Objective:In prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer, enabled dystrophin production in Duchenne muscular dystrophy (DMD) with genetic mutations amenable to skipping exon 51. The present study used a double-blind placebo-controlled protocol to test eteplirsen's ability to induce dystrophin production and improve distance walked on the 6-minute walk test (6MWT). Methods: DMD boys aged 7 to 13 years, with confirmed deletions correctable by skipping exon 51 and ability to walk 200 to 400 m on 6 MWT, were randomized to weekly intravenous infusions of 30 or 50 mg/kg/wk eteplirsen or placebo for 24 weeks (n 5 4/group). Placebo patients switched to 30 or 50 mg/kg eteplirsen (n 5 2/group) at week 25; treatment was open label thereafter. All patients had muscle biopsies at baseline and week 48. Efficacy included dystrophin-positive fibers and distance walked on the 6MWT. Results: At week 24, the 30 mg/kg eteplirsen patients were biopsied, and percentage of dystrophin-positive fibers was increased to 23% of normal; no increases were detected in placebo-treated patients (p 0.002). Even greater increases occurred at week 48 (52% and 43% in the 30 and 50 mg/kg cohorts, respectively), suggesting that dystrophin increases with longer treatment. Restoration of functional dystrophin was confirmed by detection of sarcoglycans and neuronal nitric oxide synthase at the sarcolemma. Ambulation-evaluable eteplirsen-treated patients experienced a 67.3 m benefit compared to placebo/delayed patients (p 0.001). Interpretation: Eteplirsen restored dystrophin in the 30 and 50 mg/kg/wk cohorts, and in subsequently treated, placebo-controlled subjects. Duration, more than dose, accounted for dystrophin production, also resulting in ambulation stability. No severe adverse events were encountered.

IC351 (Cialis TM ) is a selective inhibitor of PDE5. The ef®cacy and safety of on-demand dosing of IC351 in men with erectile dysfunction was assessed in a multicenter, double-blind, placebocontrolled study. One hundred seventy-nine men (mean age: 56 y) were randomized to receive placebo or IC351 at doses of 2, 5, 10 or 25 mg, taken on demand over a 3-week period. The primary endpoints were change from baseline in responses to Questions 3 (Q3) and 4 (Q4) of the International Index of Erectile Function (IIEF). IC351 signi®cantly improved IIEF Q3 scores at all doses vs placebo (P 0.003). IC351 also signi®cantly improved IIEF Q4 scores in all but the 2 mg group (P 0.0003). No signi®cant changes in laboratory values, ECGs, or blood pressure were observed. The most common adverse events were headache and dyspepsia. The conclusion of this study was that on-demand IC351 at doses up to 25 mg was well tolerated and signi®cantly improved erectile function.

MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients.

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