Many pharmaceutical and biotech companies shy away from pediatric drug development. While the genomic revolution has resulted in scores of new cancer treatments for adults, children suffering from cancer have been left behind. It takes a spirit of determined commitment to real innovation to overcome the obstacles to developing new pediatric therapies. That is what Salarius Pharmaceuticals CEO David Arthur feels his company and team are all about.

At a recent opening session of NASDAQ, Salarius became a public company. Arthur used this as an opportunity to summarize the company’s mission: “Every day we get to come into the office, go to work and take the fight to cancer.”

Salarius, based in Houston, is a clinical-stage oncology company targeting the epigenetic causes of cancers. The company’s lead candidate, Seclidemstat, is currently in clinical development for treating Ewing sarcoma, for which it has Orphan Drug designation and Pediatric Rare Disease Designation by the U.S. Food and Drug Administration (FDA).

Ewing sarcoma is a devastating pediatric bone cancer and represents a major unmet clinical need. Currently, chemotherapy, radiation and tumor resection surgery are the only options for patients, and in many cases the tumors recur or develop in a location too sensitive to risk surgery. There is a 70 percent five-year mortality rate for patients whose tumors recur after treatment or who are initially diagnosed with metastatic disease. Salarius began enrollment for a Phase 1/2 trial in Ewing sarcoma in 2018.  

The need for a new therapy for this disease is critical, as Arthur points out. “There are 400 to 500 children diagnosed with Ewing sarcoma every year in the U.S. and the average age of diagnosis is about 15. These are children and young adults with their whole lives ahead of them. But figures show that roughly 40 percent to 45 percent either do not respond or relapse from the standard of care. With those patients, there is an approximately 70 percent five-year mortality rate.”

WuXi AppTec Communications asked Mr. Arthur to share his thoughts on why pediatric drug development has lagged behind development of adult treatments and how Salarius’ drug can make a difference in children’s lives.

Mr. Arthur is an industry veteran with 25 years of experience building and leading medical and marketing organizations in product development as well as launching and managing pharmaceutical and device brands. Prior to Salarius, Mr. Arthur was Managing Director of Dacon Pharma, LLC. Additionally, he spent 20 years with Eli Lilly and Boehringer-Ingelheim in executive roles managing product development, business development, US business, global commercialization, European regional marketing and financial planning/analysis.

Mr. Arthur earned a BS in Chemical Engineering from North Carolina State University, an MBA from the Duke University Fuqua School of Business, and is a licensed Professional Engineer and Six Sigma Green Belt.

WuXi AppTec: Generally speaking, why are there so few pediatric drugs in development?

David Arthur: This is an amazing time for drug discovery and development. With the advances in genetic and diagnostic testing, we are entering a new era of medicine that is capable of developing novel treatments for rare diseases and different cancers every day. However, many drug companies remain disinclined to develop medications for pediatric uses due to small market size and the complexity involved in developing drugs for infants and children.

Salarius Pharmaceuticals has stepped up to the challenge by focusing on the development of therapies for pediatric and rare cancers with high unmet needs or for which no targeted therapies are available.

In the past 40 years, fewer than 10 drugs have been developed for use in children with cancer, a number that pales in comparison to the hundreds of therapies developed for adult cancers. Our understanding of the various childhood cancers has grown, yet roughly one out of every five pediatric cancer patients will die from their disease. Research into many rare pediatric illnesses often lacks the funding necessary to develop therapies and treat patients in clinical trials. So, with many forms of pediatric cancer, medical advances have been slow and mortality rates remain high.

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

David Arthur: No, this is a misconception. Children respond to medications in a very different way than adults. Drugs that are generally safe and effective for adults may be unsafe or ineffective — or both— for some or all pediatric age groups. It is truly unfortunate when the only available treatments are harsh and potentially debilitating, such as the standard chemotherapeutic agents. Besides the severe short-term side effects, chemotherapeutic agents are often associated with long-term consequences, and that can be especially troubling when the patients could still have 60 or more years of life expectancy. That is why Salarius is working to develop safer, less toxic treatments for this critical population.

