HOLLYWOOD, FLA. – Arbaclofen, intranasal oxytocin, and D-cycloserine for the treatment of core deficits in autism spectrum disorders are all moving forward to more advanced clinical trials on the basis of encouraging studies highlighted at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Arbaclofen, also known as R-baclofen and STX209, is an oral selective GABA-B agonist to be studied in a large phase III trial on the strength of encouraging improvements in social function seen in a 150-patient phase II study. Intranasal oxytocin showed improvements in selected aspects of social functioning as well as in irritability in a 25-patient feasibility study that cleared the way for the ongoing 300-patient SOARS-B study, sponsored by the National Institutes of Health.

D-cycloserine is earlier in development. The first placebo-controlled study is now being planned based upon favorable results on measures of social communication in an uncontrolled 20-patient pilot study.

This all comes as most welcome news. At present, the sole drugs approved for treatment of autism spectrum disorders (ASD) are risperidone (Risperdal) and aripiprazole (Abilify). They merely target the irritability associated with ASD rather than the core clinical features involving social deficits and repetitive behaviors. Meanwhile, the ASD caseload has been growing relentlessly for years. Indeed, the latest Centers for Disease Control and Prevention estimate of the ASD prevalence is 1 in 88 among U.S. children born in 2000 (MMWR 2012;61:1-19).

Arbaclofen

Dr. Paul P. Wang presented findings from a 12-week, double-blind, phase II study involving 150 subjects aged 5-21 years with autism disorder or Asperger’s disorder who were randomized to arbaclofen titrated to a maximum dose of 30 mg/day or placebo. The primary endpoint was improvement on the Aberrant Behavior Checklist–Lethargy/Social Withdrawal subscale. Such improvement was seen in the arbaclofen group, but also to a similar extent in the placebo arm. Dr. Wang was philosophical about the negative result.

"We are very early, obviously, in drug development for ASD. There is no Hamilton Autism Scale, no PANSS Autism Scale. It’s not entirely clear what scales are best psychometrically as well as being clinically valid. This is going to be a large challenge in all of the trials you’re likely to hear about in the next couple of years," predicted Dr. Wang, a behavioral pediatrician who is vice president for clinical development at Seaside Therapeutics Inc., Cambridge, Mass.

Discussant Dr. James McCracken concurred and added some advice for Dr. Wang and others searching for new ASD therapies.

"The real challenge in this area is our traditional overreliance on parent-reported observations of child behavior. It just sets us up for placebo effects that will kill any drug signal to be found. You have to work really hard to develop other measurement strategies that don’t depend so centrally on parent and caregiver report," said Dr. McCracken, professor of child psychiatry, and director of the division of child and adolescent psychiatry at the University of California, Los Angeles.

"You may be wondering, why are these people even working in this area? ASD is complicated, and the measurements are kind of lame. The secret is there are some great targets in ASD. This is a field ripe for treatment discovery," he said.

Dr. Wang said that fortunately, a post hoc analysis of a key secondary endpoint – the Vineland Adaptive Behavior Scales socialization score – showed an impressive improvement in response to arbaclofen among the 96 patients whose serial Vineland assessments were conducted by the same trained clinician and caregiver, in accord with the study protocol. Indeed, the arbaclofen group showed a mean 7.2-point gain, significantly better than the 1.8-point improvement with placebo.

Moreover, in the roughly half of study participants with an IQ of 70 or more, this effect was even more pronounced: an average gain of more than 9-points over the course of the study. To put this benefit in perspective, the mean score on the Vineland socialization measure in the general population is 100, and 1 standard deviation is 15 points.

"From a regulatory perspective and the narrow viewpoint of regulatory approval, this is a negative study. But I believe that from a scientific point of view, this is an extremely interesting study, and clinically potentially very important. We found what we believe to be a signal in the social-communicative domain that is the core impairment in autism," said Dr. Wang.

An efficacy signal also was noted in irritability and sensory symptoms, he added.

Eight patients in the arbaclofen group and two on placebo dropped out of the study because of adverse events, mostly behavioral. The only serious adverse event in the arbaclofen group involved one patient who developed suicidal thoughts on the drug, which disappeared promptly upon drug discontinuation; however, the same thing happened to one patient in the control group.

