Delivering on the Vision of Bench to Bedside: A Rare Disease Funding Community Collaboration to Develop Effective Therapies for Neurofibromatosis Type 1 Tumors

The time from target identification to new drug approval is often measured in decades. This can be even more challenging for rare diseases. Indeed, 95% of rare diseases do not have a specific therapy approved. Coordinated efforts to support research along the drug development pipeline can provide long term and comprehensive support to enable scientific breakthroughs for rare diseases. However, this requires coordination across multiple stakeholders. The present article analyzes the funding efforts of four major federal and philanthropic organizations to accelerate the advancement of MEK inhibitors to human clinical trials for NF1-associated tumors.


Introduction
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic syndrome caused by mutations in the NF1 gene (Gutmann, et al. 2017). Development of multiple tumors, including plexiform neurofibromas (pNF) and gliomas, are hallmarks of NF1. There are multiple additional manifestations and the clinical severity of NF1 is highly variable, with significant differences even within families sharing a mutation. NF1 patients are also at increased risk of developing malignancies such as malignant peripheral nerve sheath tumors (MPNST) and breast cancer (Frayling, et al. 2018). Despite their significant morbidity, therapeutic development for NF1 has been slow and challenging because of an incomplete understanding of the disease biology. Although surgical debulking is the preferred treatment option for pNFs, it can be extremely complicated, especially if the tumor is intricately involved with nerve tissue, vasculature, or a vital organ. Surgery is rarely performed for NF1 optic pathway gliomas because of their location. Symptomatic gliomas are typically managed with chemotherapeutic agents, which, though effective, are associated with long term sequelae such as cognitive dysfunction (de Blank, Berman and Fisher 2016). Thus, an effective long-term therapy for NF1 associated tumors is an unmet medical need.
The NF1 protein product, neurofibromin, negatively regulates Ras signal transduction pathways. Several preclinical studies validated mitogen-activated protein kinase (MEK), a component of the Ras-Raf-MEK-ERK signaling cascade, as a potential therapeutic target for NF1 tumors and other manifestations. At least four MEK inhibitors, PD0325901, trametinib (GSK1120212, Mekinist), binimetinib (ARRY-438162, MEK162), and selumetinib (AZD6244), have progressed to clinical trials in NF1 patients and, at the time of writing, ClinicalTrials.gov lists 19 trials where these MEK inhibitors are being evaluated for various manifestations of NF1 (Table 1). In fact, selumetinib was granted Orphan Drug Designation by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) based on encouraging results in pediatric NF1 patients with inoperable pNFs (Dombi, et al. 2016). If approved, selumetinib will be the first drug available for the treatment of NF1-associated tumors. The funding landscape of NF1-MEK research, and of NF1 research as a whole, has been shaped by the efforts of multiple federal and philanthropic organizations. In addition to the National Institutes of Health (NIH, intramural and extramural), the organizations and research programs that have played a crucial role in advancing NF1-MEK research include the Department of Defense (DoD) Congressionally Directed Medical Research Programs (CDMRP), Children's Tumor Foundation (CTF), and Neurofibromatosis Therapeutic Acceleration Program (NTAP) at Johns Hopkins University. This report presents a retrospective analysis of the NF1-MEK funding data for the years 2006-2017 including, but not limited to, funding from the above mentioned organizations. Through this analysis, the authors illustrate how the contributions across the funders during the past 10 years have made the availability of a drug for NF1 tumors a plausible reality.

Methods
To extract all available NF1-MEK funding data, Dimensions for Funders (https://www.dimensions.ai/), a database of publicly and privately funded research projects worldwide, was used. The database was queried using an intersect of two queries that were each specific for MEK inhibitor-related and NF1-related grants. The search was restricted to 2006-2017 to ensure completeness of data among the relevant funders. Results from this search were supplemented using iSearch, a portfolio analysis tool internal to NIH, and Research, Condition, and Disease Categorization (RCDC), a classification scheme used by the NIH for reporting (NIH, 1998) (NIH, 2011). The RCDC classification scheme has had a neurofibromatosis category that includes NF1, NF2, and schwannomatosis since 2008.
As a result, there was no neurofibromatosis category data from 2006-2008 available for this analysis. iSearch was used to query the neurofibromatosis RCDC category. The integrated output across datasets was manually inspected for relevance to MEK inhibitor development to treat NF1, yielding a final

Results
We identified a total of 99 NF1-MEK grants for 2006-2017 with an aggregate funding of $102.42 million. Of these, 86 grants totaling $100.7 million were funded by the NIH, CDMRP, CTF, and NTAP, making these four organizations the largest funders in this area. The remaining 13 grants for a total of $1.7 million were awarded by four organizations: the Japan Society for the Promotion of Science, Melanoma Research Alliance, St. Baldrick's Foundation, and National Natural Science Foundation of China. 1 In addition to funding several basic research studies in NF1, the NCI has conducted or funded many of the MEK clinical trials, including the first clinical trial to evaluate a MEK inhibitor (CI-1040; NCT00033384 and NCT00034827), the first selumetinib trial (NCT01089101), five other selumetinib trials (NCT01362803, NCT02407405, NCT02839720, NCT03109301, NCT03213691), two other interventional trials (NCT03190915, NCT02465060), and an ongoing natural history study. The NINDS has primarily supported preclinical studies and a national, interdisciplinary center for NF research. NINDS-funded pre-clinical contributions include establishment of a murine model of NF1-related MPNSTs, development of preclinical screening tests to compare potential therapeutics in NF1 cell lines, and completion of proof-of-efficacy studies for PD0325901.

