Koselugo: The First Non-Surgical Alternative for Rare Plexiform Neurofibroma

George Kirk

AstraZeneca Global Product Lead, Oncology R&D, George Kirk/Photo Courtesy of AstraZeneca. 

Painful. Debilitating. Disfiguring. Neurofibromatosis type I (NF1) is a rare, genetic condition impacting 1 in 3,000 people worldwide. It causes disfiguring tumors, motor dysfunction, vision problems, and can steal between eight and 15 years from sufferers. Recently, a novel treatment by AstraZeneca and Merck & Co. (MSD outside of the U.S. and Canada) became the first medicine approved for the disease in the European Union (EU).   

Koselugo (selumetinib), a kinase inhibitor, was approved in the U.S. in April 2020, and in Europe on June 22nd after demonstrating the ability to shrink the plexiform neurofibromas (PN), which can greatly reduce pain and increase quality of life for patients.

More specifically, Koselugo is designed to potentially inhibit the mitogen-activated protein kinases (MEK1 and MEK2), in the RAS/MAPK pathway, a cell signaling pathway associated with cancer cell growth and proliferation in a number of different tumor types.

People with a normally functioning NF1 gene receive an adequate amount of neurofibromin, which turns RAS down. Those born with a malfunctioning gene do not have this good fortune and have a 50/50 risk of developing PNs.

Koselugo gained its most recent EU approval on the strength of the companies’ phase II SPRINT Stratum 1 trial, where the drug reduced the size of inoperable tumors in 66% of children and showed clinically meaningful improvements in the associated symptoms, such as pain.

“It gives [patients] an option for treatment where they don’t have any options whatsoever apart from, for the lucky children, potentially surgery, but that's very few and far between,” said George Kirk, AstraZeneca Global Product Lead, Oncology R&D. “Surgery on these children is very difficult because of the location and vascularity of the tumor. When you do the surgery, you get a lot of bleeding and it's not possible to completely remove the tumor.”

Kirk described one young boy involved in the clinical trial who suffered from plexiform neurofibromas on both his neck and arms.

“After about six months of treatment with Koselugo, the tumor shrank and he was able to move his arm up and down without pain. When the investigator said, well what difference does it make, he said ‘I can swing on the monkey bars,’ because he hasn't done that for a long, long time,” Kirk said. “That's the benefit. It's really quality of life for these children. They can live a more normal life.”

Notably, Koselugo was studied in pediatric populations first, a reversal of the typical development path taken by the majority of drugs. 

“Plexiform neurofibromas show the biggest growth potential in young children, whereas growth seems to slow down in adolescence into early adulthood,” explained Dr. Thorsten Rosenbaum, head of the Department of Pediatric and Adolescent Medicine at Sana Hospital Duisburg in Germany. “The studies I’m referring to show that it is very unlikely that the plexiform neurofibroma will grow by more than 20% after the age of 18. These data provide the rationale for why it makes sense to focus on kids first.”

As a condition of the European approval, AstraZeneca and Merck (MSD) will provide safety and efficacy data from the SPRINT trial with longer follow-up. Notably, the companies are also planning another form of dosing that would expand Koselugo’s benefit to even younger children. The current regimen is a capsule taken twice daily, which is undeniably difficult at a very young age.

“Some children struggle to swallow the capsule, particularly the young children. We’ve developed a formulation that is a granule in a capsule, so you can open the capsule and you can sprinkle the formulation onto foods, onto drinks, etcetera. It's much more child-friendly,” Kirk explained.

This granular formulation also has the potential to stop the tumor in its tracks right when it begins to grow.

“If you're able to dose some children when they're younger, you may prevent the tumor from ever growing to such a large volume it becomes debilitating. That’s the exciting part about having the granular formulation. Can you treat these children when the tumor starts to grow, so you stop it growing to a point where it becomes disfiguring and debilitating?” Kirk said.

AstraZeneca and Merck (MSD) are also currently conducting a study of Koselugo in adult patients. Plexiform neurofibromas may be very small at their onset, and therefore not detected, or not problematic until adulthood. In another scenario, patients have been living with pain their entire lives. 

“The adult population who have this disease suffer in a slightly different way, because they've been living with these tumors since they were young and they’ve suffered a lot of pain,” Kirk said. “In the adults, that's a primary morbidity, and one of the endpoints we're looking at in that study is improvement in pain.”

While most NF1 PNs are benign, there is a small percentage of patients – 8-13% - whose tumors transform into malignant peripheral nerve sheath tumors (MPNSTs). AstraZeneca is working on collaborative studies looking at combining Koselugo with other drugs to address this patient population.   

Rosenbaum sees the possibility of even greater potential for Koselugo.

“Koselugo aims at the molecular pathway underlying plexiform neurofibroma formation, but this module is also responsible for many other aspects of the disease. So it might well be that Koselugo has much more potential beyond plexiform neurofibromas,” he said.

In one study, AstraZeneca and Merck (MSD) are collaborating with the Children’s Oncology Group and the University of Birmingham to tackle another tumor driven by the NF1 pathway: low-grade glioma.

“This is a tumor that can be malignant, and primarily it’s a brain tumor that tends to sit just behind the eyes and can cause loss of vision,” Kirk said.

The study has been active for 12 months, and while collaborators have already seen tumor shrinkage in a small phase II study, actual data is still 4-5 years away.

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