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BioMarin’s (NASDAQ:BMRN) Kuvan, currently in clinical development for the treatment of autism, may only produce a small benefit in children who suffer from the developmental disorder, according to experts interviewed by BioPharm Insight.
Kuvan is currently approved by the FDA to treat phenylketonuria (PKU), a rare genetic disorder where patients cannot properly metabolize foods containing the amino acid, phenylalanine. The drug is a pharmaceutical formulation of BH4, an enzyme which is deficient in PKU sufferers.
Dr Robert Ring, vice-president of translational research at Autism Speaks, a non-profit organization, explained that while it is well known that BH4 is essential for the synthesis of neurotransmitters, there is no compelling evidence linking BH4 deficiency to autism pathology. Ring, who previously served as the Head of Autism Research at Pfizer (NYSE:PFE), noted that although PKU can cause issues with cognitive development, there are no conclusive connections between that and autism.
According to Dr Richard Frye, a primary investigator on a study evaluating Kuvan in autism and assistant professor at the Department of Pediatrics at the University of Texas, said BH4 aids in the regulation of neurotransmitters, including serotonin, norepinephrine and dopamine, which he believed are abnormal in autistic children. However, Ring indicated that there is no strong evidence that these neurotransmitters are dysregulated in autistics.
BH4 also enhances blood flow to the brain and has antioxidant qualities, which would be beneficial in autistic individuals as these children have high levels of oxidative stress, Frye said.
The study run by Frye is an open-label trial in 20 patients and should conclude by the end of the year, he said. The trial will assess both metabolic and behavioral changes, including social and language deficits, over a course of 16-weeks in patients using Kuvan therapy. In addition to this study, Kuvan is also being investigated in a Phase II double-blind trial, conducted by the Children’s Health Council (CHC) in Palo Alto, California with financial underwriting from BioMarin.
Both studies will assess daily doses of 20 mg/kg of Kuvan in autistic children aged three to six years.
According to an investigator on the CHC study, the last patient will complete the 16-week long study by the end of August, at which point results will be submitted for publication in a medical journal.
A spokesperson for BioMarin said the company is not in a position to comment on the clinical study as it is an investigator sponsored trial.
Treatment with Kuvan can “wake up the brain” and would have some clinical benefit in autistic children, said Frye.
Kuvan may help the brain process information and learn social skills and language, though it is not going to replace language that should be there, Frye explained. BH4 replacement therapy is not going to “switch something on,” but may help the brain work more efficiently, he said
Historical evidence
David Evans, professor of psychology and neuroscience at Bucknell University, said the only clinical trials assessing the relationship between BH4 and autism have been small scale studies, without placebo control groups. The evidence behind the use of BH4 in autism is insufficient, and tenuous at best, Ring agreed, noting that the therapeutic effects demonstrated so far have been inconclusive.
Frye pointed to two relatively recent studies in the space as support for the use of Kuvan in autism.
The first is an open-label study of BH4 therapy in six children aged three to five years [Developmental Medicine and Child Neurology 1997.39: 313-318]. The study also implemented PET imaging to assess the role that BH4 plays in the brain.
However, lead author Dr Elisabeth Fernell from the Department of Neuropaediatrics at Astrid Lindgren Children’s Hospital, at the Karolinska University in Sweden, said the effects found in the study were not enough to warrant further development. The drug mainly improved social contact but the open-label nature of the study makes this finding inconclusive, she said. The PET imaging portion of the study demonstrated that BH4 treatment resulted in a normalization of dopamine metabolism in autistic children, said Frye.
While the dopamine system -- and correcting its imbalance with BH4 -- is of interest in autism, it is not the only factor, Fernell said. “Too little is known about brain chemistry in autism,” she added.
A second-Swedish study in 12 children had a double-blind cross-over design [J Clin Psychopharmacol 2005; 25:485-489] where participants who were on BH4 therapy unknowingly switched to the placebo drug half-way through the study and vice versa. Fernell said the effects and the compound’s benefits in relation to social contact were incremental at best.
The use of a post-hoc analysis on a non-significant result as well as the “inappropriate” use of the Childhood Autism Rating Scale (CARS), in which investigators wrongly selected specific items for analysis on a scale meant to be taken as a whole, are “major methodological problems” and further muddy the results of the study, Evans said.
None of the previous studies of BH4 in autism have used the “gold standard” for diagnosing the disease, Evans added, noting that measures such as the Autism Diagnostic Interview—Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) should be used instead. These measures are currently being implemented in the on-going CHC study.
The effects of Kuvan in autism are unlikely to be “remarkable,” Fernell said, noting that any positive benefit is apt to be small.
Ring noted, though, that it is important to test the BH4 deficiency hypothesis and draw conclusive results from a proper double-blinded study. If the CHC trial is run well, it will give a clearer picture as to whether it would be worth moving forward or halting development on BH4 therapy in autism, he said.
CSF analysis using lumbar puncture
Kuvan would not be a therapy for all children with autism, said Fernell. However, the drug’s mechanism of action may play a role in a subgroup of children with low cerebrospinal fluid (CSF) levels of BH4, she said.
In the Fernell study, the average baseline CSF level of the six children was approximately 8.66 nmol/L. In Frye’s study, only children with BH4 CSF levels below 30nmol/L from a prior lumbar puncture would be enrolled in the trial. While a very low baseline CSF BH4 level did not demonstrate efficacy in Fernell’s study, Frye indicated that it is unknown what the effects of the much higher upper-limit CSF BH4 level may be in his study.
Evans also pointed out that it would be a “terrible idea” to screen children who may benefit from Kuvan therapy using an invasive lumbar puncture procedure.
Lumbar punctures will not be performed at any point during Frye’s study. The double-blinded CHC study will not be taking CSF levels into consideration at all.
Evidence has demonstrated that Kuvan is most effective in autistic children less than five years of age, Frye said, noting that older children do not respond as well. There is no good data on how the role of BH4 changes in the body over time, he added.
Developmental physiology is a moving target, where BH4 replacement may be needed at one point in development but not at other points, Frye explained. Kuvan is also not helpful in autistic children with high levels of intellectual impairment, he said.
Extra vigilance should be taken when it comes to spreading misinformation about a “cause-and-effect” treatment approach in light of the controversy surrounding the false claim that vaccines or thimerosal -- a mercury-based preservative -- cause autism, Evans said.
Evans added that he believes the idea of treating symptoms of autism with BH4 is unlikely to be successful and is yet another “theory in a long line of false hopes.”
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