WuXi AppTec: What are the barriers to developing drugs for pediatric cancer patients?

David Arthur: Childhood cancers represent a relatively small portion of the U.S. oncology market. Of the estimated 1.7 million new cancer diagnoses expected to be made in the U.S. in 2019, 11,060 could involve children age 15 and younger, according to the American Cancer Society. Add the political backlash over high prices for new medications, and some drug industry players see little incentive to invest in pediatric oncology drug development.

But the barriers to developing new cancer drugs for children go beyond market size and potential sales. There are also scientific challenges, such as the smaller number of genetic mutations in children that can serve as therapeutic targets. The biological differences between infants, adolescents and young adults make drug development even more complex. And because experimental drug candidates sometime have toxic side effects, researchers and drug companies are reluctant to include children in clinical trials until safety has first been established in adults, a process that can take years.

WuXi AppTec: Is this landscape changing?

David Arthur: It is, though slowly. President Trump placed pediatric cancer in the national spotlight this year when he promised during his State off the Union address to add $500 million to research funding during the next decade. Also, several pieces of legislation have been passed that not only expand funding and incentives for drug makers to develop therapies for pediatric cancer patients, but also compels the inclusion of children, as well as adults in cancer drug studies starting in 2020.

For example, members of the congressional Childhood Cancer Caucus introduced legislation in September 2019 that would reauthorize the Creating Hope Act, making permanent the FDA’s rare pediatric disease Priority Review voucher program. This is a fantastic program, effectively self-funded by the pharmaceutical industry, which incentivizes drug development expressly for children with cancer and other life-threatening illnesses. Yet the rare pediatric disease Priority Review voucher program is the only voucher program created by the Creating Hope Act that is not permanent.

Certainly, the majority of Big Pharma remains attracted to adult cancer’s larger market size. But there is support available from other sources, such as not-for-profit organizations and foundations. Salarius has received more than $20 million in non-dilutive capital and in-kind support from The Cancer Prevention and Research Institute of Texas (CPRIT) and the National Pediatric Cancer Foundation (NPCF). Also, we are fortunate to have the support of shareholders who want to do good by putting their money to work to advance the development of cancer therapies for children.

WuXi AppTec: What form of pediatric cancer is Salarius targeting and why was it selected?

David Arthur: Our lead drug candidate Seclidemstat is being studied in a Phase 1/2 clinical trial for Ewing sarcoma, a rare, devastating and deadly pediatric and adolescent bone and soft-tissue cancer. In the U.S. this year, roughly 500 cases will be diagnosed in patients with an average age of 15 years. And 70 percent of patients who relapse or are initially diagnosed with metastatic Ewing will die within five years. We are talking about adolescents who should have their whole lives ahead of them. Is there any better motivation to support the development of pediatric medicines?

At Salarius, we are studying epigenetic-based strategies for the treatment of cancer. Based on that research and the lack of targeted treatments available for patients, we feel that we have a real shot at having a meaningful impact in Ewing sarcoma that could benefit the lives of these children and their families.

WuXi AppTec: Can you describe Seclidemstat? What type of drug is it and what is its mechanism of action?

David Arthur: Seclidemstat is a reversible inhibitor of lysine specific demethylase 1 or LSD1, which is an extensively-studied epigenetic enzyme that is often highly expressed in cancers. Epigenetics is the study of the regulatory system that controls how gene expression is turned on and off. If the epigenetic enzymes that regulate gene expression become dysregulated, it leads to inappropriate activation and silencing of genes, which can lead to the development and progression of cancer. Drugs that are able to safely modify the activity of these epigenetic regulators may correct the gene changes that are driving disease and provide a new treatment for these cancers.

In the case of Ewing sarcoma, a chromosomal translocation produces a fusion oncoprotein. The fusion oncoprotein recruits other proteins to alter gene expression to a cancer promoting state. Unfortunately, the oncoprotein itself is difficult to directly target because it is a highly disordered protein. An alternative strategy is to target proteins that interact with the oncoprotein. This is the approach Salarius is taking.

