'More hopeful outcomes' on the horizon for Prader-Willi syndrome
Prader-Willi syndrome, a neurodevelopmental disorder that occurs in about 1 in 15,000 births, is the most common genetic cause of life-threatening childhood obesity, which is just one of its complex symptoms. Still, it has proved extremely difficult to treat. Fortunately for the Prader-Willi syndrome community, researchers continue to test potential therapies to find a comprehensive treatment or a way to curb the most severe symptoms.
There is still much to learn about how Prader-Willi syndrome works, but each new trial brings better answers, according to Jennifer L. Miller, MD, professor in the division of pediatric endocrinology at the University of Florida. Miller has worked with patients with Prader-Willi syndrome and their families for 20 years. She told Endocrine Today that the future is bright for this population. – by Amanda Alexander
What is Prader-Willi syndrome and how it is usually diagnosed?
Miller: Prader-Willi is a genetic condition caused by lack of the paternal contribution in a part of chromosome 15. Nowadays, it is most commonly diagnosed in the first few months of life — typically within the first month of life — by a combination of low tone and hypogonadism and the babies not wanting to eat. The babies have to be fed through an NG-tube or G-tube because they will literally close their mouths and tongue out the bottle. They have no desire to take a bottle. They cannot breastfeed because they just do not have the strength. That culmination is what gets them tested.
The earlier diagnosis is actually attributable to the parent organizations because they have really gotten the word out to doctors and lay people through media, in terms of what to look for, what are the identifying signs of Prader-Willi syndrome. Now, more neonatologists are aware of it and are testing for it. Our average age of diagnosis right now is 1.2 months, which is a huge step. When I first started researching the syndrome in 2000, the average age of diagnosis was 8 years, so times have really changed.
What is the standard of care for individuals with Prader-Willi syndrome, and does the treatment change throughout their lifetime?
Miller: Growth hormone therapy is standard of care for infants and children with Prader-Willi syndrome, typically started sometime within the first year of life. Starting growth hormone early in life — before 1 year of age — definitively seems to impact body composition, growth and development milestones, both speech and gross motor. The Dutch Growth Research Foundation — led by Anita Hokken-Koelega, MD, PhD, as director and professor and head of the pediatric endocrinology department at Erasmus University Medical Center in Rotterdam — has followed those infants, and data show that there are actually improvements in cognition that continue as they grow and stay on growth hormone. It is just fascinating that they have been able to do this. They did a trial of placebo vs. growth hormone in the infants, and then everybody went on growth hormone, and they have looked at the cognitive scores all along. It is just really cool data.
Do patients with Prader-Willi syndrome currently continue the growth hormone treatment throughout their lives?
Miller: In the U.S., growth hormone is not approved to be used once the kids have stopped growing. It’s only FDA approved for growth failure, so unfortunately right now most adults with Prader-Willi syndrome are not on growth hormone treatment because they cannot get it approved through their insurances. However, it does look like there is a very positive impact of continuing growth hormone therapy, obviously in the right doses, for individuals with Prader-Willi syndrome as they are done growing and become adults. It is a big problem for the adults. You take them off growth hormone and their stamina goes down, their energy goes down, their body fat goes up, and now they are dealing with a disorder that not only has a risk for obesity already plus hyperphagia, which worsens the obesity, but now their body is changing so that the obesity becomes more significant because they have less muscle mass and more fat mass. It becomes a downward spiral.
Five years ago, you had talked about the possibility of treatment using drugs that are approved for obesity, but a recent study found that bariatric surgery failed in people with Prader-Willi syndrome in the long term. Do you think medical therapies designed for less severe forms of obesity might still work for this condition?
Miller: No, they do not, unfortunately. A lot has been tried and a lot has failed. I do not know whether all that data are actually published, but things like phentermine, which is often used in a more mild form of adolescent or adult obesity, did not work in Prader-Willi syndrome at all. The stimulants — like lisdexamfetamine (Vyvanse, Takeda) for binge eating disorder that people have tried for Prader-Willi syndrome — did not work at all. Unfortunately, the syndrome has proved to be very resilient in terms of protecting the hyperphagia and obesity.
Now, there are three phase 3 drug studies of agents in the pipeline, which is highly different than a few years ago. These are not standard of care yet, but are very exciting.
Why do you think it is that Prader-Willi syndrome is so difficult to treat?
Miller: Good question. I do not know the answer. There is seemingly a disconnect between the periphery and the brain. You can see it with the failure of bariatric surgery in the long term. They just do not get those same signals that go from the periphery or that go to the brain to say stop, you are full, you are done. That is part of the problem.
I also believe there is an intrinsic problem with the hypothalamus and the areas that control hunger and fullness. That problem still remains somewhat of a mystery in terms of how to fix it. We have done studies where we have tried drugs that, theoretically, if the problem was just a signaling problem, would have worked. The drug setmelanotide from Rhythm Pharmaceuticals, which is working really well in other rare genetic causes of obesity, did not work at all in Prader-Willi syndrome. That tells you how complicated the syndrome must be, because if you look at the literature, you know that drug is working beautifully for patients with proopiomelanocortin deficiency or leptin receptor mutations and things like that. Prader-Willi syndrome is clearly more complex than those single gene causes of obesity and hyperphagia.
Is there anything you want to add?
Miller: In my opinion, this is an exciting time for individuals with Prader-Willi syndrome and their families. Other than growth hormone, there is really no standard of care treatment right at this moment, but the fact that we have three phase 3 trials going on to address the appetite issues is quite remarkable. In my mind, this means that there is going to be an answer in the near future for these families and individuals affected by the syndrome.
When I started doing this work 20 years ago, we basically talked about group homes from the time the kids were diagnosed. “They are never going to live independently because of their appetite, which they cannot control, the end.”
Now I say, “I think there will be an answer, and I think there is a possibility your kid could live independently, and we are working on it.”
That is a really nice change in the message of the syndrome. As an endocrinologist, now I can share much more hopeful outcomes than I used to be able to, and that really keeps me loving my job because I can give hope to families. I don’t know when we will have an answer — maybe it’s not these three drugs, maybe it’s something different — but we do know that people are at least very interested in solving this problem and trying to make life better for these people and that is huge.
Reference:
Bakker NE, et al. J Clin Endocrinol Metab. 2017;doi:10.1210/jc.2016-2962.
For more information:
Jennifer L. Miller, MD, can be reached at millejl@ufl.edu.
Disclosure: Miller reports no relevant financial disclosures.