During my residency many years ago I rotated through a locked psychiatric ward, a place depicted in many movies and television shows but entirely new to me at the time. This was my first real glimpse at the people who were severely affected by thought disorders such as schizophrenia. The treatment options included antipsychotic or major tranquilizers like Thorazine and Haldol, both of which are in the dopamine antagonist D2 class of drugs. They helped control the symptoms of schizophrenia but at a high cost to the patient. This family of drugs was notorious for causing people to develop strange, involuntary movements of their tongue, face, lips, and jaw as well as what are called choreoathetoid movements of the extremities and trunk.
Those movements are collectively called tardive dyskinesia, a subgroup of dyskinesia movements typically occurring in people treated with long-term antipsychotic drugs. Tardive dyskinesia is associated with the “typical” antipsychotics like Thorazine and Haldol, but there are a number of other medications that also cause the troubling condition, including the more recently approved “atypical” antipsychotic medications, such as Clozaril, Seroquel, and Zyprexa, as well as drugs in entirely different classes such as Reglan, a drug used for GI motility disorders. Between 20% and 50% of the people who take antipsychotics on a long-term basis develop tardive dyskinesia, and the condition may persist after people stop taking the medication. Tardive dyskinesia affects people’s quality of life but it goes beyond that. The involuntary movements can interfere with speech, walking, and swallowing. Some people have a hard time breathing because of it. In severe cases, people can develop joint inflammation and lip or tongue lacerations.
The standard of care for tardive dyskinesia is to reduce the dose of the antipsychotic drug or switch to one of the atypical antipsychotics that are somewhat less likely to cause tardive dyskinesia.
Physicians have treated tardive dyskinesia in a variety of off-label ways, ranging from benzodiazepines to botulinum toxin injections (Botox) to vesicular monoamine transporter 2 (VMAT2) inhibitors such as tetrabenazine. The FDA approved tetrabenazine in 2008 as a treatment for the jerky, involuntary movements associated with Huntington’s disease—called chorea—but not for tardive dyskinesia.
But now two new treatments for tardive dyskinesia are available. Valbenazine, developed by Neurocine Biosciences, was approved in April 2017 and is being marketed under the name Ingrezza. Deutetrabenazine, brought to market by Teva, was approved a few months later and is being sold under the name Austedo. Like tetrabenazine, they are in the VMAT2 family. The mechanism of action is unclear, but it’s thought to be mediated through the reversible inhibition of VMAT2, which regulates monoamine uptake from the cytoplasm to the synaptic vesicle.
There’s a great deal of published information available on the new tardive dyskinesia drugs. In addition to the usual trove of FDA documents, the Institute for Clinical and Economic Review (ICER) in Boston published a 165-page evidence report in November. Many of the details that follow are taken from the ICER report, which is based on FDA documents.
Ingrezza’s approval was supported by several studies, but the main Phase 3 trial included 234 patients. The main Phase 3 trial of Austedo included 293 subjects. The Abnormal Involuntary Movement Scale (AIMS), a scale commonly used to evaluate the presence and severity of tardive dyskinesia, was used as the primary endpoints in these studies. The complete AIMS contains 12 items, but the Ingrezza and Austedo trials used a subset of seven items that are termed the “dyskinesia portion” of the AIMS.
In the Ingrezza trial, the primary efficacy endpoint was the mean change from baseline in the AIMS dyskinesia score at the end of Week 6. People in the Ingrezza study were given either a 40- or 80-mg dose of the drug or placebo. After the initial six-week double-blind period, subjects could be re-consented to enter the 42-week extension period where those originally randomized to receive Ingrezza continued at their then current dose and those who initially received placebo were randomized to receive either 40 mg or 80 mg of Ingrezza. The two Austedo trials tested 24- and 36-mg doses of the drug against a placebo over a 12-week period.
The results for the primary endpoint were statistically significant, but as is true with all clinical trials, the proof is in the detail.
The AIMS difference in those treated with 40 mg of Ingrezza was –1.9 points (baseline 9.7); with 80 mg, –3.2 (baseline 10.4); and with placebo, –0.1 (baseline 9.9). This gave a placebo subtracted difference of –1.8 to –3.1 in the two different dosing schedules.
The AIMS difference in those treated with 24 mg of Austedo was –3.2 (baseline 9.4); with 36 mg, –3.3 (baseline 10.1); and with placebo, –1.4 (baseline 9.5). That makes for a placebo subtracted difference of –1.8 for the 24-mg dose and –1.9 for the 36-mg one.
In the Phase 3 Ingrezza study, only 121 (61%) of patients completed the entire 48-week study.
The Ingrezza and Austedo studies also included a measurement called patient global impression of change (PGIC). Unlike AIMS and other tardive dyskinesia measures, PGIC is based on patient self-reporting, not outside raters of symptoms. According to the ICER report, unpublished PGIC data on the Phase 3 Ingrezza trial that were part of a FDA review document show that, on average, the Ingrezza groups (40 mg and 80 mg) and placebo did not differ in their tardive dyskinesia symptom improvement, although a Phase 2 did show an improvement. The ICER report says that PGIC data from the Austedo trial favor the drug but the difference compared with placebo was not statistically significant.
Tardive dyskinesia is without question a disturbing and disabling condition. ICER, which was scheduled to make its policy recommendation in late December after we went to press, notes that the antipsychotics are often used off-label for illnesses ranging from obsessive-compulsive disorder to insomnia. Hundreds of thousands of people might benefit from drugs that ameliorate tardive dyskinesia. And Ingrezza and Austedo did show a large enough effect on the condition using relatively objective measures to warrant FDA approval.
But let’s consider the prices. ICER pegged the wholesale acquisition cost (WAC) of a daily 80-mg dose of Ingrezza at $75,789 and the WAC for a daily 36-mg dose of Austedo at $90,071.
ICER went on to compute the cost per quality-adjusted life year (QALYs). QALYs often stir up a hornets’ nest of controversy because of all the judgments about what goes into the quality of life. The evidence base may be thin or uneven. In the case of tardive dyskinesia, there isn’t a huge amount of research to go on, and the condition may, in fact, cause more harm and distress than the current research shows. Still, QALYs are a way to organize the thinking about the price and benefits of medical intervention. ICER calculated that at the current WAC, Ingrezza would cost $752,080 per one QALY gained and Austedo, $1,100,773. Cost-effectiveness research suggests that $150,000 is a reasonable price for a QALY. To hit that threshold, Ingrezza’s annual cost would need to be $11,260, according to ICER, and Austedo’s, $9,158.
Even without all this elaborate ICER number crunching just consider the fact that these drugs reduced AIMS score modestly from roughly 10 to 7 at their higher doses and that the patient self-reported improvement was unimpressive.
I am sympathetic to people who suffer from tardive dyskinesia. But the price of Ingrezza and Austedo make me wonder the high prices charged by the pharmaceutical industry are at all sustainable.