Towards the Realization of a Dream: Ending the Rare Disease Neurofibromatosa, a Conversation with the Children’s Tumor Foundation’s President Annette Bakker, Ph.D.

Innovation That Matters
Children’s Tumor Foundation

By Rich Soll (Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx).

The mission of the Children’s Tumor Foundation (CTF) reads “drive research, expand knowledge, and advance care for the neurofibromatosis (NF) community.”  Sounds simple, yet despite disease complexity, this research-oriented foundation is making substantial progress towards its mission. The foundation was formed in 1978 with a focus on patient advocacy and education. However, it was not until the 1990’s that the neurofibromatosis genes were discovered – some of the biggest discoveries at the time were made by Francis Collins, Ray White, Jim Gusella and others. More strikingly, it has been nearly 30 years since those initial discoveries, and only now are we seeing effective therapies emerging.

NF is actually a collection of 3 rare diseases. The physical manifestations of all three forms of NF are highly variable and progressive, but how the disorder progress is very unpredictable and diverse.

NF1 prevalence is about 1 in 2,500 making it the largest of the three.  NF1 is a loss of function induced by mutation of the NF1 gene, found on chromosome 17, encoding the GTPase neurofibromin, leading to either dysfunctional or loss of NF1, which in turn causes hyperactivation of the RAS signaling pathway.  Individuals with NF1 have a predisposition to benign and malignant tumor formation on nerves, patients also suffer from learning disabilities and bone deformation and about 10% of the benign tumors become highly malignant.

The NF2 gene, located on chromosome 22, encodes for the cytoskeletal as well as a signaling protein called merlin or schwannomin. The protein is made in the nervous system, particularly in Schwann cells, and acts a tumor suppressor.  Mutations of the NF2 gene cause NF2, a condition characterized by tumors of the nervous system including bilateral benign tumors in the nerve sheath of the auditory-vestibular nerve, resulting in hearing loss, meningioma, ependymoma, neuropathic pain and cataract leading to visual problems. NF2 affects 1 in 25,000 individuals. There are no therapies to address this cell function other than surgical removal of the tumors and treatment of the eye lesions.  Patients suffer from deafness, blindness, brain tumors and neuropathy.

Schwannomatosis affects 1 in 40,000.  Benign tumors grows on spinal and peripheral nerves causing severe, debilitating pain and neurological dysfunction. Loss of the genes SMARCB1 (also called INI1), and LZTR1 together with loss of NF2 appear to be causative to tumor development. The pain associated with Schwannomatosis is so intense, patients cannot get out of bed. Currently, there are no therapeutic options.

In all NF patients, the tumors are so highly vascularized, bleeding is a real problem in surgery.  Further, the tumors are so intertwined with the nerves, that upon tumor removal, the functionality of the zone where the tumor was located is removed.

I had an opportunity to talk to the president of CTF, Annette Bakker about CTF, the patient’s journeys and what future prospects there might be for those affected with NF.

“Over the last several years, we have seen significant interest in finding therapies for NF as measured by the increase in the number of clinical trials; we’ve more than tripled the number of clinical trials over the last five years,” commented Annette, “this is remarkable because for our stakeholders, the NF patients, there is now hope.”

AstraZeneca’s MEK inhibitor selumetinib achieved breakthrough therapy designation with the regulators earlier this year (April 2019) and is currently at the registration phase.  In clinical phase 2 trials, the drug demonstrated for the first time that 70% of the patients, children ages 2 -18 suffering from inoperable plexiform neurofibromas, experienced greater than 20% reductions of these large tumors, some up to 52% reduction in size.

“The encouraging results seen with selumetinib have stimulated a number of clinical trials,” exclaimed Bakker, “in the order of 7-8 MEK inhibitors in clinical trials currently.”

“For NF2, the anti-angiogenic oncology drug Avastin is used, but long-term exposure results in some pretty-nasty side effects, including kidney toxicity, and for girls, early menopause has been observed. Also because of the mechanism of Avastin, wound healing problems have been observed,” stated Bakker, “so the drug does work but at a price; it’s not fantastic.”

Combination therapies using drugs repurposed from oncology may become a central opportunity in the cases of NF1 and NF2” noted Bakker. “Getting the right medication and finding the regimen at the right moment is so important with the pediatric population. When I see a little kid with a little bump above his eye, I ask myself if this kid’s going to get highly disfigured or will it stay a little bump.  We do not have enough information to know if we should treat these tumors from growing bigger.”

Information is critically important to CTF.  The foundation has been incentivizing the research community to share their data by providing funding at Sage Bionetworks, for bioinformaticians, and computer biologists, to integrate the data and effect transformation of information to knowledge.

