology in their brains than do controls. It is not yet clear how the inhibitor reduces pathology, Tsai said. When treated at six months of age, the 5xFAD mice learn better than untreated animals. SC-027 also normalizes gene expression in the 5xFAD animals, dialing down genes involved in inflammation and cell death. Tsai said she is interested in taking SC-027 to human trials, but many challenges remain, including toxicity at high doses.—Madolyn Bowman Rogers.

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References

News Citations

  1. Clinical Trials Roundup: Four Hits, No Home Runs
  2. New York: Catalyst Conference on Stem Cells, Cognitive Aging, and AD
  3. Early Casualty, Neurogenesis Cripples Cognition in AD Mice
  4. Honolulu: Tomm40 Reported to Track With Brain Atrophy, Cognition
  5. Trial Updates: B Vitamin Back in Vogue? Diabetes Drug Less Sweet
  6. Can Phagocytosis, Memory Effects Revive Diabetes Meds?
  7. Paris: Beyond Genomics, French Science Draws on Populations, Patients
  8. Europe Asks If Reforming Health Habits Can Prevent Dementia
  9. It’s an HDAC2 Wrap— Memory-suppressing DNA Modifier Identified
  10. SfN: Epigenetic Changes in Alzheimer’s and Cognitive Decline
  11. Does Epigenetic Modification by Aβ Offer New Take on Therapy?

Paper Citations

  1. Chen S, Wang JM, Irwin RW, Yao J, Liu L, Brinton RD. Allopregnanolone promotes regeneration and reduces β-amyloid burden in a preclinical model of Alzheimer's disease. PLoS One. 2011;6(8):e24293. PubMed.
  2. Brinton RD. Neurosteroids as regenerative agents in the brain: therapeutic implications. Nat Rev Endocrinol. 2013 Feb 26; PubMed.
  3. Irwin RW, Wang JM, Chen S, Brinton RD. Neuroregenerative mechanisms of allopregnanolone in Alzheimer's disease. Front Endocrinol (Lausanne). 2011;2:117. PubMed.
  4. Singh C, Liu L, Wang JM, Irwin RW, Yao J, Chen S, Henry S, Thompson RF, Brinton RD. Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice. Neurobiol Aging. 2011 Jul 29; PubMed.
  5. Miller BW, Willett KC, Desilets AR. Rosiglitazone and pioglitazone for the treatment of Alzheimer's disease. Ann Pharmacother. 2011 Nov;45(11):1416-24. PubMed.
  6. Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T. Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 2011 Sep;32(9):1626-33. PubMed.
  7. Ritchie CW, Ritchie K. The PREVENT study: a prospective cohort study to identify mid-life biomarkers of late-onset Alzheimer's disease. BMJ Open. 2012;2(6) PubMed.

Other Citations

  1. the triple transgenic mouse model

External Citations

  1. press release
  2. PREVENT study
  3. >5xFAD mice

Further Reading

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