SAN DIEGO—Last year came to an end on a rather disappointing note for Neurocrine Biosciences Inc., which announced that valbenazine, its selective vesicular monoamine transporter 2 (VMAT2) inhibitor, fell short of the primary endpoint in its Phase 2b T-Force GOLD study. The study was evaluating the safety, tolerability and efficacy of valbenazine as a treatment for moderate to severe Tourette syndrome in children and adolescents, and the primary endpoint was the change from baseline of the Yale Global Tic Severity Scale (YGTSS) at week 12.
Tourette syndrome typically has an onset in early childhood, and tends to affect boys more commonly than girls. According to the Genetics Home Reference of the U.S. National Institutes of Health, somewhere between one and 10 of every 1,000 children are likely affected by this neurological condition. Tourette syndrome is characterized by rapid, non-rhythmic stereotyped motor and vocal tics such as grimacing, extremity movement, throat-clearing and the repetition of words or phrases. The YGTSS rates the overall severity of motor or vocal tic symptoms based on number, frequency, intensity, complexity and interference.
Valbenazine, also known as Ingrezza, is approved by the U.S. Food and Drug Administration for the treatment of adults with tardive dyskinesia, which is characterized by uncontrollable, abnormal and repetitive movements of the face, torso or other parts of the body. As noted on Neurocrine’s website, the drug is thought to cause “reversible reduction of dopamine release at the nerve terminal by selectively inhibiting the pre-synaptic human vesicular monoamine transporter type 2 (VMAT2),” thereby helping to regulate nerve signaling in tardive dyskinesia patients. The VMAT2 protein packages neurotransmitters such as dopamine for release in presynaptic neurons. Ingrezza works to selectively inhibit VMAT2 without binding to VMAT1 or other dopaminergic (including D2), serotonergic, adrenergic, histaminergic or muscarinic receptors.
“There is a significant need for new medicines in Tourette syndrome, as current treatment options are limited for the approximately 400,000 people living with this condition in the United States. Tourette syndrome is a disruptive and often socially isolating condition, primarily affecting children and adolescents, that is characterized by involuntary motor and vocal tics … We plan to complete a full analysis of the T-Force GOLD study in order to better understand the activity of valbenazine in pediatric patients with Tourette syndrome, after which we will determine next steps for the program,” says Dr. Eiry W. Roberts, chief medical officer at Neurocrine.
Investor outlook on the future of valbenazine in Tourette syndrome seems to be bleak in the wake of this news. Leerink Partners removed its sales forecasts for Ingrezza in Tourette syndrome (TS), remarking that “While we recognize the last TS trial (T-Force PLATINUM) is still ongoing, we think at this point there is a high degree of skepticism for the TS indication and low chance of the trial being positive now that three trials have failed so far.
“Given the two prior Phase 2 failures in TS in adult (T-Forward) and pediatric/adolescent (T-Force GREEN) patients, this news is a disappointment to investors, and we’ve seen a ~14-percent drop in the stock at close. It is possible some drew confidence from the previous subgroup analysis in T-Force GREEN, showing substantial tic reduction in children with correct dose exposures, but we have not had any subgroup analyses from this current top-line readout of T-Force GOLD. Overall, we believe the missed endpoint (which encompasses all dose groups) is clear evidence of the minimal efficacy of Ingrezza in TS, as management also noted that the placebo responses were as expected and there was no imbalance in the baseline.”
Neurocrine isn’t counting valbenazine out in terms of potential utility in other indications beyond tardive dyskinesia, however. While Roberts declined to detail any specific indications, she tells DDNews that Neurocrine is “very interested in evaluating the potential of VMAT2 inhibitors in other movement disorders and other CNS conditions.”
The company is still continuing apace with its efforts in other areas as well, according to Roberts, who notes that “We anticipate a number of significant clinical and regulatory milestones in 2019, including NDA submissions for opicapone (in-licensed from Bial) for the treatment of Parkinson’s disease and elagolix (out-licensed to AbbVie) for the treatment of uterine fibroids. In addition, we expect to report data from a Phase 2a study in Q1 2019 of an investigational therapy for the potential treatment of congenital adrenal hyperplasia. This genetic disorder results in the deficiency of a key enzyme involved in the production of adrenal steroids. Because of this deficiency, the adrenal glands have little to no cortisol biosynthesis, which results in significant life-long morbidity. Lastly, we continue to focus on internal research efforts, and anticipate moving one additional compound into the clinic in 2019.”