Koselugo (selumetinib) is the first drug indicated for the treatment of children as young as 2 years old with neurofibromatosis type 1. The disease must be symptomatic and characterized by inoperable plexiform neurofibromas.

Koselugo, offered by AstraZeneca, is approved by the U.S. Food and Drug Administration (FDA) in April 2020.

Before Koselugo, there was no specific pharmacological treatment for neurofibromatosis type 1.

Koselugo’s list price is $12,500 per month for an average American patient, although doses vary by weight.

Koselugo was approved by the European Medicines Agency (EMA) in July 2021: selumetinib is indicated for the treatment of symptomatic, inoperable plexiform neurofibromas in paediatric patients with neurofibromatosis type 1 aged 3 years and above.

Koselugo (selumetinib).


What is Neurofibromatosis Type 1

There are three clinically and genetically different forms of neurofibromatosis: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis.

The most common (1 case per 2,500-3,000 people) is neurofibromatosis type 1, also known as von Recklinghausen’s disease, or peripheral neurofibromatosis.

Distinctive features of neurofibromatosis type 1 include (in order of clinical manifestation): skin hyperpigmentation lesions (so-called café-au-lait macules), axillary and/or inguinal freckles, Lisch nodules (iris hamartomas), benign soft tumors on the skin and under the skin (cutaneous neurofibromas).

Neurofibromatosis type 1 is a complex multisystem disease caused by an autosomal dominant mutation in the NF1 gene encoding the neurofibromin.

Neurofibromin, a member of the GTPase-activating protein family, is responsible for negatively regulating the activity of the RAS/MAPK signaling pathway by accelerating the hydrolysis of Ras-bound guanosine triphosphate (GTP). Genetic breakdown impairs control of cell growth and neuronal development.

In 30–50% of cases of neurofibromatosis type 1, plexiform neurofibromas, which are tumors from the nerve sheaths, develop. They can lead to disfigurement, motor problems, pain syndrome, breathing difficulties, visual disturbances, and bladder and bowel dysfunction. Plexiform neurofibromas, usually manifesting in early childhood and with varying degrees of severity, can shorten life expectancy by as much as 15 years.

Long-term care for patients with neurofibromatosis type 1 is aimed at early detection and symptomatic treatment of complications as they occur. In the medical care of children with neurofibromatosis type 1, the frequency of visits to medical facilities should be increased to address complications as they occur. The decision to perform diagnostic tests depends on the history and physical signs. Clinical evaluation appears to be more useful in detecting complications than screening studies in asymptomatic patients.

The treatment approach for various tumors associated with neurofibromatosis type 1 depends on the type of tumor, its impact on neighboring tissues, and its associated complications. Surgical treatment and pain management of plexiform neurofibromas can be challenging. Surgical resection is often limited to cytoreduction of a specific area of a large lesion.

Neurological disorders in neurofibromatosis type 1 that may require specific treatment are cognitive impairment, attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, learning disabilities, seizures, and peripheral neuropathy.

Prolonged bone dysplasia and scoliosis in neurofibromatosis type 1 may require orthopedic intervention. Other bone abnormalities, such as osteoporosis, may not respond to typical treatments.


Koselugo: Efficacy of Selumetinib in Treatment of Neurofibromatosis Type 1

The SPRINT (NCT01362803) phase II clinical trial (non-randomized, open-label, multicenter) enrolled patients (n=50) of pediatric age (median age 10.2 years; 3.5–17.4) with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN).

Inoperability was defined as the inability to completely resect the PN without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN.

Participants’ disease had to be characterized by a severe course, including disfigurement, motor dysfunction, pain, respiratory dysfunction, visual impairment, bladder and/or bowel dysfunction.

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The primary endpoint was stated as the overall response rate (ORR) which was meant the proportion of patients with complete response (disappearance of the target PN) or a confirmed partial response (at least a 20% reduction in PN volume registered during the evaluation within 3–6 months). Target PN (plexiform neurofibroma that caused relevant clinical symptoms or complications) was assessed volumetrically on MRI.

The results of treatment of neurofibromatosis type 1 with Koselugo were as follows:

  • Partial response (PR) was demonstrated in 74% of patients (n=37/50; 95% CI: 60–85) and confirmed partial response (cPR) in 70% (n=35/50). Meanwhile, 56% of participants (n=28/50) showed a prolonged response, one that lasted approximately one year.
  • The median time to first response was 8 months (4–20) and the median time to best response was 16 months (4–36).
  • The median change in target neurofibroma volumes at the best response was −27.9% (−55.1% — +2.2%).
  • The median duration of response (DoR) and median progression-free survival (PFS) has not yet been achieved. At the same time, the PFS at 3 years was fair for 84% of patients.


Koselugo: Safety of Treatment of Neurofibromatosis Type 1 With Selumetinib

Among the most common toxic effects of Koselugo administration: gastrointestinal symptoms (nausea, vomiting, diarrhea), asymptomatic elevation of creatine phosphokinase, acne, and paronychia.