Neurofibromatosis Research Program (NFRP).
The NFRP at CDMRP was identified as the second largest federal contributor to NF1-MEK funding, having awarded approximately $35.4 million across 17 grants in 2006-2017. Nearly 89% of the dollar amount was directed towards clinical studies. Unlike the NIH, the NFRP allocates a congressionally appropriated budget each year for all forms of NF research. Through the NF Clinical Trials Consortium (NFCTC), the CDMRP has invested more than $27 million in developing all the infrastructure of the consortium and conducting 10 interventional trials, including two trials with MEK inhibitors in pNFs (PD0325901, NCT02096471) and Low-Grade Gliomas (binimetinib, NCT02285439). In addition to initiating clinical trials, the NFRP also funded eight Investigator-Initiated Research Awards ($7.2 million) and five Exploration -Hypothesis Development Awards ($726,504). Other funding mechanisms include the New Investigator Award to encourage non-NF investigators to conduct research in this area, and the Clinical Trial Award (1 award, $540,104).
Children's Tumor Foundation. The CTF was the leading non-federal philanthropic funder of NF1-MEK research in 2006-2017, during which time it awarded almost $6.2 million through 34 grants. As the oldest US-based philanthropic foundation dedicated to all forms of NF, CTF has historically acted as a discovery research seeder and gap funder through its funding mechanisms such as the Young Investigator Award, Drug Discovery Award, and Clinical Research Award. Of the 34 grants, 17 ($1.4 million) were Young Investigator Awards (YIA), ten ($371,123) were Drug Discovery Initiatives (DDI), five ($664,000) were Clinical Research Awards (CRA) and one ($159,500) was a Contract Award (CA). The CTF's Neurofibromatosis Preclinical Consortium (NFPC, funded from 2008-2013) awarded almost $3.4 million for preclinical studies, followed by the Neurofibromatosis Therapeutic Consortium (NFTC, funded conjointly with NTAP from 2013-2016) that continued funding for $3.6 million. During the 2008-2013 period, the two consortia conducted more than 95 preclinical studies of 38 drugs or drug combinations through collaborations with 18 pharmaceutical companies (Maertens, et al. 2017). Over 40 studies included a MEK inhibitor either as a single agent or in combination (unpublished results). These programs generated critical data in support of MEK as a valid target for NF1-driven tumors, providing the preclinical basis that justified the initiation of clinical trials (NCT02096471, NCT02124772, NCT02285439, NCT01362803, NCT02407405) with MEK inhibitors (Chang, et al. 2013) (Jessen, et al. 2013).
Neurofibromatosis Therapeutic Acceleration Program. The NTAP, although founded only in 2012, has emerged as the second largest non-federal non-profit funder of NF1-MEK research. Focused specifically on accelerating the development of therapeutics for pNF and cutaneous neurofibromas (cNF), since its inception NTAP has teamed up with CTF for the co-sponsoring of preclinical testing through the NFTC consortium. It has also invested over $3.7 million in MEK research, playing a critical role in facilitating the clinical evaluation of selumetinib in children with pNF (NCT02407405).

FIGURE 2: Timeline of NF1-MEK research awards by major funding organizations
Legend: Bubble size is proportional to the grant size and each grant is placed on the timeline based on its award date. The position of bubbles is jittered on the graph to facilitate visualization. Almost all grants are multi-year funding; for display purposes, the total amount is attributed to the initial year.

Discussion
The retrospective analysis of the MEK funding landscape of the past 10 years has shown that the critical NF funders (NIH, CDMRP, CTF, and NTAP) have played distinct and complementary roles in the success of developing a MEK inhibitor to treat NF1 associated tumors. While NIH and CDMRP have provided the bulk of research dollars across all stages of NF research, CTF has seed funded NF research with a stream of small grants in the basic and translational research area. At the same time, funding for over $7 million in preclinical studies (NFPC and NFTC) allowed researchers to gather essential information to start clinical studies. Specific funders, like NIH and NTAP, have catalyzed critical steps and funded or co-funded preclinical or clinical stage projects that were essential to both launch and complete MEK clinical trials in people with NF1. The NF1-MEK example illustrates the net outcome of the highly complementary approaches of the funding agencies and the yield of sustained funding investments across all stages of research. Overall, these programs and grants have enabled a MEK inhibitor to move along the drug discovery pipeline through clinical trials and to hopefully demonstrate its safety and effectiveness for patients in the near future.
The Dimension for Funders platform and similar platforms allow transparency in funding that allow stakeholders to coordinate efforts. This is particularly valuable in a rare disease community to maximize resources and ensure that follow on studies that are necessary to realize clinical benefit are pursued. Such integrated funding data also allows funders to identify gaps and overlaps in their investments so they work more effectively together to foster a community of researchers that has the tools and knowledge to advance NF research. As a next step, all NF funders are now collaborating on the largest data sharing effort ever initiated for NF. Spearheaded by CTF in 2014, all NF funders are now incentivizing their applicants to share their NF data openly on the recently launched NF data portal (www.nfdataportal.org). The portal is part of the largest NF Open Science Initiative (NF-OSI) to support the NF data discovery needs of computational biologists, bench scientists, clinicians, and the public. Participants in the NF-OSI benefit from early access to data and support for data sharing and re-use within the NF community.
Understanding the unique potential of each funding organization and leveraging each other's strengths will bring us close to the next big discovery.