The Children’s Tumor Foundation (CTF) has entered a new phase in its strategic NF research model by announcing a significant impact investment in a Phase 2b clinical trial at NFlection Therapeutics, a biotechnology company focused on the discovery and development of effective, targeted therapies for rare disorders.

The trial involves NFX-179, a MEK inhibitor which is showing promise in shrinking cutaneous neurofibromas in NF1 patients, is a topical treatment which has successfully passed a Phase 1/2a trial.

The current intervetional, randomized, double-blind, vehicle-controlled, parallel group Phase 2 dose-response study, is expected to enroll 168 patients and will more rigorously test the drug’s safety and effectiveness.

The NFX-179 treatment is for cutaneous neurofibromas (cNF), which are tumors that grow in the skin or right underneath the skin, and result in severe, disfiguring bumps on the skin. The vast majority of NF1 patients have cNF that are responsible for significant negative effects on the quality of life, including pain, itching, and emotional / appearance concerns as a result of bullying or discrimination.

NFX-179 is a topical, metabolically labile, MEK inhibitor, which is the same mechanism used in selumetinib (Koselugo®; AstraZeneca and Merck & Co), which has previously received FDA and EMA approval for inoperable plexiform neurofibromas. Selumetinib is an oral drug that has systemic impact on the body and was approved by the U.S. Food and Drug Administration (FDA) for use in patients with inoperable plexiform neurofibromas, a common manifestation in the disease neurofibromatosis type one (NF1).

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Efficacy of selumetinib was investigated in SPRINT (NCT01362803), a National Cancer Institute (NCI) sponsored, open-label, multicenter, single-arm trial in pediatric patients with NF1 and a measurable target PN that could not be surgically removed without risk of substantial morbidity. [1]

Patients in the efficacy population (N=50) were also required to have at least one significant morbidity related to the target PN. Morbidities present in ≥20% of patients included disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment, and bladder/bowel dysfunction. Patients received selumetinib 25 mg/m2 orally twice a day until disease progression or unacceptable toxicity.

The primary efficacy outcome measure was overall response rate (ORR) as assessed by NCI and defined as the percentage of patients who experienced ≥20% reduction in tumor volume on Magnetic Resonance Imaging (MRI) confirmed on a subsequent MRI within 3-6 months. The ORR was 66% (n=33; 95% CI: 51,79). All patients had a partial response, and 82% of responders had sustained responses lasting at least 12 months. An independent central review of ORR was performed using the same response criteria and demonstrated an ORR of 44% (95% CI: 30,59).

The primary safety data were from 74 pediatric patients with NF1 and PN who received selumetinib during SPRINT. The most common adverse reactions (≥40% of patients) were vomiting, rash, abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, fever, acne, stomatitis, headache, paronychia, and pruritus.

CTF was an early-stage funder of both animal and in-human studies that led to the discovery that MEK has the potential to shrink tumors.

‘Soft’ topical inhibitor
This new use of MEK as a ‘soft’ topical inhibitor designed specifically for cutaneous neurofibromas is to impact locally while minimizing side effects. There is a high unmet need for this treatment. CTF is making a landmark impact investment in these next phase topical studies to help accelerate the development of this promising treatment, which should it prove successful, means more quickly delivering important life-changing treatments to patients.

CTF’s investment strategy in NF drug development is a diversified portfolio approach to tackling all forms of NF, from early-stage investments in young investigators to established academic initiatives in the Discovery Fund, to large-scale, open data collaboratives such as Synodos. CTF has operated as a strategic partner to all stakeholders who can help bring effective treatments to the patients. This first-in-its-history impact investment further establishes CTF as a co-investor with pharma/biotech in innovative NF research, expanding opportunities to increase the NF drug development pipeline.

“We’re thrilled to be working with NFlection on this incredible opportunity to bring life-changing treatments to NF patients,” said Annette Bakker, President of the Children’s Tumor Foundation.

Seed funder
“CTF is mainly known as a seed funder, willing to take risk, and willing to put a lot of sweat equity to advance the science and the treatments. With our recent investments in science and pharma, we are sending a clear message that if we want to accelerate treatments, NF deserves serious funding. With the tremendous support of the CTF Board of Directors and the CTF Business Advisory Council, we are ready to demonstrate ‘skin-in-the-game’. This will hopefully increase confidence for others to invest in NF. NF research provides good return, both as a research investment for pharma and biotech, and most importantly, the ultimate return of better lives for the millions affected who are waiting for our help.”

“We’re thankful to the Children’s Tumor Foundation for this investment in our work,” said William Hodder, CEO of NFlection Therapeutics.

“We believe – with good reason, based on our previous results – that this treatment has the potential to help so many. We’re also grateful for the connectivity CTF brings with this partnership to NF patients, clinics, and experts. It is known from other disease foundations that investments from medical research foundations like CTF may convince other investors that supporting NFlection is the right path forward,” Hodder added.

Genetic disorder
Neurofibromas are a group of genetic disorders known as neurofibromatosis or schwannomatosis. It affects 1 in 3,000 births of all populations (about 2.5 million worldwide), and can cause deafness, blindness, bone abnormalities, disabling pain, learning disabilities, and cancer.

Over the past decade, CTF has worked to grow the NF field, which in addition to expanding partnerships with academic researchers, public/government researchers and funders, now has a growing number of pharma/biotech companies in the space. In addition to NFlection, they include Alexion/AstraZeneca, Takeda, SpringWorks, Novartis, Vivace, Pfizer, Healx, and NF2 Therapeutics, just to name a few.

“The evolution of NF research has come so far in recent years, thanks in large part to the herculean efforts of the Children’s Tumor Foundation. With this investment, we are taking the first step in our new approach to ending NF,” said Gabriel Groisman, Chairman of CTF’s Board of Directors.

“The Foundation’s Board of Directors and the Business Advisory Council have made the bold decision that it’s time to start directly investing in select impact opportunities in the private sector that have the potential of bringing relief to NF patients as quickly as possible. Pharma and biotech can now look to CTF as a true partner, not just for knowledge and access to stakeholders, but also as a strategic investor. We at CTF are all in to find treatments and ultimately a cure for NF,” Groisman Concluded.

Clinical trials
NFX-179 Topical Gel Treatment for Adults With Neurofibromatosis 1 (NF1) and Cutaneous Neurofibromas (cNF) – NCT05005845
AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors – NCT01362803

Highlights of Prescribing Information
Selumetinib (Koselugo®; AstraZeneca and Merck & Co)[Prescribing Information]

[1] SPRINT: Phase II study of the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN). DOI: 10.1200/JCO.2018.36.15_suppl.10503 Journal of Clinical Oncology 36, no. 15_suppl (May 20, 2018) 10503-10503.
[2] Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med. 2020 Apr 9;382(15):1430-1442. doi: 10.1056/NEJMoa1912735. Epub 2020 Mar 18. Erratum in: N Engl J Med. 2020 Sep 24;383(13):1290. PMID: 32187457; PMCID: PMC7305659.

Featured image by National Cancer Institute on Unsplash

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