Summary of Oxytocin / Carbetocin Therapy Research for PWS to date (updated August 2019)
Oxytocin (OT) is a naturally occurring hormone released from the hypothalamus in the brain. It is associated with maternal care, bonding, feeding in infancy, social cognition, OCD, anxiety and appetite control. A reduction in the number of neurons that produce oxytocin and reduced oxytocin receptor (OTR) gene expression in PWS are believed to play a role in PWS psychopathology. It is suggested the disruption of oxytocin feedback in the hypothalamic paraventricular nucleus possibly influences vasopressin (AVP) signalling (another, related hypothalamic hormone). Use of OT administered via nasal spray as a therapy for improving behaviours is being actively studied in PWS and other conditions where altered OT pathways are associated with behaviour, such as autism spectrum disorder (ASD), Fragile X and Williams syndrome.
Its potential as a treatment for PWS has generated much interest in the PWS community with an international fundraising effort taking place to specifically support the phase 2 oxytocin study by Drs. Jennifer Miller and Dan Driscoll at the University of Florida. However, early clinical trials of intranasal oxytocin in PWS produced conflicting results. The first, a pilot study by Dr. Tauber in France, 2011, trialled a single oxytocin dose in a small group of adults and observed a significant increase in trust and decreased sadness tendencies with less disruptive behaviour after 2 days. Hopes were raised that oxytocin may improve socialisation in PWS and longer term and dose-effect studies were recommended. A second study by Dr. Stewart Einfeld at The University of Sydney, 2014, looked at longer term treatment in adolescents and young adults. 30 families took part in this trial (including some from New Zealand), but the results found that oxytocin had little impact on any measure (behaviour, OCD tendencies, hyperphagia and sleepiness). An increase in temper outbursts was also observed with higher dose oxytocin. Researchers have remained optimistic because oxytocin signalling is very complex and it is believed that finding the correct formulation and dose may be crucial to the success of oxytocin therapy.
The phase 1 study by Dr Miller et al at The University of Florida trialled OT in 24 children (5-11 years) and the results were encouraging. Improvements were observed in behaviour, social responsiveness and hyperphagia. They concluded, “The results from this study suggest that low dose intranasal oxytocin is safe for individuals with PWS and may result in reduction in appetite drive, and improvements in socialization, anxiety, and repetitive behaviors. Further long-term studies with a larger population of participants are necessary to confirm these findings.” Their phase 2 study is currently underway.
Meanwhile, a similar phase 2 study trialling intranasal OT in 50 children and adolescents (5-17) is being conducted by Dr Eric Hollander and his team at The Albert Einstein College of Medicine in New York and is currently recruiting (completion date expected to be Aug 2020.) They will be assessing affects of oxytocin on appetite, repetitive behaviours, quality of life, weight and body composition and measuring salivary oxytocin and hormone levels. A third, similar phase 2 trial by Dykens et al (sponsored by Ferring Pharmaceuticals) evaluated intranasal OT in a large group of children and adolescents (10-18) and was declared a success with clinically meaningful improvement in hyperphagia and associated compulsive behavioral symptoms compared to placebo. This trial is very interesting because a slightly different form of OT was used (FE992097) to specifically target only the OT receptor which may reduce impact on other systems, i.e. AVP signalling. (In comparison, the initial studies by Drs.Tauber, 2011, and Einfeld, 2014, used Syntocinon, a synthetic substance identical to natural oxytocin.) The rights to this Ferring Pharmaceuticals oxytocin-like drug, Carbetocin, have been purchased by Levo Therapeutics and a large scale phase 3 trial for LV-101 (carbetocin) is now recruiting 7-18 yr olds at sites across the USA and Canada (CARE-PWS), with an estimated completion date of December 2020. Levo Therapeutics is a company formed by the parent of child with PWS and is dedicated to advancing treatments for PWS and similar disorders. There is much excitement about Carbetocin because it was specifically designed to limit any potential unwanted side effects, it was well tolerated and it is the closest oxytocin-like therapeutic option to being approved for use in PWS.
