Part 1 of a two-part story. See part 2.
While Alzheimer’s therapies that target amyloid β production and clearance grab the lion’s share of the headlines, they comprise but a fraction of the strategies under investigation. At the Alzheimer's Association International Conference (AAIC), held July 14-18 in Boston, Massachusetts, speakers laid out approaches ranging from anti-amyloid therapies to cholinergic transmission, inflammation, and regeneration. Some researchers detailed Phase 3 or 2 data, others discussed compounds entering Phase 1, and some approaches have yet to make the jump to human trials (see Part 2 of this series). In line with recent trends in the field, most researchers aim to intervene early in the disease, and some are launching large prevention trials with the goal of delaying symptom onset in preclinical Alzheimer’s disease (AD) populations. Read on for a sample of the clinical trial data presented at AAIC.
Anti-amyloid strategies have garnered intense interest, but the field is still waiting for a home run in this area. Baxter International Inc. recently announced that its intravenous immunoglobulin (IVIG), Gammagard, missed its primary endpoints in a Phase 3 trial (see ARF related news story), but at an AAIC press briefing, principal investigator Norman Relkin at Weill Cornell Medical College, New York City, was not ready to give up. Relkin fleshed out the prior topline results with preliminary biomarker data. IVIG treatment lowered levels of Aβ42 in the blood and boosted anti-amyloid antibodies in cerebrospinal fluid (CSF), Relkin said. It also thinned out fibrillar Aβ deposits in the brain, as shown by Amyvid PET scans. Relkin said investigators are still analyzing MRI and FDG PET scans to learn about IVIG’s effect, if any, on brain atrophy and metabolism. Those data will come in the fall. “I am optimistic that there are signals worthy of further study,” Relkin told Alzforum, although he added it was too soon to plan another trial.
Planned subgroup analyses showed that people with moderate AD or who carry an ApoE4 allele responded better to the treatment, improving on some cognitive measures. Looking back, the 24 patients in the Phase 2 trial of Gammagard, which had been declared a success, happened to fall into that group, Relkin said. In those phase 2 patients, Gammagard appeared to slow cognitive decline and brain shrinkage over an 18-month extension trial (see ARF related news story). Some of those patients have now been treated for more than eight years. “I cannot tell you they have not progressed, but it is much slower than expected. At least two are still in the mild state of the disease,” Relkin said. AD is normally fatal within eight to 10 years, but some cases of slow progression occur naturally, too.
Other IVIG therapies have recently met with mixed results. Octapharma AG’s IVIG missed its primary endpoints in a Phase 2 trial of AD patients (see ARF related news story), but looks promising so far in a small Phase 2 trial in people with mild cognitive impairment (MCI) (see ARF related news story). Grifols Biologicals, Inc., Sutter Health, and Behring AG in Bern, Switzerland, are also testing pooled antibodies, although they have not reported data yet (see ARF related news story).
Enhancing Cholinergic Transmission
Consider the α7 nicotinic acetylcholine receptor, now gaining luster as an AD target (see ARF related news story; ARF related news story). At last year’s AAIC, researchers reported that EnVivo Pharmaceuticals’ α7 agonist met its endpoints in a Phase 2b trial (see ARF related news story). This year a new player joined the club, to great audience interest. Laura Gault at pharmaceutical company AbbVie, Chicago, Illinois, presented data from a 12-week Phase 2 trial of her company’s α7 agonist ABT-126. AbbVie spun off from Abbott Laboratories in 2012. The trial enrolled nearly 300 participants with mild to moderate AD and an average age of 74. They received either placebo, one of two doses of ABT-126, or the approved AD drug donepezil, an acetylcholinesterase inhibitor. The trial had few dropouts, and adverse events were mild and similar to those seen with donepezil. People complained mostly about headaches and gastrointestinal problems, Gault said. This trial began in 2009, and ended in 2010.
The low dose of ABT-126 had no effect. On the higher dose, participants reached similar cognitive gains to those seen on donepezil, modestly improving their scores on memory tests in the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) compared to the placebo group. Analysis showed that participants with higher levels of ABT-126 in their blood performed significantly better on the ADAS-Cog than those with less drug exposure. The relationship showed no evidence of a plateau, implying that people could improve more at higher doses, Gault said. Additional toxicology studies in animals and prior Phase 1 studies suggested that higher doses of ABT-126 would be well-tolerated, she claimed. Based on this, AbbVie is running two 24-week Phase 2b studies enrolling about 400 AD patients apiece that will explore higher doses. Gault declined to specify what any of the doses are. The first trial will again compare ABT-126 to donepezil and placebo, while the second will look at whether a combination of ABT-126 and an acetylcholinesterase inhibitor will provide additional benefit. Those trials are set to read out next year.
Recent research points to a prominent role for neuroinflammation in AD pathogenesis (see ARF webinar; ARF related news story). At last year’s 5th Clinical Trials in Alzheimer’s Disease conference, held 29-31 October in Monaco, Bruno Imbimbo of Chiesi Pharmaceuticals in Rockville, Maryland, reported that the company’s compound CHF5074 dialed down inflammatory signaling from microglia and improved cognition in a 12-week Phase 2 trial run in the U.S. and Italy (see ARF related news story). CHF5074, a derivative of nonsteroidal antiinflammatory drugs, was originally thought to modulate γ-secretase. Animal and cell culture studies have since shown that it acts on microglia to suppress cytokine signaling and stimulate phagocytosis of amyloid deposits, according to data presented at AAIC 2013.
