Nils Bundgaard (1), Ana de Vera (2), Catherine Dutreix (2), Daniel Kaschek (1)
(1) IntiQuan AG, Basel, Switzerland; (2) Santhera AG, Pratteln, Switzerland
Objectives:
Vamorolone (Agamree) is a synthetic steroidal drug approved for the treatment of Duchenne Muscular Dystrophy (DMD), a life-threatening genetic disease occurring in around 1:3600-6000 children. Most patients exhibit a physical deterioration starting around five years of age and are unable to walk by the age of twelve. Vamorolone was studied in five clinical studies assessing a dose range between 0.1-20 mg/kg/day and investigating the impact of selected covariates, including formulation, prandial state, and hepatic impairment. The effect of vamorolone on disease progression was assessed in patients between four to seven years of age considering doses between 0.25-6 mg/kg/day. The three main efficacy endpoints considered to assess disease progression were NSAA total score (17-item test) [1], six-minute walking distance, and time to stand velocity. In this work, the dose-exposure-efficacy relationship was assessed to support the selection of the optimal clinical dose, in the light of the generally high variability in disease progression and constrained by safety marker response.
Methods:
The dose-concentration relationship of vamorolone was previously described by a one compartmental distribution model with sequential 0-order and 1st-order absorption and linear elimination clearance [2]. The model was updated with data from n=117 patients (pediatrics) and n=126 healthy volunteers (adults) to assess the influence of additional covariates including formulation and prandial state, and support extrapolation to younger age groups. The overlaying effects of disease progression and treatment on efficacy endpoints complicated the assessment of impact of long-term (>6 months) treatment in DMD patients. Informed by functional efficacy data over 48 weeks in n=152 patients (4-7 years of age) treated with vamorolone or placebo, exposure-response modeling using a sigmoid Emax model was conducted to investigate the treatment effect of vamorolone compared to placebo. Here, disease progression and the influence of baseline characteristics on efficacy including age, previous treatment, and disease severity were considered. Finally, the selected model was used to simulate different age-brackets of interest over a dose range of 2-6 mg/kg/day to identify an efficacious dose.
Results:
Vamorolone exhibited dose-proportional PK and no accumulation after two weeks of treatment at the tested dose range. The population PK model of vamorolone was updated to include body weight based allometric scaling on absorption and clearance and covariate effects of race, hepatic function, prandial state, and formulation. Interestingly, flip-flop kinetics were identified, where the elimination of vamorolone was limited by the absorption rate rather than the elimination rate [3]. Clinically, DMD patients are defined by onset of symptoms by the age of 5 years and, historically, loss of ambulation before 12 years of age. Disease progression over 48 weeks as characterized by the change from baseline in NSAA total score, six-minute walking distance, and time to stand velocity, was described by time-dependent processes following an approximately parabolic progression. The treatment effect on the different endpoints over time was characterized via sigmoidal exposure-response models including placebo response. Treatment was found to impact the speed of disease progression and age at which the functional endpoints reached their maximum. The predicted placebo-corrected efficacy showed that a similar one-year treatment effect of about 5 points was to be expected for vamorolone doses of 2, 4, and 6 mg/kg/day when considering NSAA. Also, the six-minute walk test and time to stand velocity showed a distinguished effect from placebo, indicating, however, an increase in efficacy with increasing doses between 2 and 6 mg/kg/day.
Conclusions:
Disease progression was found to be highly individual and the determining factor in the expected treatment effect. After accounting for disease progression, treatment with vamorolone at doses of 2-6 mg/kg/day indicated a marked effect on efficacy endpoints compared to placebo across all age groups (4, 5, 6-7 years). Overall, the analysis supported treatment with an initial dose of 6 mg/kg/day and potential down titration to 4 or 2 mg/kg/day, based on safety markers.
References:
[1] Scott E, Eagle M, Mayhew A, Freeman J, Main M, Sheehan J, Manzur A, Muntoni F, North Star Clinical Network for Paediatric Neuromuscular Disease. Development of a functional assessment scale for ambulatory boys with Duchenne muscular dystrophy. Physiotherapy Research International. 2012 Jun;17(2):101-9.
[2] Mavroudis P, van den Anker J and Conklin Lea, 2019, Population pharmacokinetics of vamorolone (VBP15) in healthy men and boys with Duchenne muscular dystrophy. J Clin Pharmacol vol. 59: 979– 988.
[3] Yáñez J.A., Remsberg C.M., Sayre C.L., Forrest M.L., Davies N.M., Flip-flop pharmacokinetics – delivering a reversal of disposition: challenges and opportunities during drug development, Therapeutic Deliveries, 2011.
Reference: PAGE 32 (2024) Abstr 10938 [www.page-meeting.org/?abstract=10938]
Poster: Drug/Disease Modelling - Paediatrics