Posted on by Dr. Francis Collins
Amid all the headlines and uncertainty surrounding the current COVID-19 pandemic, it’s easy to overlook the important progress that biomedical research is making against other diseases. So, today, I’m pleased to share word of what promises to be the first effective treatment to help young people suffering from the consequences of a painful, often debilitating genetic disorder called neurofibromatosis type 1 (NF1).
This news is particularly meaningful to me because, 30 years ago, I led a team that discovered the gene that underlies NF1. About 1 in 3,000 babies are born with NF1. In about half of those affected, a type of tumor called a plexiform neurofibroma arises along nerves in the skin, face, and other parts of the body. While plexiform neurofibromas are not cancerous, they grow steadily and can lead to severe pain and a range of other health problems, including vision and hearing loss, hypertension, and mobility issues.
The good news is the results of a phase II clinical trial involving NF1, just published in the New England Journal of Medicine. The trial was led by Brigitte Widemann and Andrea Gross, researchers in the Center for Cancer Research at NIH’s National Cancer Institute.
The trial’s results confirm that a drug originally developed to treat cancer, called selumetinib, can shrink inoperable tumors in many children with NF1. They also establish that the drug can help affected kids make significant improvements in strength, range of motion, and quality of life. While selumetinib is not a cure, and further studies are still needed to see how well the treatment works in the long term, these results suggest that the first effective treatment for NF1 is at last within our reach.
Selumetinib blocks a protein in human cells called MEK. This protein is involved in a major cellular pathway known as RAS that can become dysregulated and give rise to various cancers. By blocking the MEK protein in animal studies and putting the brakes on the RAS pathway when it malfunctions, selumetinib showed great initial promise as a cancer drug.
Selumetinib was first tested several years ago in people with a variety of other cancers, including ovarian and non-small cell lung cancers. The clinical research looked good at first but eventually stalled, and so did much of the initial enthusiasm for selumetinib.
But the enthusiasm picked up when researchers considered repurposing the drug to treat NF1. The neurofibromas associated with the condition were known to arise from a RAS-activating loss of the NF1 gene. It made sense that blocking the MEK protein might blunt the overactive RAS signal and help to shrink these often-inoperable tumors.
An earlier phase 1 safety trial looked promising, showing for the first time that the drug could, in some cases, shrink large NF1 tumors . This fueled further research, and the latest study now adds significantly to that evidence.
In the study, Widemann and colleagues enrolled 50 children with NF1, ranging in age from 3 to 17. Their tumor-related symptoms greatly affected their wellbeing and ability to thrive, including disfigurement, limited strength and motion, and pain. Children received selumetinib alone orally twice a day and went in for assessments at least every four months.
As of March 2019, 35 of the 50 children in the ongoing study had a confirmed partial response, meaning that their tumors had shrunk by more than 20 percent. Most had maintained that response for a year or more. More importantly, the kids also felt less pain and were more able to enjoy life.
It’s important to note that the treatment didn’t work for everyone. Five children stopped taking the drug due to side effects. Six others progressed while on the drug, though five of them had to reduce their dose because of side effects before progressing. Nevertheless, for kids with NF1 and their families, this is a big step forward.
Drug developer AstraZeneca, working together with the researchers, has submitted a New Drug Application to the Food and Drug Administration (FDA). While they’re eagerly awaiting the FDA’s decision, the work continues.
The researchers want to learn much more about how the drug affects the health and wellbeing of kids who take it over the long term. They’re also curious whether it could help to prevent the growth of large tumors in kids who begin taking it earlier in the course of the disease, and whether it might benefit other features of the disorder. They will continue to look ahead to other potentially promising treatments or treatment combinations that may further help, and perhaps one day even cure, kids with NF1. So, even while we cope with the COVID-19 pandemic, there are reasons to feel encouraged and grateful for continued progress made throughout biomedical research.
 Selumitinib in children with inoperable plexiform neurofibromas. New England Journal of Medicine. Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC. 18 March 2020. N Engl J Med. 2020 Mar 18. [Epub ahead of publication.]
 Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P1, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. N Engl J Med. 2016 Dec 29;375(26):2550-2560.
Neurofibromatosis Fact Sheet (National Institute of Neurological Disorders and Stroke/NIH)
Brigitte Widemann (National Cancer Institute/NIH)
Andrea Gross (National Cancer Institute/NIH)
NIH Support: National Cancer Institute
Posted on by Dr. Francis Collins
It’s been more than a quarter-century since my colleagues and I were able to identify the gene responsible for cystic fibrosis (CF), a life-shortening inherited disease that mainly affects the lungs and pancreas . And, at a recent event in New York, I had an opportunity to celebrate how far we’ve come since then in treating CF, as well as to honor a major force behind that progress, Dr. Bob Beall, who has just retired as president and chief executive officer of the Cystic Fibrosis Foundation.
Thanks to the tireless efforts of Bob and many others in the public and private sectors to support basic, translational, and clinical research, we today have two therapies from Vertex Pharmaceuticals that are targeted specifically at CF’s underlying molecular cause: ivacaftor (Kalydeco™), approved by the Food and Drug Administration (FDA) in 2012 for people with an uncommon mutation in the CF gene; and the combination ivacaftor-lumacaftor (Orkambi™), approved by the FDA in July for the roughly 50 percent of CF patients with two copies of the most common mutation. Yet more remains to be done before we can truly declare victory. Not only are new therapies needed for people with other CF mutations, but also for those with the common mutation who don’t respond well to Orkambi™. So, the work needs to go on, and I’m encouraged by new findings that suggest a different strategy for helping folks with the most common CF mutation.