Koselugo: The First Non-Surgical Various for Uncommon Plexiform Neurofibroma


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

Painful. Debilitating. Humiliating. Neurofibromatosis type I (NF1) is a rare genetic disorder that affects 1 in 3,000 people worldwide. It causes disfiguring tumors, Engine- Functional disorders, visual disturbances and can steal from those affected between eight and 15 years of age. Recently a novel treatment for AstraZeneca and Merck & Co. (MSD outside of the US and Canada) became the first drug approved for the disease in the European Union (EU).

Koselugo (selumetinib), a kinase inhibitor, was approved in the USA in April 2020 and in Europe further June 22 after demonstrating the ability to shrink plexiform neurofibromas (PN), which can greatly reduce pain and improve patients’ quality of life.

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

People with a normally functioning NF1 gene receive adequate amounts of neurofibromine, which reduces RAS. Those born with a faulty gene are unfortunate enough to have a 50/50 risk of developing PNs.

Koselugo received its most recent EU approval from the company’s Phase II SPRINT Stratum 1 study, in which the drug reduced the size of inoperable tumors in 66% of children and showed clinically meaningful improvements in associated symptoms such as pain.

“There are [patients] a treatment option where they have no options, except for the happy children, possibly surgery, but that is very few, ”said George Kirk, AstraZeneca Global Product Lead, Oncology R&D. “These children are very difficult to operate because of the location and vascularity of the tumor. During the operation there is profuse bleeding and it is not possible to completely remove the tumor. “

Kirk described a young boy who was involved in the clinical trial who suffered from plexiform neurofibromas on the 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 the difference it makes, he said, ‘I can swing on the monkey bars’ because he hasn’t done it in a long time, ”said Kirk. “That’s the advantage. It really is quality of life for these children. You can lead a more normal life. “

Notably, Koselugo was first studied in pediatric populations, a reversal of the typical evolutionary path of most drugs.

“Plexiform neurofibromas show the greatest potential for growth in young children, while growth seems to slow down in adolescence and into early adulthood,” explains Dr. Thorsten Rosenbaum, Head of the Clinic for Child and Adolescent Medicine at the Sana Clinic in Duisburg. “The studies I am referring to show that it is very unlikely that the plexiform neurofibroma will grow more than 20% after the age of 18. These data provide the rationale for why it makes sense to focus on children first. “

As a condition for European approval, AstraZeneca and Merck (MSD) will provide safety and efficacy data from the SPRINT study with a longer follow-up period. In particular, the companies are also planning a different dosage form designed to extend the benefits of Koselugo to even younger children. The current regimen is to take one capsule twice a day, which is undeniably difficult at a very young age.

“Some children have difficulty swallowing the capsule, especially young children. We created a formulation that is granules in a capsule so you can open the capsule and sprinkle the formulation on food, drink, etc. It’s much more kid-friendly, ”Kirk explained.

This granular formulation also has the potential to directly stop the tumor as it begins to grow.

“If you are able to dose some children when they are younger, you can prevent the tumor from ever growing to such a large volume that it becomes weak. That’s the exciting thing about the granular formulation. If the tumor begins to grow, can you treat these children to stop it from growing to the point where it becomes disfiguring and debilitating? ”Said Kirk.

AstraZeneca and Merck (MSD) are also currently conducting a study of Koselugo in adult patients. Plexiform neurofibromas can be very small to begin with and therefore go undetected or problematic by adulthood. In another scenario, patients live with pain all their lives.

“The adult population with this disease suffers slightly differently because they have lived with these tumors since they were young and in a lot of pain,” said Kirk. “In adults, this is a primary morbidity and one of the endpoints we are investigating in this study is improvement in pain.”

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

Rosenbaum sees even more potential for Koselugo.

“Koselugo targets the molecular pathway that underlies the formation of plexiform neurofibromas, but this module is also responsible for many other aspects of the disease. So it could well be that Koselugo has a lot more potential beyond plexiform neurofibromas, ”he said.

AstraZeneca and Merck (MSD) are working with the Pediatric Oncology Group and the Birmingham University to fight another tumor that is powered 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 lead to vision loss,” said Kirk.

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


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