The WuXi AppTec Communications team is excited to kick-off a new series on pediatric cancer that highlights companies seeking novel therapies for children, long a challenging space. Drug development advances in the last decade have produced new treatments for many diseases. However, since most of those new medicines were discovered and developed for adults, children have often been excluded from this progress.

Research has shown that children do not respond to medications in the same way as adults. Even if pediatricians prescribed drugs to children “off-label” children could respond differently than adults in terms of safety and efficacy.

“Children are not small adults,” said Dr. James Breitmeyer, President and CEO of Oncternal. Oncternal, the first company profiled in this new series, is a San Diego based oncology company developing TK 216 for Ewing sarcoma, a rare pediatric cancer. TK216 is a small molecule therapeutic candidate that inhibits the biological activity of ets-family transcription factor oncoproteins, which are the main disease drivers in Ewing tumors.

“Ewing sarcoma is a very serious bone cancer affecting children and young adults, and the effects can be devastating,” said Dr. Breitmeyer. “These patients have an urgent need for additional treatment options and TK216 represents a potential new therapy for this unmet medical need.”

Ewing sarcoma is a cancer that occurs primarily in the bone or soft tissue. While it can develop in any bone, it is most often found in the hip bones, ribs or long bones. It can involve the muscle and the soft tissues around the tumor and can also metastasize to other areas of the body, including the bone marrow, lungs, kidneys, heart, adrenal glands and other soft tissues.

The disease can occur at any time during childhood, but most commonly develops during puberty, when bones are growing rapidly – typically between the ages of 10 and 20.

WuXi AppTec asked Dr. Breitmeyer to share his thoughts with our readers on why pediatric drug development has been slow in the past and how he sees Oncternal’s TK 216 becoming an effective, novel treatment for Ewing.

Dr. Breitmeyer has served as President, CEO and Director of Oncternal since 2015. Previously Dr. Breitmeyer was President of Bavarian Nordic, Inc. and Executive Vice President of Bavarian A/S, a multinational corporation headquartered in Denmark, from 2013 to 2015.  He has been a director of Zogenix, Inc. since 2014 and a director of Otonomy, Inc. since 2018, and was their acting CMO from 2012 to 2013. He also served as the EVP of Development and CMO of Cadence Pharmaceuticals Inc., from 2006 to 2012, and the CMO of Applied Molecular Evolution Inc., from 2001 to 2006. Dr. Breitmeyer was also the founder, President and CEO of the Harvard Clinical Research Institute, and CMO and Head of Research & Development for North America at Serono Laboratories Inc. He earned his B.A. in Chemistry from the University of California, Santa Cruz and his M.D. and Ph.D. from Washington University School of Medicine.

WuXi: Why are so few pediatric drugs, in general, in development?

James Breitmeyer: Developing pediatric drugs can be challenging due to the small numbers of patients and the variability in pediatric subpopulations, such as between newborns and adolescents. It’s been a priority for the FDA to overcome these disincentives by offering incentives for pediatric drug development. Oncternal is strongly in favor of the FDA’s incentives for pediatric drug development—thoughtful drug development is critical to public health. We believe Oncternal could be eligible for a Rare Pediatric Disease Priority Review Voucher if the program is still active upon approval of one of our drugs, and that incentive is real.

WuXi: How does developing drugs for children differ from adults? Aren’t children just small adults?

James Breitmeyer: Children are not just small adults—The FDA considers pediatric development to extend to age 16 because there are significant differences and changes, especially with regards to drug metabolism and physiology that vary between age groups. There are even more dramatic changes when you consider infants and newborns. Due to these biologic differences in pediatric development, it is very important to understand drug effect and drug metabolism between subpopulations of pediatric patients.

WuXi: Are there ethical issues different from adult drug development?

James Breitmeyer: The ability of children to understand their disease and understand the risk and benefits of an experimental therapy varies substantially by age. Therefore, it is essential to make every effort to communicate about the clinical trial and the risks involved in terms the child can understand. It is also essential to make sure you have fully informed consent from parents or guardians.

WuXi: What are the major regulatory challenges in developing drugs for pediatric cancer patients?

