Guiding star of science leads AstraZeneca to breakthrough in child tumour therapy

Global product lead George Kirk hails the triumph of selumetinib, which has just won FDA approval

The power of science has been the guiding star for a drug that has weathered storms to land an approval that has given hope to an underserved cohort of children suffering from the rare genetic disorder neurofibromatosis type 1 (NF1).

Selumetinib was given ‘breakthrough therapy’ status and rapidly green-lit by the FDA last month (April) following a promising National Cancer Institute (NCI) Cancer Therapy Evaluation Program sponsored phase 2 trial. Approvals in Europe and other countries are expected next year.

But faith in its science was tested to the limit as the MEK inhibitor failed multiple cancer trials in its original targets of small cell lung cancer and melanoma in adults, while its licensing became embroiled in a royalties dispute.

“Collaborating with our partners at the NCI, we stuck with the science and it has paid off,” said George Kirk, AstraZeneca’s global product lead for selumetinib. George has been glued to the therapy since it first showed promise for the paediatric population with NF1, an incurable genetic condition that affects one in 3,000-4,000 people.

It is characterised by soft lumps on and under the skin, coffee-coloured pigmentation and tumours that emerge along nerve sheaths, known as plexiform neurofibromas (PN), with a debilitating range of symptoms including bladder/ bowel dysfunction, high blood pressure and leukaemia, and can reduce life expectancy by up to 15 years. Anecdotal data also suggests NF1 has a detrimental impact on childhood development, but clinical studies are needed to tease out its neurological traits.

Strategic partnership

“It is really exciting that we can make selumetinib available to patients who suffer from NF1-PN,” added George. “The main reason we stuck with this was that the science was telling us to, but the positive impact on patients was critical. There is no existing treatment for children with NF1- PN so when you hear their stories and how the condition has affected them, it is very compelling. It really drove us on and now we have the first drug to shrink the tumours. It is already having a transformative impact.

“We have a rich oncology portfolio in AstraZeneca and we want to use that in a positive way in paediatric populations, not just in adult cancers. It is about doing the right thing and following the science.”

It is being developed in a strategic partnership with Merck & Co/MSD, formed in 2017, to maximise the potential of PARP and MEK inhibitors. The drug will be sold under the Koselugo brand name in the US.

Selumetinib, taken as a twice-daily oral capsule, sparked huge interest when it was granted Orphan Drug Designation by the US FDA in February 2018 and by the European Medicines Agency six months later. The SPRINT trial data – showing a 66% response in patients with NF1-PN – only confirmed that promise and was celebrated by patient groups.

“It’s a huge deal for the patients and their families,” said George. “These tumours are slow-growing and vary in size, which leads to complications depending on the location of the tumour. They can hinder mobility, for example, and can cause considerable pain.

Neutralising mutations

“One patient, a boy with a tumour in his upper arm which stopped his mobility, responded after treatment to the point that the tumour shrank and he was able play-wrestle with his sister and play on the monkey bars. He can now do the things that normal kids do.

“Another example is a patient who had a tumour around her neck and face which was blocking her airway. She needed a tracheotomy to breathe but, after treatment, the tumour receded and she was able to remove that tracheotomy and breathe on her own for the first time in a long time. “Each patient story is slightly different because it depends on the tumour location, but we do know that the majority experience pain and suffer impact on their daily functioning. Just moving around, something we take for granted, can be difficult and painful.”

The genetic condition was being mapped from the 18th century but the official discovery is placed at 1849 when the disorder was first detailed as an autosomal dominant disorder and named NF1. Around a third of people with NF1 will develop a medical condition during their lifetime.

The NF1 gene provides instructions to make neurofibromin which acts as a tumour suppressant but if it mutates, tumour cell growth can proliferate. In around 50% of carriers, the altered gene is inherited while the rest of cases are caused by a sporadic mutation. Selumetinib counters that condition’s effects by regulating the MAP kinase pathway, effectively neutralising the mutation’s ability to prompt tumour growth.

“I’ve been working on selumetinib since 2012, a year after we received a proposal from the National Cancer Institute (NCI) for a phase 1 study in children and we felt the science was very strong. With the first data set in 2016, which was just a study to establish a suitable dose for children, we discovered that the tumours shrank which was really exciting and, although we were also developing selumetinib in the adult solid tumour space, the science here was really strong.”

Strong values

“It was the first treatment to shrink these tumours, so it was the start of a journey towards the approval of the first-ever treatment for these patients and the hope for some form of curative treatment or a cure in the future. With the latest phase 2 data, the hope is that we can treat these patients when the tumours start to grow, so we can restrict how large they get and reduce their impact.

“Even though it doesn’t stop tumour growth completely, it is still a massive deal for patients and their families. And we have some children who you wouldn’t even know had tumours because they have shrunk and are no longer visible. More importantly, many of them can now do the things that all children do.”

Plexiform Neurofibroma tumours in NF1 are slow growing, so tracking patients in the phase 2 study will continue and George confirmed that AstraZeneca research is also probing selumetinib’s ability to tackle adult cancers and NF1-related conditions.

AstraZeneca is on a roll with regulatory approvals pouring in from its 150+ clinical trial programmes, with heightened productivity in its oncology sector. Its performance and long-term promise continues to impress the markets.

“I’ve been at AZ for 23 years and have seen a lot of change, but the values we have now are very strong,” added George. “One of our key values is following the science and I think selumetinib is a great example of us living those values.”