Additionally, CTF is advancing care with initiatives such as the clinical network where people have an opportunity to speak to a research nurse on the CTF staff who can really help them understand their care and guide them to the best doctor that is out there. Educational brochures and patient engagement amongst other materials are designed to turn the patients into advocates for themselves and their families.

How has the foundation evolved over time?  From a patient support organization to the present where the organization funds peer review grants on specific targets of interest.  “We play a pretty unique role in the R&D ecosystem supporting disruptive technology, discovery and preclinical development to clinic,” emphasized Bakker, “our organization is here to not just to fund new discoveries, but to empower the critical work that guarantees that awesome discoveries are turned more quickly into effective treatments. We like good publications, sure, but we like even more to see patients that are not suffering from NF anymore.”

CTF plays three main roles:

  1. Be the global connector to all stakeholders
  2. Build and manage Synodos
  3. Help to de-risk NF assets for pharma and biotech

On a global scale, the CTF platform is connected to the patient groups; to Pharma and biotech; to the academic community as a funder and convener; to the patients as educators; and to the government through the FDA, EMA and on the Hill to lobby for NF research.

One of the more powerful platforms created by CTF is called Synodos, a network of academic researchers and patients working collaboratively on end-to-end initiatives (from drug discovery to clinical testing). All data is shared – right from the start, not after publication.  Along those lines, the data is entered into a portal managed by the foundation; using integrators, the data becomes richer and richer.  Indeed, for NF2, a comprehensive drug discovery & development pipeline was built within the Synodos for the NF2 project.  Novel NF2 clinical trial candidates were recently identified using drug repurposing and this paradigm.  “Within three years of setting up the Synodos, we delivered two clinical candidates, developed new animal models, generated a lot of data points of value to drug discovery, and brought people of various disciplines together,” exclaimed Bakker.  “This has been transformational for the NF community.”

Pharma and biotech alike are tapping into CTF’s resources.  When asked why this was happening, Bakker replied “we educate, we give them broad resources; we take the risks; we help to de-risk potential drugs and to help develop target product profiles.  We provide a mechanism for them to learn about neurofibromatosis.”

What have been some of the key milestones for CTF?  “We were the “seed funders” of the demonstration that MEK inhibition led to the shrinkage of plexiform neurofibromas in animal models,” noted Bakker, “Synodos for the discovery of NF2 clinical trial ready inhibitors is yet another milestone.  Along the way, we’ve created patient registries, collected patient samples, and more recently engaged the FDA in a very positive way in one of the FDA listening sessions where five of our patients told their stories about what it means to live with NF.”

As a result of these recent milestones, CTF now works with multiple companies, has close ties with AstraZeneca and Takeda, partnerships with a couple of Pharma, and was involved in the spinout of SpringWorks from Pfizer.

But what challenges does the organization see? “Education, to overcome the lack of awareness of NF and the innovative approach CTF is taking to tackle it, these are the most pressing challenges globally, but also a great opportunity,” remarked Bakker, “being a rare disease, most people have never heard of NF, so our first goal is to improve and to enhance visibility, and to educate the people about NF and CTF.”

“Towards that goal, WuXi AppTec’s partnership with CTF has made substantial contributions to raising awareness for NF and CTF, particularly in China, where the WuXi content team, under the leadership of Dr. Hui Cai, has capitalized on its WeChat media platform,” commented Bakker. “I now personally receive WeChat emails on a regular basis concerning various aspects of dealing with NF and enthusiastic messages about the initiatives of CTF.”

The second challenge CTF faces is fundraising, as CTF has many more ideas than can be funded.  “We must find new sources of capital to continuously build and improve the platform we’ve created so that better medicines are delivered to the patient,” stated Bakker. “Driving towards a self-sustainable platform is challenging if it relies solely on philanthropic approaches as the donor income can be highly variable year-to-year.

The third challenge lies in the preclinical space where animal models reside within academic enterprises.  “Getting the academics and pharma/biotech companies to collaborate to make the so essential connections between testing drugs from companies and the academic animal models is tough because these centers are not always equipped to test a multitude of drugs in their models and intellectual property negotiations can be very frustrating,” observed Bakker, “so coming up with a better business model to accelerate preclinical drug testing becomes urgent. Collaborations with a CRO such as WuXi would be very desirable.”

In closing, Bakker reflected on what keeps her inspired and motivated.  Without pause, she answered “it touches me to talk to patients, to see the journey they’re going through.  We’re losing way too many patients, and this makes me very motivated to think that one day, I might be able to say that we’ve accomplished our vision and that we can say: “we have ended NF.”

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