High-grade glioma is a deadly brain cancer with no effective long-term treatments, typically leaving children and adults with less than two years to live following diagnosis.

Oncoceutics Inc. is tackling this challenge with a new investigational drug, ONC201, which is a small molecule that binds to a specific dopamine receptor in the brain. Dopamine, a neurotransmitter, affects cell behavior and has been implicated in the cancer’s growth.

Lee Schalop, M.D., the company’s chief operating officer and co-founder, said there has been little progress in treating high-grade glioma due to its heterogeneity and lack of biomarkers that could select patients who have a better chance of responding to certain therapies. High-grade glioma cells are quite varied, which means a drug that is effective on some of the cells doesn’t work on others.

Surgery and radiation are the front-line treatments, but in most cases the cancer recurs – leaving no additional viable treatment options for patients. “There is a long list of drugs that have not succeeded in treating high-grade glioma,” Schalop observed.

ONC201 is in clinical trials in the US for treatment of patients with high grade gliomas that harbor a genetic mutation called H3 K27M, which defines a subtype within the family of high-grade gliomas and is associated with a particularly poor prognosis. The mutation allows a targeted therapeutic approach with ONC201 against this subtype, which is more sensitive than other gliomas to the drug. This tumor type occurs in 10 percent of all glioma patients, mostly children and young adults.

As part of an exclusive series spotlighting the inside perspectives of thought leaders on topics shaping the future of new medicines, WuXi AppTec Communications spoke with Schalop about his company’s technology and the challenges of developing new therapies for high-grade glioma patients.

Before earning his medical degree at Albert Einstein College of Medicine, Schalop spent more than 19 years in the financial industry with major Wall Street firms, including Morgan Stanley, J.P. Morgan, Credit Suisse and Banc of America Securities. He joined Oncoceutics soon after receiving his medical degree in 2008 and was promoted to chief operating officer in 2016. Schalop earned dual undergraduate degrees from University of Pennsylvania’s Wharton School and College of Arts and Sciences.

WuXi: What are the challenges involved in diagnosing and treating high-grade glioma? How important is early detection?

Lee Schalop: High-grade glioma is the deadliest type of brain cancer. However, unlike some other cancers, the challenges are not about making the diagnosis. The diagnosis is relatively straightforward using magnetic resonance imaging (MRI).

Patients usually have symptoms like seizures or headache and fatigue, and an MRI is taken. If it’s suggestive of a brain cancer, a biopsy is done, and the diagnosis is confirmed by looking at the tumor tissue under a microscope. Unfortunately, early detection does not really change the outcome even if the tumor can be fully surgically resected because high-grade glioma almost always comes back.

So the big challenge and unmet medical need is not diagnosis; the challenge is the lack of efficient treatments. High-grade glioma has proven to be an extraordinarily difficult cancer. The overall survival for patients after they’re newly diagnosed is between 12 and 18 months. That outcome really hasn’t changed meaningfully in as long as people have been measuring the success of various treatments for high-grade glioma.

WuXi: How would you describe the evolution of drug research in high-grade glioma over the past 20 years? How much progress has been made?

Lee Schalop: Almost none. The only drug that’s been approved in the past 20 years is Avastin (bevacizumab). It received Accelerated Approval from the US Food and Drug Administration (FDA) for recurrent/refractory disease, and then when the data were analyzed for full approval it did not increase survival, which is the typical threshold for full FDA approval. So there is no expectation that bevacizumab may prolong survival in these patients despite continued use.

There is a long list of drugs that have not succeeded in showing improved overall outcome in high-grade glioma patients, causing a lot of frustration for patients and physicians as well as setbacks for companies interested in this space.

WuXi: Why has it been so difficult to find druggable targets for high-grade glioma?

Lee Schalop: This is a wonderful question since it addresses one of the major reasons for failure in this disease. Let me answer with a multipronged reply.

First, it is hard to find a target that offers pathways and mechanisms to achieve a therapeutic effect. Second, even when a pathway or mechanism is identified, it is difficult to find a compound that engages these pathways or mechanisms. And third, compounds that engage these pathways or mechanisms are frequently too toxic or cannot be given in a way to reach high enough concentrations in a patient for a long enough time.

One of the most critical questions for developing therapies for brain cancers is: Can a drug make it into the brain and into the tumor that resides in the brain?

This is a hurdle that the vast majority of drug candidates, which show good effects in the test tube, cannot overcome simply because they don’t pass the blood brain barrier. This barrier exists to protect the brain, the body’s most critical organ, from invasion by substances that can be harmful, such as infectious agents, toxins and other compounds that circulate in the blood.

As a result, there have been many drugs that have been hypothesized to work against high-grade glioma, and they have generated very nice data in models, both in test tubes and animals. However, when these drugs were tested in clinical trials, they ultimately failed.

In addition, high-grade glioma is a very difficult cancer to target because it is so heterogeneous. By heterogeneous, I mean the cells in the tumor are different. So even if the cancer treatment works on some of the cancer cells, it doesn’t work on all of the cancer cells.

WuXi: Why did you choose to focus on high-grade glioma?