28% of patients (n=14/50) had to reduce the dose of selumetinib because of adverse events, while 5 of these patients interrupted treatment at some point because of the severity of adverse events possibly caused by the drug.


Koselugo: Mechanism of Action of Selumetinib

Selumetinib is an oral low-molecular-weight ATP-independent inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). MEK1 and MEK2 proteins, which are essential for activation of the RAS/RAF/MEK/ERK signaling pathway, often exhibit increased activity that results in, among other things, cell proliferation. Suppression of MEK1/MEK2 leads to inhibition of ERK phosphorylation, resulting in a decrease in the number of neurofibromas and their volume and inhibition of cell proliferation.

Selumetinib was developed by Array BioPharma, now owned by Pfizer, which bought it in July 2019 for $11.4 billion, thereby gaining access to a decent set of anticancer drugs, both already commercialized and under registration. In 2013, Array licensed selumetinib to AstraZeneca, which in turn agreed with Merck & Co. in 2017 to jointly develop and commercialize this therapeutic molecule.


Koselugo: Importance and Value of Selumetinib for Patients

AstraZeneca has highlighted the rationale for treating neurofibromatosis type 1 with Koselugo. To this end, a direct and age-adjusted comparison was made of the clinical outcomes provided by selumetinib with those seen in the natural history of the disease, hitherto devoid of any specific therapy.

Thus, patient data (n=93) collected in clinical study NCT00924196, which examined the natural history of neurofibromatosis type 1, showed that the median change in tumor volume was +76.5% (−39.6% — +1428.7%) over a median follow-up period of 6.8 years (1.0–17.1). At the same time, 76% of patients (n=71/93) had a minimum of 20% tumor growth over the entire follow-up period, whereas 43% (n=40/93) had a minimum of 20% annually. None of the patients demonstrated a decrease in tumor volumes of at least 20% per year.

The spider diagram illustrates the difference in the growth of plexiform neurofibromas in neurofibromatosis type 1. Patients who received Koselugo (selumetinib) are marked in red; untreated patients are marked in blue.

In contrast, selumetinib administration (n=48) resulted in a median change in neurofibroma volume of −22.6% (−55.1% — +30.4%) over a median period of 2.8 years (0–3.2). None of the patients who received Koselugo showed tumor growth greater than 20% per year (−27.0% — +19.8%).

And while in the natural history of neurofibromatosis type 1, the progression-free survival rate was 1.3 years (95% CI: 1.1–1.6), this rate during selumetinib treatment was still not mature as only 12% of patients (n=6/50) experienced disease progression during the 3.2-year follow-up period.

Example of the effectiveness of neurofibromatosis 1 therapy. A plexiform neurofibroma on the neck of a 10-year-old boy decreased in volume by one-third over 12 months with Koselugo (selumetinib) treatment.

Administration of Koselugo to patients with neurofibromatosis type 1 resulted in significant improvements in important patient outcomes related to pain, motor dysfunction, airway impairment, and overall quality of life.

The same boy. Two pictures were taken five years apart most clearly confirm the therapeutic efficacy of Koselugo (selumetinib) for the treatment of neurofibromatosis type 1.


Selumetinib: What’s Next

Selumetinib is being studied in the treatment of various cancer diseases: together with Tagrisso (osimertinib), EGFR inhibitor, for EGFR-mutant non-small cell lung cancer (NSCLC), in comparison with standard chemotherapy for glioma, in combination with Imfinzi (durvalumab), PD-L1 blocker, for solid tumors.

Previously, selumetinib failed three phase 3 clinical trials in the treatment of uveal melanoma, KRAS-mutant NSCLC, and thyroid cancer.

Meanwhile, biotech startup NFlection Therapeutics is dealing with NFX-179, an experimental highly selective MEK inhibitor implemented in a gel formulation. Rather than oral administration accompanied by toxicity, it is said to be optimal to apply the MEK inhibitor to the skin at the site of neurofibromas in neurofibromatosis type 1. NFX-179 is a metabolically labile “soft drug” that rapidly broken down in the bloodstream and therefore does not result in significant adverse systemic MEK suppression effects.



Koselugo (selumetinib). Prescribing information. US. [PDF]

Koselugo (selumetinib). Prescribing information. Europe. [PDF]

Koselugo (selumetinib). FDA CDER. Multi-disciplinary review and evaluation. [PDF]

Koselugo (selumetinib). European public assessment report (EPAR). [PDF]

Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med. 2020 Apr 9; 382(15): 1430–1442. [source]

Neurofibromatosis in the era of precision medicine: development of MEK inhibitors and recent successes with selumetinib. Curr Oncol Rep. 2021 Mar 15;23(4):45. [source]

FDA approval summary: selumetinib for plexiform neurofibroma. Clin Cancer Res. 2021 Mar 12. [source]

Selumetinib: the first ever approved drug for neurofibromatosis-1 related inoperable plexiform neurofibroma. Curr Med Res Opin. 2021 Mar 23;1-6. [source]

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Tanya von Reuss

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