(+)-α-dihydrotetrabenazine (ADE 513) / Adeptio Pharma - LARVOL DELTA

Assessment of Dose Proportionality and the Effect of Food on a Once-Daily Extended-Release Tablet Formulation of Deutetrabenazine in Healthy Participants. (PubMed, Clin Drug Investig) - "The once-daily formulation of deutetrabenazine exhibited dosage strength proportional pharmacokinetics for doses up to 48 mg and there was no observed effect of food."

Journal • CNS Disorders • Huntington's Disease • Movement Disorders

SOM3355: a unique pharmacological profile combining VMAT1 inhibition, VMAT2-mediated dopamine modulation, and β1-adrenergic antagonism for the treatment of movement and neuropsychiatric disorders. (PubMed, Front Pharmacol) - "By combining synergistic β1-adrenergic antagonism, VMAT2-mediated dopamine modulation, and VMAT1 inhibition, SOM3355 may address monoamine neurotransmitter imbalances within basal ganglia and cortical circuits involved in motor and neuropsychiatric manifestations of HD. In summary, the translational profile of SOM3355, aligned with its clinical evaluation to date, supports its positioning as a potential novel therapeutic alternative for the treatment of HMDs and neuropsychiatric conditions like HD, tardive dyskinesia and Tourette Syndrome."

Journal • CNS Disorders • Huntington's Disease • Mental Retardation • Movement Disorders • Psychiatry • Tourette Syndrome

Pharmacokinetics and Bioequivalence of 2 Deutetrabenazine Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions. (PubMed, Clin Pharmacol Drug Dev) - "Both formulations were well tolerated, with only mild and transient adverse events and no serious safety findings. These results demonstrate that the test and reference deutetrabenazine tablets are bioequivalent in healthy Chinese adults under both nutritional states."

Clinical • Journal • PK/PD data • CNS Disorders • Huntington's Disease • Movement Disorders

Valbenazine Sprinkle: An Alternative Formulation of Valbenazine for Oral Administration in Patients With Dysphagia. (PubMed, Clin Transl Sci) - "Overall results from both cohorts for the 90% CIs of the geometric mean ratios indicated bioequivalence between the whole sprinkle capsule or granules sprinkled on applesauce and reference, with minor exceptions. These findings support that the VMAT2 inhibitor valbenazine can be used with multiple modes of oral administration."

Journal • Gastrointestinal Disorder • Huntington's Disease • Movement Disorders

Population Pharmacokinetic and Exposure-Efficacy Analyses of Valbenazine in Patients with Huntington's Disease: Supporting Dose Selection for Chorea Management. (PubMed, J Clin Pharmacol) - "Together, results from the population PK model and E-R analyses reinforce the evidence base for valbenazine efficacy in reducing chorea severity, as demonstrated by the notable decrease in TMC scores compared to baseline. They also endorse the selection of dosing regimens ranging from 40 to 80 mg QD for the treatment of chorea in patients with HD."

Journal • PK/PD data • Huntington's Disease • Movement Disorders

Nigrostriatal dopaminergic integrity in relation to prefrontal cortex activity and gait performance during dual-task walking in older adults. (PubMed, medRxiv) - "Results were similar in adjusted regression analyses; DTBZ binding in sensorimotor striatum was associated with lower likelihood to be in the PFC-/gait-(OR=0.28; 95% CI: 0.08, 0.94) or the PFC+/gait+ (OR=0.29; 95% CI: 0.10, 0.84) groups compared to PFC-/gait+ reference group. These results provide support for dopaminergic involvement in sustaining gait automaticity at older ages."

Journal

A Model-Informed Drug Development Approach Supporting the Approval of an Unstudied Valbenazine Dose for Patients With Tardive Dyskinesia. (PubMed, J Clin Pharmacol) - "Results from this analysis provided the key evidence to establish efficacy of 60 mg QD without the need for an additional clinical trial. The availability of valbenazine 60 mg dose fills an existing medical need for patients with TD who could benefit from this third effective dose."

Journal • Movement Disorders

A Bioequivalence Comparison Between the Once-Daily Extended-Release Tablet and the Twice-Daily Tablet Formulations of Deutetrabenazine at Steady State. (PubMed, Clin Pharmacol Drug Dev) - "Relative bioavailability was assessed for C of the active metabolites; the GMR was 78% for total (α+β)-HTBZ. At steady state, deutetrabenazine administered as the once-daily formulation was bioequivalent to the twice-daily formulation for both AUC and C and the active metabolites were bioequivalent with regard to AUC ."

Journal • Huntington's Disease • Movement Disorders

Relationship Between Interleukin-6 (IL-6) Blood Levels and Treatment Outcome in Patients With Treatment-Resistant Bipolar Disorder Depression (TRBDD) (ACNP 2022) - "Valbenazine is the valine ester of [+]-alpha-dihydrotetrabenazine ([+] α-HTBZ) and is extensively metabolized to its sole HTBZ metabolite, [+]-α-HTBZ, which is believed to be responsible for the majority of the pharmacologic activity of valbenazine. Valbenazine and deutetrabenazine have both been shown in well-controlled trials to be safe and effective for the treatment of TD; however, differences in their pharmacodynamic profiles may have important clinical implications. Deutetrabenazine is metabolized to 4 deuHTBZ stereoisomers, the most abundant of which ([-]-α-deuHTBZ) has negligible interaction with VMAT2 in vitro and appreciable affinity for several off-target receptors- these findings were similar to what has been reported for tetrabenazine. Based on relative potency and abundance, [+]-β-deuHTBZ appears to be the primary contributor to VMAT2 inhibition of deutetrabenazine."

Clinical • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry • IL6

Pharmacokinetic and Pharmacologic Characterization of the Dihydrotetrabenazine Isomers of Valbenazine and Deutetrabenazine (ACNP 2022) - "Valbenazine is the valine ester of [+]-alpha-dihydrotetrabenazine ([+] α-HTBZ) and is extensively metabolized to its sole HTBZ metabolite, [+]-α-HTBZ, which is believed to be responsible for the majority of the pharmacologic activity of valbenazine. Valbenazine and deutetrabenazine have both been shown in well-controlled trials to be safe and effective for the treatment of TD; however, differences in their pharmacodynamic profiles may have important clinical implications. Deutetrabenazine is metabolized to 4 deuHTBZ stereoisomers, the most abundant of which ([-]-α-deuHTBZ) has negligible interaction with VMAT2 in vitro and appreciable affinity for several off-target receptors- these findings were similar to what has been reported for tetrabenazine. Based on relative potency and abundance, [+]-β-deuHTBZ appears to be the primary contributor to VMAT2 inhibition of deutetrabenazine."

PK/PD data • CNS Disorders