Synonyms: BACE inhibitor
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2/3)
Company: Janssen, Shionogi Pharma
This is a tablet drug affecting amyloid precursor protein (APP) and its processing products. It inhibits APP cleavage by the enzyme BACE, the rate-limiting step in Aβ generation. The rationale of BACE inhibition is that it represents an upstream interference with the amyloid cascade. BACE inhibition is sometimes envisioned as long-term maintenance therapy to limit Aβ production after an initial round of immunotherapy to remove existing amyloid deposits.
In 2012, Janssen licensed this compound from Shionogi, which had conducted its preclinical development.
In March 2013, Janssen began a series of Phase 1 trials of JNJ-54861911. A first single-ascending-dose study in 56 healthy volunteers was followed by a second in 70 healthy elderly volunteers. Both assessed safety parameters as well as pharmacological measures relating to drug exposure and concentrations of Aβ fragments in CSF and plasma. Conducted in Belgium, both studies are completed, as is a similar study in 24 healthy volunteers in Japan. In October 2014, three additional studies in 46 healthy volunteers were either ongoing or in preparation. They are evaluating the effect on the concentration, metabolism, and excretion of JNJ-54861911 and of various other drugs commonly used by the elderly, including coffee, anxiolytic, or diabetes drugs. One trial in 64 people is assessing whether JNJ-54861911 affects heart function.
In December 2013, the first trial in prodromal Alzheimer's disease began, enrolling 48 people in Belgium, the Netherlands, Spain, and Sweden. Study participants must be cognitively impaired as measured by the CANTAB Elect test battery, and have evidence of amyloid deposition either as per a pathological Aβ/tau CSF assay result or per flutemetamol amyloid PET scan. Participants will take either 10 or 50 mg of JNJ-54861911 or placebo once daily for four weeks. They will be assessed on a range of biomarker outcomes related to drug exposure, metabolism, and target engagement, i.e., the concentration of various APP and Aβ fragments in CSF and plasma.
In December 2014, Phase 2 began with a multinational trial in Europe. It compares a six-month, once-daily course of 10 or 50 mg of JNJ-54861911 to placebo in 100 people with a CDR rating of 0 to 0.5, plus evidence of amyloid pathology supplied either by CSF or PET—i.e., people who have asymptomatic to predementia Alzheimer's disease. This study will assess safety, exposure, target engagement, and a downstream effect in the form of CSF tau concentration. The trial lists no clinical/cognitive outcomes.
By March 2015, Janssen listed another Phase 1 trial in Japan to compare a one-month course of 10 or 50 mg to placebo in 18 people who are clinically normal as measured by a CDR of 0, yet have evidence of brain amyloid deposition as evidenced by low CSF Aβ42 levels. Called "asymptomatic at risk of AD," this population represents an earlier stage of AD pathophysiology than predementia or prodromal AD, as people with a measurable impairment would be excluded. This trial measures markers of drug exposure and target engagement. In July 2015, a double-blind safety extension study of up to two years was added for up to 100 patients who have completed prior Phase 1 or 2 trials.
In March 2015, Janssen reported results of a single-ascending- and a multiple-ascending-dose study in healthy elderly participants at the AD/PD conference in Nice, France. According to this presentation, the inhibitor was safe and well-tolerated in 94 people studied thus far. It reportedly entered the blood and CSF with favorable pharmacokinetics and pharmacodynamics, and dose-dependently reduced Aβ1-37, Aβ1-38, Aβ1-40, and Aβ1-42. Reduction of the BACE cleavage product sAPPβ tracked reduction of Aβ, whereas levels of sAPPα rose (see Mar 2015 news). A 5 mg dose was reported to reduce CSF Aβ concentration by half; 25 mg by 80 percent, 50 mg by 90 percent.
In July 2015, a long-term safety and tolerability study began enrolling 100 patients from previous Phase 1 and 2 trials who were willing to continue their randomized, blinded treatment for another year.
In October 2015, EARLY, a Phase 2/3 study, began in asymptomatic people at risk of developing Alzheimer's dementia. This risk is determined by a CDR score of 0 combined with CSF or PET evidence of brain amyloid accumulation. The trial enrolls people aged 60 to 85. To limit screen failures, 60- to 64-year old candidates must have either a family history of dementia, previously known ApoE4 genotype, or previously known biomarker evidence of amyloid deposition. The primary endpoint is slowing of cognitive decline, as measured by change on the Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC) between baseline and 54 months of treatment with either 10 or 25 mg of drug, or placebo. Secondary outcomes include 10 different functional, clinical, neuropsychological, exposure, and biomarker measures. This trial will enroll 1,650 participants at 121 locations in Europe, Australia, Japan, North America, and Mexico. It will run until the year 2023. For more detail on the EARLY trial, and a brief Phase 1 data summary, see Aug 2016 conference news.
In January 2016, Janssen added a Phase 1 study in 32 healthy adults in Germany to evaluate drug interactions between JNJ-54861911, the antidiabetic metformin, and rosuvastatin.
See all trials at clinicaltrials.gov.
Clinical Trial Timeline
- At AD/PD Meeting, New BACE Inhibitor Struts Its Stuff
- New Ways to Target Aβ and BACE Show Promising Phase 1 Data
- Kennedy ME, Stamford AW, Chen X, Cox K, Cumming JN, Dockendorf MF, Egan M, Ereshefsky L, Hodgson RA, Hyde LA, Jhee S, Kleijn HJ, Kuvelkar R, Li W, Mattson BA, Mei H, Palcza J, Scott JD, Tanen M, Troyer MD, Tseng JL, Stone JA, Parker EM, Forman MS. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients. Sci Transl Med. 2016 Nov 2;8(363):363ra150. PubMed.