Blaze Bioscience is literally lighting the way for cancer surgeons to remove children’s brain tumors without harming their healthy neural tissues.

The company is developing drugs that use optimized CDPs, also called cystine-dense miniproteins, derived from natural organisms such as scorpions, violets and sunflowers. The CDP in Blaze’s lead product, tozuleristide, binds to cancer cells and, when combined with a dye, makes the diseased cells glow to help surgeons avoid removing healthy tissue and resect all of the tumor.

Tozuleristide was designed using Blaze’s Tumor Paint technology, invented by researchers at the Fred Hutchison Cancer Center, Seattle Children’s Hospital and the University of Washington. The diagnostic drug, which combines a CDP from scorpion venom with a fluorescent dye, is being evaluated in the US in a pivotal clinical trial of pediatric patients undergoing surgery to remove brain tumors.

Current techniques rely on “pre-operative scans entered into a neuro-navigation system and the surgeon’s skill,” said Blaze President and CEO Heather Franklin. “There is nothing like tozuleristide in development or on the market for children undergoing brain cancer surgery.”

Franklin said the company expects to file a New Drug Application (NDA) in 2021 for approval of tozuleristide by the US Food and Drug Administration (FDA). She said clinical studies have also been conducted in skin and breast cancers, and the technology may be applicable for other solid tumor cancers.

Franklin added that Blaze also hopes to introduce its technology to other countries, such as China, “where surgery is a mainstay of cancer therapy and we believe we could help millions more patients and surgeons.”

As part of an exclusive series spotlighting the insider perspectives of thought leaders on topics shaping the future of new medicines, WuXi AppTec Communications spoke with Franklin about her company’s technology and the challenges of developing new therapies for pediatric cancer patients.

Before joining Blaze, Franklin was senior vice president of business development and alliance management at ZymoGenetics and also held positions at Amgen and Targeted Genetics. She earned a Bachelor of Science from the University of North Carolina-Chapel Hill, a Master of Science from the University of Washington and an MBA from the Wharton School of the University of Pennsylvania.

WuXi: Why are there so few pediatric drugs in development?

Heather Franklin: The good news is that this is changing through a number of US government efforts to provide incentives and obligations, including the Creating Hope Act and Race for Children Act.

Historically, patient organizations such as the Cystic Fibrosis Foundation and the Muscular Dystrophy Association, which have taken venture philanthropy approaches to partner with companies to advance drug development, were the ones making major strides in pediatric therapies possible. 

Often there also are perceived additional risks in developing pediatric drugs beyond these being smaller markets. The advent of successful products for rare diseases demonstrated that even these markets can generate good returns for investment in drug development.  When the benefits of your therapy can last decades, as in the case of pediatrics, versus months or years in the case of many other therapeutics, then it shifts the value proposition in favor of developing pediatric drugs.

But the safety bar is much higher for a drug developed for children for the same reasons; they may be negatively impacted for decades. And the negative impacts may be greater for pediatric patients who are still developing.

A negative safety event in a pediatric patient during a clinical trial, whether eventually attributed to a drug or not, can derail a whole product category, as was seen in gene therapy two decades ago. Thankfully the technology recovered and we are seeing wonderful advancements in that area.

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

Heather Franklin: Children are not just small adults. This is clear in one of the areas of focus of our drug development, where many pediatric brain tumors are quite distinct from adult brain tumors in terms of underlying cause and location.

Additionally, kids are still growing and developing, which poses a number of challenges from simple things like what is the right dose given that children vary widely in size to potential differences in side effect profiles.

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

Heather Franklin: First off is the extra emphasis on safety. Phase 1 studies focused strictly on safety, such as those that are done in normal volunteers in adult drug development, aren’t allowed in pediatric clinical trials.

Even studies on pediatric patients, which might have some benefit, can be difficult to enroll as you are asking a parent to consent to treating their precious child with an unproven drug.

So enrollment rates in pediatric studies can be slow based on the need to take less risk with children on top of the smaller number of children with a particular disease as compared to adults. 

There are also additional challenges early in clinical trials such as sometimes needing to develop a separate dosage form for children.

On the other end of the spectrum, I do believe the regulatory agencies are very willing to work with companies developing drugs that can help children provided this safety concern is adequately addressed. So a safe and effective medication can see a rapid approval once that data is collected.

WuXi: What clinical development challenges do you face?

Heather Franklin: In designing our clinical development program for a diagnostic drug in children with brain cancer, one of the toughest issues to address is how to show there is a low rate of false negatives as opposed to true negatives. This is because it isn’t feasible to sample brain tissue the surgeon believes is truly negative, particularly in a child.

