Tamoxifen in Duchenne muscular dystrophy: A multicentre, randomised, double-blind, placebo controlled phase 2 safety & efficacy trial

Dirk Fischer, University of Basel Children's Hospital

30th April 2017

The applicants plan to perform a placebo-controlled trial with Tamoxifen (TAM) in 80 ambulant and 20 non-ambulant boys with Duchenne muscular dystrophy. The primary outcome in the ambulant group will be the change of MFM D1 sub-score from baseline to week 48, and in the non-ambulant group the change of MFM D2 sub-score. Further outcome measures will include MFM total score, NSAA, timed function tests, QMT, quantitative muscle MRI, laboratory measures of disease activity, quality of life-scores and clinical and paraclinical parameters of side-effects.

The proposal is based on preclinical experiences with oral application of TAM mdx5Cv mice showing increased force production and resistance to repeated contractions of the triceps muscle, improved structure of leg muscles and diminished fibrosis of heart and diaphragm. Investigations in an independent lab in mdx mice treated with TAM, PRED, TAM+PRED, mdx controls and wild type controls showed better strength on grid grip test, improved force-frequency relationship in tetanic muscle stimulation, and reduced diaphragm fibrosis and macrophage infiltration especially in the TAM+PRED group.

TAM has been used since many years in adult females with breast cancer and adults with other malignancies. Furthermore, its use has been reported in a large number of pubertal boys with gynecomastia without major side-effects. Based on these data the drug seems to be ready for a clinical trial in DMD, although its exact mode of action on dystrophic muscle is not clearly understood and some concerns about possible oncogenic side-effects in eventual life-long use have been raised.

TACT welcomed this clinical initiative and discussed with the applicant questions of optimal dosage, study design, variability of the primary outcome measures, feasibility of such a high number of clinical investigations and the usefulness of only a small number of non-ambulant patients. Given the fact that TAM is marketed by several companies the committee recommended to search early contacts to regulatory experts to discuss ways into the market for this new indication.

To request a full copy of the report please contact the applicant Dirk Fischer

17 Oct 2017