Joel Ross at the Memory Enhancement Center in Eatontown, New Jersey, led the U.S. portion of the trial. The trial enrolled about 100 people with mild cognitive impairment (MCI). Over the initial three months, those who carried an ApoE4 allele improved on several cognitive measures, while non-carriers did not, Ross said at an AAIC press briefing. Most participants continued on drug in an open-label extension phase. Ross said that ApoE4 carriers in the open-label extension have maintained their cognitive gains over 88 weeks of treatment. They score better on several measures of verbal memory, as well as tests of attention and executive function, compared to their baseline performance. Non-carriers showed no immediate benefit, Ross said; however, their cognitive abilities have remained stable for the nearly two years of the extension study. With regard to biomarkers, patients on drug showed linear decreases of inflammatory markers such as TNF-α and sCD40L in CSF.
What might account for the greater effect of CHF5074 in ApoE4 carriers? These people are believed to experience more neuroinflammation than non-carriers, Ross said (see, e.g., ARF related news story ).
Biotech startup CereSpir Inc. announced July 26 that it will license CHF5074 from Chiesi, with plans to develop and commercialize the product (see press release). CEO Daniel Chain founded the company for this purpose. Chain told Alzforum that he hopes to start a Phase 3 trial in ApoE4 carriers in 2014. Participants will either have amnestic MCI or be asymptomatic but with affected parents. Roughly half of AD patients have at least one copy of ApoE4.
Boosting Brain Insulin
Diabetes is a risk factor for Alzheimer’s (see AlzRisk analysis). In small trials, insulin administered through the nose has appeared to help people with MCI or early AD maintain cognition and daily function (see ARF related news story; ARF related news story). However, because of rapid metabolism in the CNS, this treatment results in a short spike of brain insulin. At AAIC, principal investigator Suzanne Craft, now at Wake Forest School of Medicine, Winston-Salem, North Carolina, discussed a Phase 2 trial of a long-acting insulin analogue called detemir. Marketed by the company Novo Nordisk, this compound lasts from 12 to 22 hours in the brain, resulting in a smaller jump in insulin and longer overall exposure. Detemir better mimics basal insulin levels in the brain, Craft noted (see Hennige et al., 2006; Tschritter et al., 2007). The trial was sponsored by the University of Washington and the National Institute on Aging.
Aptly named SNIFF-LONG 21 (Study of Nasal Insulin to Fight Forgetfulness—Long-acting Detemir—21 Days), the study enrolled 60 adults with early AD or amnestic MCI to receive placebo, 20 international units (IU), or 40 IU of detemir. 40 IU is less than 2 milligrams. After three weeks, treatment groups showed no improvement on a verbal memory composite test that served as primary outcome measure. Participants on the higher dose performed better in tests of visual retention and working memory, and a pre-planned subgroup analysis suggested that ApoE4 carriers taking 40 IU of detemir made strides in verbal memory, while non-carriers declined. The enhancement was robust and appeared in the majority of carriers, Craft claimed, although the numbers of ApoE4 carriers in this one subgroup were small. In addition, people whose insulin resistance at baseline was high, as assessed by the Homeostasis Model of Assessment–Insulin Resistance (HOMA-IR) test, scored better on memory tests after three weeks, while those with low baseline insulin resistance declined. The interactions with ApoE genotype and insulin resistance seem to be independent effects, Craft said.
Curiously, the opposite pattern had occurred in prior trials of regular insulin: ApoE4 non-carriers did better on verbal memory tests, while carriers did not (see Reger et al., 2006). The reason for this discrepancy is unclear. To compare the effects of insulin and detemir side by side, Craft is conducting the 4-month Phase 2 trial SNIFF-LONG 120 of 90 people with early AD or MCI. The primary outcome measure will be changes on the ADAS-Cog. Participants receive 40 IU of either insulin or detemir, or a saline placebo. The researchers will measure insulin and detemir levels in CSF to estimate drug exposure, which may provide clues for why only certain groups respond to the treatment, Craft said.
For Phase 1, preventative, and preclinical studies, see Part 2 of this series.—Madolyn Bowman Rogers.
- Gammagard™ Misses Endpoints in Phase 3 Trial
- Toronto: In Small Trial, IVIg Slows Brain Shrinkage
- Research Brief: Octapharma IVIg Iffy in Phase 2 Trial
- Quick-and-Early IVIG Therapy: Hints of Promise
- Zuers—Meeting Mixes Translational News and Debate
- Aβ and α7: Sordid Affair Begins With Healthy Partnership?
- Chicago: Nicotinic AChRs: α4β2 Iffy for AD, More Promise With α7?
- Experimental α7 Agonist Meets Cognitive and Clinical Endpoints
- Enter the New Alzheimer’s Gene: TREM2 Variant Triples Risk
- CTAD: ApoE Carriers Sought for Trial of NSAID Derivative
- ApoE Disrupts Brain Networks, Helps Microglia Clear Aβ
- Honolulu: Intranasal Insulin Trial Claims Promise in MCI, AD
- Paper Alert: Intranasal Insulin Data Fuels Push for Phase 2B Trial
- Hennige AM, Sartorius T, Tschritter O, Preissl H, Fritsche A, Ruth P, Häring HU. Tissue selectivity of insulin detemir action in vivo. Diabetologia. 2006 Jun;49(6):1274-82. PubMed.
- Tschritter O, Hennige AM, Preissl H, Porubska K, Schäfer SA, Lutzenberger W, Machicao F, Birbaumer N, Fritsche A, Häring HU. Cerebrocortical beta activity in overweight humans responds to insulin detemir. PLoS One. 2007;2(11):e1196. PubMed.
- Reger MA, Watson GS, Frey WH, Baker LD, Cholerton B, Keeling ML, Belongia DA, Fishel MA, Plymate SR, Schellenberg GD, Cherrier MM, Craft S. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging. 2006 Mar;27(3):451-8. PubMed.
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