Arbaclofen is the active isomer of racemic baclofen, which was approved by the Food and Drug Administration in 1977 for treating spasticity in multiple sclerosis patients aged 12 and up. Baclofen also is widely used in the treatment of spasticity in cerebral palsy patients, many of whom are much younger than age 12. Its safety is well established. Baclofen is a strongly sedating drug; roughly one-third of cerebral palsy patients have to discontinue it for that reason. Yet only 8% of arbaclofen-treated patients in the phase II study reported any sedation.

Intranasal oxytocin

Oxytocin levels have been shown to be decreased in children with ASD; oxytocin-related genes are associated with increased risk for ASD; and patients with ASD have increased methylation of the oxytocin receptor. Therein lies the therapeutic rationale for exogenous oxytocin therapy.

Oxytocin is being used by thousands of patients as a complementary and alternative therapy for ASD, with numerous anecdotal reports of good benefit and tolerability but no published data. Internet pop-up ads tout oxytocin as "the love hormone." Alternative medicine providers use a host of different preparations and doses, typically with no monitoring of vital signs or documentation of outcomes. It’s not a healthy situation.

"We felt like it was time to act now," noted Dr. Linmarie Sikich, a psychiatrist at the University of North Carolina, Chapel Hill.

She and her coinvestigators therefore obtained a grant from Autism Speaks to conduct a phase II feasibility study in which 25 children with autistic disorder by DSM-IV criteria were randomized to 8 weeks of double-blind, twice-daily intranasal oxytocin flexibly dosed at 4-64 IU daily or placebo, followed by open-label oxytocin for all for an additional 8 weeks, then 3 months off-treatment before final follow-up. Eleven children were nonverbal, and 14 had fluent speech.

Oxytocin therapy was associated with improvement in multiple measures of social functioning, compared to placebo. Moreover, the benefits remained stable, and in some cases, increased during the 3 months after the end of treatment. Even the low-functioning, nonverbal young children were able to tolerate intranasal oxytocin.

Typical parental reports were that their child was more engaged at school, more compliant at home, more tolerant of peers, and better able to recognize the feelings of others, Dr. Sikich said.

The phase III SOARS-B study entails 6 months of double-blind intranasal oxytocin or placebo, then 6 months of open-label oxytocin for all, followed by 6 months off-therapy. Potential biomarkers of response as well as genetic samples are being obtained.

"We think the core social symptoms that are our target aren’t going to change in 8 weeks," she said "We think seeing meaningful clinical change is going to take more time."

Oxytocin is off patent. It lacks profit potential. As a result, pharmaceutical industry interest in developing it as an ASD therapy is nil. So Dr. Sikich and her academic colleagues are trying to do so, going so far as to arrange for intranasal oxytocin to be compounded in the United States to avoid the unpredictable shipment delays from European suppliers that occurred in the phase II study. She described working with the Food and Drug Administration in this effort as an eye-opening experience fraught with numbing hassles, bureaucratic indecision, and delays.

"Collaborating with pharma is a lot easier. I was not at all prepared for all of the things we’ve had to do that pharma typically does, and all of the associated costs," she said.

D-cycloserine

An antibiotic used as a second-line treatment for tuberculosis, D-cycloserine is a partial glycine agonist that binds with glutamate at the NMDA receptor to promote calcium conductance and normalize NMDA neurotransmission.

Based upon favorable animal studies, Dr. Maria R. Urbano and her colleagues conducted a 10-week uncontrolled, randomized, double-blind trial comparing D-cycloserine once-daily at 50 mg or once-weekly at 50 mg for 8 weeks in 20 patients with ASD. Participants were 14-25 years old, and all had an IQ above 70. Dr. Urbano chose this age range deliberately.

"I’m particularly interested in older adolescents and young adults with ASD, because in this group it’s imperative to try to interact socially as they try to launch from their families. There are too many of my patients who are sitting at home at age 20 or 21 doing nothing," observed Dr. Urbano, a psychiatrist and codirector of the ASD program at Eastern Virginia Medical School, Norfolk.

Ten of the 20 patients were deemed clinical responders based upon at least a 16-point (1 standard deviation) improvement in scores on the Social Responsiveness Scale. The mean improvement over the course of the study was 17.9 points, with no differences in the rate or magnitude of response between the two dosing arms. Since the efficacy was the same, once-weekly dosing will be used in the placebo-controlled trial now being planned. Once-weekly dosing might lessen the risk of side effects or tachyphylaxis, she noted.

Dr. Sikich and Dr. Urbano reported having no relevant financial interests. Dr. McCracken is a consultant to Roche and Seaside.

Promising autism drugs progress through pipeline