But we worked with FDA to address that challenge as we designed our pivotal clinical trial. The trial is now up and running at seven centers – soon to be nine centers – across the US. We anticipate completing enrollment in 2020 and filing an NDA in 2021.

WuXi: Why did you select central nervous system tumors as a pediatric cancer indication?

Heather Franklin: Pediatric brain cancer is the number one cancer killer of children. Even if a tumor is resected there can be many negative impacts if normal tissue is accidentally removed from a child’s developing brain. And if they do not get all of the tumor, it may mean increased radiation and/or chemotherapy for that patient, which can have life-long negative side effects.

So this is the application of our Tumor Paint technology where the potential benefits of complete resection and the avoidance of negative effects of taking too much tissue are most pronounced.

WuXi: What kind of diagnostic drug are you developing and what is the mechanism of action?

Heather Franklin: Tozuleristide is a diagnostic drug which can be injected intravenously as soon as one hour prior to surgery and appears to still provide meaningful contrast between tumors and normal tissue if surgery takes place even 36 hours later. This is a useful feature in a hospital setting where surgeries in some cases may be emergencies or in other cases may be delayed. It is being investigated for its potential to accurately detect tumors during surgical procedures.

While the mechanism of action hasn’t been fully elucidated, laboratory tests have demonstrated it binding both to several different proteins found on cancer cells and binding to many different cancer cell types themselves. These findings were confirmed in our veterinary clinical trial and now we have seen many different tumor types light up in our clinical trials. It appears to be a general mechanism that is at work in most cancer types.

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

Heather Franklin: While there is an imaging agent recently approved for detection of high grade gliomas in adult brain cancer patients, there is nothing available for children undergoing brain cancer surgery.

Current techniques include use of pre-operative scans entered into a neuro-navigation system and the surgeon’s skill. Some major hospitals have intra-operative MRI (magnetic resonance imaging) units where the surgeons stop surgery to take a scan mid-surgery, but there is nothing like tozuleristide in development or on the market for children undergoing brain cancer surgery.

WuXi: What other cancer indications are you targeting?

Heather Franklin: Our Phase 1 program studied adult brain, breast and skin cancers, all of which are areas of interest. We see head and neck cancer and sarcomas as indications similar to brain cancer where successful surgery is critical to downstream outcomes and preservation of function.

Beyond that we believe this product may be applicable to most cancer surgeries such as cancers of the gastrointestinal tract as well as prostate and lung cancer surgeries.

And beyond addressing many different types of cancer surgery we would also like to bring the technology to countries such as China where surgery is a mainstay of cancer therapy and we believe we could help millions more patients and surgeons.

WuXi: What are the top three impediments to delivery of better medicines, faster and cheaper to patients?

Heather Franklin: Oddly, access to patients is a key impediment as new approaches and combination approaches to cancer therapy explode. So, it becomes even more critical to be thoughtful about how we approach clinical trials and come up with new algorithms that can detect signals of efficacy – or futility – with fewer patients.

I believe the FDA is receptive to this idea, and I’m looking forward to seeing elegant implementations of this approach.

I think restoring trust to the pharmaceutical industry is a key as well. Trust needs to be earned and with trust we can re-explore the risk-benefit equation which underlies drug development and approvals possibly resulting in accelerated pathways to patients.

You see a desire to shift this equation in movements like the Right to Try Act (The US law enables patients with life-threatening diseases to try unapproved drugs if they failed all approved treatments and cannot enter a clinical trial).

I don’t necessarily believe that is the right approach since we do want patients enrolling in clinical studies generating hard data on risks and benefits of a product, but perhaps that movement is indicative that we could continue our shift towards more accelerated approvals and shared risk.

WuXi: What would be the one thing that has the most potential to lead to a paradigm shift from treatment to cure in cancer? 

Heather Franklin: I think we are mistaken when we try to think of there being a “magic bullet” for cancer. Cancer is many different diseases and ever changing and mutating. The ways to tackle each of these is often multi-factorial.

Immunotherapy, including T-cell therapy, holds great promise. We believe that reducing tumor burden with a more successful surgery is a factor that will help out these new therapies as well. 

Artificial intelligence and machine learning efforts looking at early diagnosis and other markers of cancer are intriguing. All of these technologies will come together to profoundly change how we treat cancer.

As I sometimes tell my investors, I would be happy to someday be put out of the cancer surgery business. Unfortunately, I don’t think that day is on the horizon quite yet.