Lee Schalop: All of our early work showed that high-grade glioma was very sensitive to ONC201. Moreover, collaborations with a host of very experienced researchers confirmed that high-grade glioma was very sensitive to ONC201. Early research showed that the drug passes the blood brain barrier and makes it into the tumor that we target.

It still was a tough decision to make given the history of drug failures in high-grade glioma, but we decided that we would take this risk. All of us at Oncoceutics cannot thank those individuals enough who gave us encouragement in the early days to embark on this path, in particular, Patrick Wen, the Direct of the Center for Neuro-Oncology at the Dana-Farber Cancer Institute.

WuXi: What progress have you made so far?

Lee Schalop: We have determined that ONC201 works best against a subset of high grade gliomas. About 20,000 individuals get diagnosed each year with high-grade glioma in the US, with a subset possessing a H3 K27M mutation. We found that ONC201 works quite well for patients that have this mutation. In particular, we’ve seen a number of patients benefit from significant tumor shrinkage.

WuXi: How is the drug being tested? Is it a single agent?

Lee Schalop: It’s a single agent. Available options for patients are surgery, temozolomide and radiation, depending on their specific disease characteristics. Unfortunately, the tumor always comes back. So when the tumor comes back the patients start on ONC201. Our intention is to move ONC201 towards a frontline therapy for high grade gliomas. In this case it would be given in combination with radiation.

WuXi: What is the mechanism of action for ONC201?

Lee Schalop: ONC201 works by antagonizing dopamine receptor D2 (DRD2). Dopamine effectively feeds the cancer, and by blocking the dopamine receptor, you are blocking the growth of the cancer.

WuXi: What are the risks of blocking dopamine?

Lee Schalop: The way this drug works is incredibly specific, so it only binds to DRD2. Moreover, it binds to the receptor in a unique way which allows it to act much more potently at killing cancer cells than other dopamine receptors. It’s not blocking all of the dopamine receptors; that would dilute the antitumor effect of ONC201. The drug also is given infrequently – only once a week.

We have seen no side effects that are typical with excess dopamine blockage, such as Parkinson-like symptoms, in the nearly 400 patients who have been treated with ONC201.

WuXi: What regulatory challenges have you faced in clinical development?

Lee Schalop: The challenges are typical for developing a drug for a rare disease that is immediately life threatening. There are not that many patients. In addition, many patients do not have the energy or ability to enroll in a clinical trial. Nevertheless, we have been successful in mobilizing the neuro-oncology community to send patients to our clinical trials, which are now open at multiple sites across the US. Nonetheless, progress is slow because it’s hard to find patients that have this specific genetic mutation.

WuXi: You are developing ONC201 for adults and children. What are some of the differences in developing drugs for adults and children? What are the challenges you face, particularly with respect to children?

Lee Schalop: The challenges with children are two-fold. One is that you have to be very careful with your dosing. We have worked with the Children’s Oncology Group to develop an algorithm to find the appropriate dose for children, based on the adult dose, which involves the weight of the children and their body surface area. We’ve developed a relatively sophisticated way to convert the dosing to the children.

Secondly, while we are working with the FDA for approval of ONC201 for adults based on tumor shrinkage, this will be difficult for approval with children because of the way their tumors grow.

Instead, for children, we will need to seek approval based on survival.  And traditionally the FDA requires that survival studies have a comparative arm, or a control arm. This means that half the patients get the drug and half the patients don’t. For children, this will prove to be completely impossible because no parent will allow their child to go into a trial where there’s a 50 percent chance they will get a placebo.

WuXi: What lessons have you learned during the drug development process?

Lee Schalop: We have certainly learned that there is a larger unmet need than we thought. We have also learned that the community is very closely connected and highly motivated to work with us. The medical centers, the experts, the patient advocacy groups, foundations that support patients with brain cancer, the National Cancer Institute, the FDA and everyone involved in the field have given us encouragement and support.

This support from the outside is best exemplified by a quote from Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence (OCE), who said in a recent interview in The ASCO Post, “We have taken a very active approach to really rapid approvals of our drugs without sacrificing quality by having a smarter approach to how we review these drugs. At the end of the day, I ask: will the American public be better off with this drug than without it?”

WuXi: What other drugs do you have in development? Are they based on the same platform?

Lee Schalop: Yes they are. Our next two compounds are ONC206 and ONC212. They share in common with ONC201 a core structure of three rings. These three rings are relatively unusual from a medicinal chemistry perspective, and they have proven to be very important in terms of binding to GPCRs (G-protein-coupled receptors).

ONC201 binds to the GPCR DRD2; ONC206 also binds to the GCPR DRD2, although differently. ONC212 binds to a different GPCR, called GPR132.

GPR132 has been implicated in leukemia, and our intention is to do a clinical trial for patients with leukemia.

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

Lee Schalop: It’s molecular targeting. It’s moving away from the idea that if one person has breast cancer and another person has breast cancer that they should get the same treatment. Or even if someone seems to have a certain type of breast cancer from a histological review (the old way of looking at cancer based on what it looked like under the microscope) that they should get the same treatment. Instead, today what’s important is which genes are activated and what can be molecularly targeted in that cancer.