Salarius’ lead compound, Seclidemstat, targets the LSD1 enzyme, which is known to interact with the Ewing sarcoma oncoprotein. Salarius licensed the technology from the University of Utah’s Huntsman Cancer Institute, where it was developed by Dr. Sunil Sharma, Salarius’ scientific founder. By inhibiting LSD1 from associating with the oncoprotein, we have shown the ability to reverse the aberrant gene expression. In animal models, Seclidemstat has been shown to slow down, or stop the growth of Ewing sarcoma tumors, and we hope to have a similar therapeutic impact in our ongoing clinical trials.

WuXi AppTec:  What do you mean by a reversible LSD1 inhibitor?

David Arthur: There are a number of companies researching LSD1 inhibitors. We believe Seclidemstat is one of only two reversible LSD1 inhibitors now in the clinic, and that is an important distinction.

An irreversible inhibitor permanently binds to the FAD cofactor within the LSD1 enzyme. Since LSD1 is required for cell homeostasis, irreversibly inhibiting the protein leads to adverse effects which are considered “on-target” as they are related to the biology of LSD1, such as hematological toxicity.

In contrast, Seclidemstat reversibly binds to LSD1 allowing it to maintain some degree of functionality; we have not observed any hematological toxicity to date. This gives us the opportunity to explore more flexible dosing schedules which can potentially allow for a higher chance of therapeutic activity.  

WuXi AppTec: How does Seclidemstat differ from the treatments already available to children with Ewing sarcoma?

David Arthur: Right now, children and young adults diagnosed with Ewing sarcoma have few treatment options, and to be honest, none of them are good. There are no targeted therapies approved for the disease. The standard of care is surgery to remove the primary tumor, radiation and often multi-regimen chemotherapy. In roughly 40 percent to 45 percent of cases, patients don’t respond to the standard treatment or suffer a relapse. Among these patients, there is around a 70 percent mortality rate within five years.

WuXi AppTec: So, Salarius hopes to provide a less toxic, more effective therapy. Am I right?

David Arthur: You’re absolutely right. In fact, that is the exact mission of the National Pediatric Cancer Foundation, and it is one of the reasons Salarius has received, and continues to receive, such tremendous support from the organization.

WuXi AppTec: What is the clinical path forward for Seclidemstat?  Can it be accelerated?

David Arthur: Seclidemstat is now in a Phase 1/2 clinical trial involving patients who have failed to respond to previous treatment or who have suffered a recurrence of their tumors. Right now, we are establishing a maximum tolerated dose and developing a safety profile. Patients will be treated with that maximum tolerated dose in a dose expansion phase of the trial. Early safety and efficacy data should be available in 2020, and once we have compiled full results, Salarius will meet with the FDA and talk about the most efficient and expeditious path forward.

Is there an opportunity for accelerated approval? We hope so given the unmet need in Ewing sarcoma. Seclidemstat already has Orphan Drug Designation and Rare Pediatric Disease Designation from the FDA. If proven safe and efficacious in early clinical studies, Seclidemstat could qualify for Breakthrough Status, which provides access to programs that accelerate drug development and FDA approval. Also, Seclidemstat could be eligible for priority review and upon approval, receive a Pediatric Priority Review Voucher.

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

David Arthur: As I mentioned earlier, Salarius has been fortunate to receive tremendous financial support from both the Cancer Prevention and Research Institute of Texas (CPRIT) and the National Pediatric Cancer Foundation. In fact, the NPCF is funding a significant portion of our ongoing Phase 1/2 study of Ewing sarcoma. The NPCF has also assisted with the initiation of our clinical studies. Salarius is using the foundation’s network of research hospitals, called Sunshine Project Hospitals. This is a great example of industry and not-for-profit foundations working together to address an unmet need.

WuXi AppTec: 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?”

David Arthur: Developing a therapy targeting the root cause of the disease that is safe and effective would be a giant step forward.