Dr. Tauber and her team in France are also conducting a phase 2 trial by expanding their initial OT trial in adults for a longer duration trial with multiple doses and using advanced brain imaging analysis. They aim to find the optimal schedule and dose for adults with PWS.
Oxytocin studies are still experiencing mixed results. A recently published study from the Netherlands by Kuppens, Donze and Hokken-Koleaga, 2016, produced initially disappointing results with no significant improvements observed overall. However, when they examined age subgroups they noticed there were positive results in some of the children younger than 11. Their study had involved participants age 6-14 years and they concluded, “This study suggests that intranasal oxytocin administration has beneficial effects on social behaviour and food-related behaviour in children with PWS younger than 11 years of age, but not in those older than 11 years of age.”
There is still much to learn about oxytocin levels in PWS, the genetic variability of the oxytocin receptor gene, the impact of the OT system on the developing brain in PWS and why there are variable responses to oxytocin. Researchers believe we need these answers in order to effectively calculate dose and the optimal age for treatment. In 2015, FPWR funded further oxytocin research by Dr. Stewart Einfeld’s team in Sydney. One study aims to understand the true nature of the oxytocin abnormality associated with PWS which will help direct oxytocin or vasopressin interventions. They intend to discover if there are similarities with the reduced levels of 9-amino-acid active oxytocin and increased extended oxytocin found to be present in people with ASD. They also intend to find out more about the hypothesised suppressed oxytocin receptor which could make the OT system inactive, even when high levels of OT are administered. It’s possible that vasopressin receptors may be responding to administered oxytocin so they will measure plasma levels of the two forms of oxytocin vasopressin and DNA levels of the oxytocin gene. Dr Einfeld and his team are currently recruiting patients with and without PWS ages 13-30 years. A second study will investigate potential respiratory sinus arrhythmia abnormalities in PWS and how they may relate to emotional and behavioural problems and oxytocin / vasopressin abnormalities. Other studies being funded are the evaluation of factors that may affect the efficacy of intranasal oxytocin treatment in PWS by Dr Driscoll at the University of Florida and an exploration of the wake promoting effects of oxytocin by Dr Scammell at Harvard University.
Research in France has focused on early alterations from birth in the OT system and pathways of OT receptors in the perinatal period. In 2015, a French research team led by Dr. Meziane published results of a study examining the OT system in mice deficient in Magel 2 genes (deficient genes associated with both PWS and autism, causing deficits in social recognition, interaction and a reduced learning ability) and found modifications of the OT system that change from birth to adulthood. Daily administration of OT in the first postnatal week was sufficient to prevent deficits in social behaviour and learning abilities in adult males, and partly restore a normal OT system. FPWR have funded a study by Dr. Muscatelli to further understand the relationship between the inactivation of Magel 2 and the alteration of the OT system and to investigate how an administration of oxytocin acts during brain development to allow a long term effect in Magel 2 deficient mice. This study will increase knowledge about adequate supplemental therapy in infancy and provide insight into effective OT administration at different points of the OT system maturation (infancy to adulthood).
An exciting, recent discovery by Dr Tauber and her team confirm and extend the findings of Dr Meziane. They found that oxytocin improves feeding and social interaction in infants with PWS. 18 infants (age 3 wks to just under 6mths) were given oxytocin doses on different schedules and regardless of dose, all of the babies showed improvements in feeding skills with 88% being normalised after treatment. Some aspects of social behaviour also improved – measured facial expression, eye contact and interaction with parents. Brain scan images also revealed improved connectivity in the OFC brain region which is involved in emotional decision making. It is not yet clear if there is a long term impact of this early treatment and whether oxytocin has a ‘rescue’ effect, but this is an area of interest for further study.
It is hoped that the combined knowledge gained from these past and ongoing trials will refine understanding of the potential of oxytocin therapy and determine most effective use of oxytocin in children and adults with PWS. If benefit is clearly proven, multiple trials confirming this will help support approval (and the subsequent funding) of oxytocin for PWS in New Zealand. It is important to note that trials are in early stages and we forward caution about purchasing and using available forms of oxytocin before more is known about dose and safety.