James Breitmeyer: There are no major regulatory challenges. We have found regulatory agencies to be cooperative and helpful, especially when we seek advice about pediatric drug development. From our experience we’ve found that pediatric experts in the FDA are eager to offer assistance and advice in pediatric development programs.

WuXi: What clinical development challenges do you face?

James Breitmeyer: The major challenge we’ve faced working in a rare pediatric cancer has been recruiting enough participants for clinical trials. To address this issue, we have worked with patient advocacy groups and social media outreach to target patient populations and educate the public on rare disorders and alternative treatment options.

WuXi: What disease are you targeting and why did you select it?

James Breitmeyer: Ewing sarcoma is the second most common pediatric bone tumor. Patients with recurrent or metastatic Ewing sarcoma have a less than 40 percent overall survival rate after five years. In the last 30 years, no new therapies have been approved by the FDA specifically for Ewing sarcoma.

WuXi: What kind of drug are you developing?

James Breitmeyer: We set out to create a drug that targeted the Achilles’ heel of Ewing sarcoma. This target is EWS-FLI1, an oncogenic fusion protein which is one of the primary causes of Ewing sarcoma, and had been called ‘undruggable.’ TK216 demonstrates that not only is EWS-FLI1 druggable, but that the potential of TK216 inhibiting a broader range of tumors driven by similar oncogenes is an unexpected benefit.

WuXi: How does your drug differ from what’s already available to children for this disease?

James Breitmeyer: Standard of care for Ewing sarcoma, which is usually initially diagnosed as a bone tumor, consists of radical surgery, radiation therapy and combination chemotherapy. Unfortunately, in too many cases the frontline standard therapy is not effective and disease either reoccurs or metastasizes. If disease reoccurs or metastasizes, there is no standard second line therapy available. Therefore, alternative treatment options are critical to address this unmet medical need.

WuXi: What is the mechanism of action of your drug?

James Breitmeyer: TK216 is an investigational, small molecule inhibitor that affects Ewing sarcoma cells by a different mechanism of action than any available therapy, and is in fact the first potential treatment to directly inhibit a key cause of Ewing Sarcoma. TK216 targets the ETS family of oncoproteins. ETS transcription factors are important in embryonic development; however, when mutations in cancer cells such as fusion with other proteins or overexpression occur, ETS family oncoproteins have been associated with tumor initiation, progression and metastasis. Approximately 85 percent of Ewing sarcomas contain a genomic rearrangement that results in the fusion of the FLI1 gene, an ETS family member, and the EWSR1 gene, an unrelated transcription factor. Agents that block the EWS-FLI1 fusion protein were initially identified by Dr. Jeff Toretsky at Georgetown University. In collaboration, Oncternal was then able to develop more potent molecules with anti-cancer activity in preclinical models. The mechanism of action includes inhibiting transcriptome function and the activation of RNA Helicase A by EWS-FLI1.

WuXi: Do you engage patients, their parents and patient advocacy groups in your clinical development programs? If so, how are they involved?

James Breitmeyer: Engaging with patients, their parents and patient advocacy groups is a great way to get feedback and learn about real world impacts of disease, and issues around risk and benefit of potential therapies. All three stakeholder populations are essential to involve in clinical development and Oncternal regularly works with several Ewing sarcoma advocacy groups.  

WuXi: Are there creative trends or policies that have facilitated delivery of better medicines to patients?

James Breitmeyer: The FDA has launched a number of initiatives in the last few years that have had significant impacts on the process of developing novel therapies for the treatment of cancers. For example, breakthrough designation appears to be very successful at creating an acceleration of development timelines that include an enhanced level of communication between the developing companies and the FDA. These initiatives are very welcome to both patient communities and the biotech industry, and appear to be improving the efficiency of oncology drug development and potentially shortening development time. TK216 has received orphan drug designation and Fast Track status and we are very happy with our working relationship with the FDA.

WuXi: For the disease area you are working on, what would be the one thing that would have the most potential to lead a paradigm shift “from treatment to cure”?

James Breitmeyer: Ewing sarcoma is caused by two genes combining through genetic translocation, an event that creates a fusion protein with half of the characteristics of each gene products. By directly targeting the cause of Ewing Sarcoma and inhibiting the oncogenic process we hope one day to be able to shift the paradigm from short-term control to long-term remission and even a cure.