Background

ALZT-OP1 is a combination regimen of two FDA-approved drugs, cromolyn (designated ALZT OP1a) and ibuprofen (designated ALZT OP1b). In the ALZT-OP1 regimen, cromolyn is delivered via an oral, dry-powder inhaler; ibuprofen is swallowed separately as an oral tablet. 

Ibuprofen is a nonsteroidal anti-inflammatory with an extensive history of preclinical and clinical evaluation in AD (see Ibuprofen). Widely used to treat asthma, cromolyn is a prescription drug. It is a mast-cell stabilizer that acts as an anti-inflammatory compound by suppressing cytokine release. 

One study conducted at Massachusetts General Hospital reported that cromolyn inhibits aggregation of Aβ monomers in vitro, and decreased soluble Aβ levels in the brains of APPswe/PS1ΔE9 mice after peripheral administration in vivo (Hori et al., 2015). In Tg2576 AD mice, three months’ dosing with cromolyn alone, or in combination with ibuprofen, prevented accumulation of insoluble brain Aβ42 and Aβ40. Cromolyn alone or with ibuprofen promoted microglia recruitment to plaques, and phagocytosis of β-amyloid deposits. Ibuprofen alone had no effect (Zhang et al., 2018).

Cromolyn acted synergistically with two other drugs, bromocriptine and topiramate, to diminish Aβ42 and Aβ40 production, and the Aβ42/20 ratio, in neurons derived from induced pluripotent stems cells from Alzheimer’s patients (Kondo et al., 2017).

For details on the proposed mechanism of action of this combination therapy, cromolyn delivery via the lungs, and preclinical treatment experiments, see patent WO 2014066318 A1. 

Findings

In June and July 2015, AZTherapeutics compared two dosing regimens of ALZT-OP1, each lasting two days, in a Phase 1 plasma/CSF pharmacokinetic crossover study conducted with 26 healthy volunteers at Panax Clinical Research in Florida.  The combination appeared safe, with mild to moderate adverse events reported in three subjects. Both drugs achieved CSF concentrations judged sufficient to reduce amyloid production and inflammation (Brazier et al., 2017).

In September 2015, the company started an 18-month Phase 3 study. It aimed to enroll 600 people with early AD as verified by subjective memory complaint, impairment on a logical memory test, abnormally low CSF Aβ levels, and a CDR of 0.5. The trial compares four groups: cromolyn active plus ibuprofen active, cromolyn active plus ibuprofen placebo, cromolyn placebo plus ibuprofen active, cromolyn placebo plus ibuprofen placebo. The primary outcome is change on the CDR-sum of boxes; secondary outcomes are treatment-emergent adverse events. The study listing contains no additional outcome measures such as psychometric tests or biomarkers. Conducted at 90 trial sites in North America, Australia, and Eastern European countries, this study aims for 100 completers per group and is set to run until December 2020. This trial completed enrollment of 620 participants in July 2019.

For all clinical trials on this combination therapy, see clinicaltrials.gov.

Clinical Trial Timeline