Background

Originally developed by Transition Therapeutics, ELND005 was temporarily taken over by Elan Corporation, Speranza's parent company. In 2014, ELND005 reverted to Transition Therapeutics, which was acquired by Opko Health in 2016.

ELND005 is scyllo-inositol, an oral inositol stereoisomer that is thought to neutralize toxic, low-N Aβ oligomers and prevent them from aggregating. Scyllo-inositol has been reported to lead to dose-dependent decreases in amyloid pathology, insoluble Aβ40 and Aβ42, and subsequent plaque accumulation in TgCRND8 mice. The compound was also reported to rescue Aβ-induced toxicity to synaptic transmission in mouse hippocampi and to erase learning deficits in transgenic mice. The treatment appeared to work both when it was begun before symptoms appeared, and after the disease process was established. Beneficial effects via neuronal autophagy and preservation of choline acetyltransferase have also been proposed. Preclinical and some clinical data were published (e.g. Townsend et al., 2006; Fenilli et al., 2007; Ma et al., 2012).

Findings

In Phase 1, a first study in eight healthy volunteers and a second, ascending-dose study in 13 healthy volunteers, done in 2005 and 2006, indicated that the treatment was safe and well-tolerated. Subsequent studies raised further questions, however, and Phase 1 characterization of this compound's metabolism continued. In 2015, a renal clearance study concluded (company release). Some pharmacokinetic data were formally published (Liang et al., 2013).

A Phase 2 trial in 353 patients with mild to moderate Alzheimer’s disease tested doses of 500, 2,000, and 4,000 mg/day taken for 18 months. Primary endpoints were the Neuropsychological Test Battery (NTB) and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scores. In June 2009, a long-term extension began, enrolling 103 participants who had completed the study's randomized portion. Primary endpoints of the extension were safety, tolerability, and clinically important changes in laboratory assessments; this study completed in mid-2011. After an interim analysis, in December 2009 investigators dropped the 2,000 or 4,000 mg/day doses in both the randomized and the extension study due to a higher number of serious adverse events in patients on these doses. Besides an increased rate of infections, the adverse events included nine deaths, though they were never definitively linked to ELND005 (see Dec 2009 news). The trial continued with 500 mg/day. Falls, depression, and confusion were the most common side effects at this dose, and the data safety monitoring committee deemed its tolerability to be acceptable. This Phase 2 study was negative on its primary endpoints of cognitive or functional improvement. At 500 mg/day, ELND005 did appear to reduce Aβ levels in a CSF substudy (see Salloway et al., 2011).

Pre-specified subgroup analysis indicated that some patients on the low dose had improved on some neuropsychiatric measures, and Elan decided to continue to explore those. A new mechanism of action was proposed whereby ELND005, i.e. scylloinositol, lowers brain levels of its endogenous isoform myoinositol, and exerts effects similar to lithium in the treatment of bipolar disorder (see Jun 2012 conference news).

In November 2012, Elan started a Phase 2 trial, evaluating a single dose of ELND005 in 350 people with moderate to advanced Alzheimer's for its effect on the agitation and aggression subscores in the Neuropsychiatric Inventory-Clinician rating scale (NPI-C). Called HARMONY, this was a 12-week trial with an 18-week safety extension, which enrolled 296 participants. The FDA fast-tracked ELND005 for this indication in July 2013.

In 2012, Elan started a Phase 2 study of AZD-103 as an add-on therapy in 400 patients with bipolar disorder; this program was discontinued in 2014.

In 2013, a four-week Phase 2 trial began evaluating 250 and 500 mg daily of AZD-103 in 23 young adults with Down’s syndrome. This trial was completed in November 2014, and reported at the CTAD conference to have had an acceptable safety profile and exposure levels at the 500 mg dose that support further development (see Dec 2014 conference news). For all trials of this drug, see clinicaltrials.gov.

In June 2015, Transition Therapeutics announced that the HARMONY trial had missed its primary efficacy endpoint, noting a greater-than-expected decline in agitation in the placebo group on the NPI-C scale used in this trial. In July, the company terminated the long-term extension of this study (see company release). In October 2015, the company announced that, based on posthoc analysis, the trial results numerically favored the most severely symptomatic treatment group on 20 of 21 symptoms that comprise the primary outcome measurement (see company press release).

For all trials with this drug, see clinicaltrials.gov.

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