Research Field Clinical trials, Drug discovery, Neuroscience, Neurological

A Rare Opportunity for Change

Much research and development focuses on the so-called big four cancers (breast, bowel, lung, and prostate), but treatment options for patients living with rarer cancers can be less forthcoming. Neurofibromatosis type 1 (NF1) is one such cancer, affecting one in every 3000–4000 individuals in the USA (1). Triggered by a mutation in the NF1 gene, it causes a variety of symptoms, including patches of brown skin pigmentation (known as cafe au lait spots), tumors underneath the skin, and learning and behavioral challenges. Another significant issue associated with the condition is that up to half of the people who live with it develop plexiform neurofibromas – tumors that can grow along nerve sheaths (1). And because these tumors can grow in various locations and vary in size, they can cause a wide range of symptoms, including reduced mobility, airway and bladder dysfunction, as well as disfigurement. Though treatments exist for these secondary symptoms, no drug was able to address NF1 directly – until now.

Koselugo, a MEK inhibiting drug developed by AstraZeneca, received approval from the FDA in April 2020 to treat NF1 in pediatric patients. During NF Awareness Month (, we spoke with George Kirk, Global Medicines Lead, R&D Oncology at AstraZeneca, to uncover the story behind the development of the drug.

How does NF1 affect patients?

Living without medicines that actually treat the condition is a challenge for many patients. From managing breathing with tracheostomies to the need for analgesics (and stronger drugs) for pain management, NF1 patients are fighting against the disease every day of their lives. Though surgery to remove plexiform neurofibromas is available, it is only applicable to around 15 percent of patients, and it is very difficult to remove tumors growing along nerves without causing further damage. In addition, patients who have plexiform neurofibromas also have a greater risk of developing other types of cancer. Up to 15 percent of patients develop malignant peripheral nerve sheath tumors, which can significantly reduce life expectancy.

What is the story behind Koselugo?

Koselugo has been in development for over 16 years. The MEK inhibiting drug was initially developed by Array BioPharma, a subsidiary of Pfizer. The company had just begun early clinical trials in humans when AstraZeneca licensed the product and began its own phase I and II trials. Though MEK inhibitors had previously been shown to be effective in skin cancers like melanoma, they have had limited success in other forms of cancer. The focus of AstraZeneca’s trials was to examine the efficacy of the drug in other cancers affecting adults, including uveal melanoma, thyroid, and lung cancers. Unfortunately, the drug failed across three studies between 2013 – 2016. 

Although these trials were unsuccessful, the drug hadn’t been written off. In 2011, we were approached by the Cancer Therapeutics Evaluation Program (CTEP) and the National Cancer Institute (NCI) in the USA, which was interested in investigating the potential of Koselugo in pediatric patients with NF1 and plexiform neurofibroma. There was a large volume of preclinical data that indicated the possibility of success of the drug for this particular disease indication. Within a few years of conducting the first phase I trials in children, we saw a massive reduction in tumor volume – a positive step forward for a drug that had experienced many setbacks.

In 2014, the NCI presented their phase I trial data at the American Society of Clinical Oncology – a huge moment for our team because it was one of the first major milestones on the road to receiving approval for this drug. More importantly, it showed us that the science had pointed us in the right direction and that we had been right to stick with Koselugo, despite its failures.

What lessons were learned during the development of the drug?

Finding and collaborating with  partners with the right expertise, such as CTEP and the NCI,  is important for the development of any product – but more so when a medicine is intended to treat a small patient population. Koselugo was the first drug to be approved for the treatment of NF1 in children, so we were entering new territory when determining the clinical benefit of the drug and putting together a regulatory submission for the FDA. Fortunately, we were closely supported by our colleagues at the NCI, as well as others within regulatory bodies.

It sounds like a rewarding project to be involved in…

I’ve spent the majority of my career working on oncology projects – and seeing much needed therapeutic options become reality is something I hold dear. Though it’s difficult, or arguably impossible, for us who haven’t lived with cancer – or specifically NF1 – to fathom what life must be like for these patients, by making a difference in any way possible we can offer our support. 

Hearing the individual stories of patients who have partaken in the clinical trials for Koselugo is extremely rewarding. During the course of the trial, we had an example of a six-year-old patient who had tumors and plexiform neurofibromas in her face and neck. Because of the symptoms of NF1, she was unable to breathe without a tracheostomy. While taking Koselugo, the tumors shrunk, enabling her to breathe on her own. Though there is no way of quantifying the impact of the treatment on that particular patient’s life, knowing that she was able to regain independence and attain an improved quality of life is motivating to say the least. Overall, the reaction from the patient community has been incredible. 

I was lucky enough to speak to the Children’s Tumor Foundation – an NF1 patient advocacy group and research organization – about the drug. I had the chance to talk with a number of patients and families, and so it was a very special and humbling call.

Is enough being done to address pediatric cancers?

The short answer is that there is always more that can be done. There’s certainly a lot of progress being made in the oncology space, but there are fewer options for the treatment of pediatric cancers than adult cancers. And that reality is highlighted by the fact that the approval of Koselugo was only the third in 20 years for a drug with an initial indication for pediatric cancer.

Advances are being made, particularly in hematological cancers like leukemia, but the pharmaceutical industry needs to devote more resources into treatments for children, and consider pediatric needs much earlier in the development cycle.

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About the Author
Maryam Mahdi

Deputy Editor

After finishing my degree, I envisioned a career in science communications. However, life took an unexpected turn and I ended up teaching abroad. Though the experience was amazing and I learned a great deal from it, I jumped at the opportunity to work for Texere. I'm excited to see where this new journey takes me!

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