The Movement Disorder Society

MDS 18th International Congress of Parkinson's Disease and Movement Disorders, Volume 29,
June 2014 Abstract Supplement

Movement Disorders 2014
Stockholm, Sweden June 8-12, 2014.


Safety, tolerability, and pharmacodynamics of AZD3241, a myeloperoxidase inhibitor, in Parkinson's disease

Posener,  J.A., Hauser,  R.A., Stieber,  M., Leventer,  S.M., Eketjäll,  S., Minkwitz,  M.C., Ingersoll,  E.W., Kugler,  A.R.

Cambridge, MA, USA

Objective:

To evaluate the safety, tolerability, and pharmacodynamics of AZD3241, a myeloperoxidase (MPO) inhibitor, in patients with Parkinson's disease (PD).

Background:

MPO is a key inflammatory enzyme, and is implicated in the pathophysiology of PD and other neurodegenerative disorders. AZD3241 is a potent and selective MPO inhibitor that has efficacy in preclinical pharmacology models of PD and multiple system atrophy. In Phase 1 studies, AZD3241 has been found to be safe and well tolerated in healthy human subjects. A study using PET methodology demonstrated an effect on microglia activation in brain among PD patients.

Methods:

Fifty-one patients with PD diagnosed according to UKPDS Brain Bank criteria were randomly assigned (1:1:1) to double-blind oral administration of AZD3241 300 mg BID, AZD3241 600 mg BID, or placebo for 12 weeks. Adverse events, vital signs, clinical laboratory tests, electrocardiograms (ECGs), and plasma MPO concentrations were monitored over the course of treatment.

Results:

There were no deaths or serious adverse events in subjects who received AZD3241. While discontinuations due to adverse events (AEs) were comparable with AZD3241 300 mg BID and placebo, 6 out of 16 patients randomized to AZD3241 600 mg BID discontinued due to AEs. AEs that occurred more frequently with AZD3241 than placebo included headache, nausea, vomiting, and muscle spasms, which were mild or moderate in severity. Mean thyroid stimulating hormone (TSH) levels increased with AZD3241 relative to placebo and then decreased following discontinuation of AZD3241. Most subjects did not have TSH levels above normal, and the elevations that occurred were mild. Mean uric acid levels decreased with AZD3241 relative to placebo, then returned toward placebo levels following discontinuation of study treatment. No individual subject had an abnormal uric acid level that developed over the course of study treatment. There were no other clinically relevant findings involving laboratory tests, vital signs, or ECGs. Mean plasma MPO specific activity decreased with AZD3241 600 mg BID relative to placebo.

Conclusions:

AZD3241 300 mg BID is safe and well tolerated in PD; the 600 mg BID dose is safe, and is well tolerated in most but not all PD patients. AZD3241 administration produces a decrease in plasma MPO specific activity.

To cite this abstract, please use the following information:
Posener, J.A., Hauser, R.A., Stieber, M., Leventer, S.M., Eketjäll, S., Minkwitz, M.C., Ingersoll, E.W., Kugler, A.R.; Safety, tolerability, and pharmacodynamics of AZD3241, a myeloperoxidase inhibitor, in Parkinson's disease [abstract]. Movement Disorders 2014;29 Suppl 1 :698