Small Molecule Drug ONC201 Brings Hope To Patients With High-grade Glioma

- May 08, 2020-

Five years ago, Kristina was diagnosed with high-grade glioma (HGG). This is the most common invasive primary brain cancer, and the overall survival of newly diagnosed patients is only 12-18 months! Kristina immediately underwent surgery and radiotherapy, but the tumor continued to grow, she became more and more difficult to walk, and she also had a language barrier. The step-by-step desperation of the god of death forced the young girl to fight against water. She chose to receive treatment with an experimental drug. Unexpectedly, a miracle really happened. This drug had an amazing effect on Kristina: her tumor had shrunk, and there was no obvious side effects except for occasional fatigue. Casting a beam of life for her is ONC201, a drug candidate developed by Oncoceutics.

This opponent is not simple

As we all know, many cancers are difficult to diagnose due to technical limitations or deep tumor latency. However, for high-grade gliomas, the challenge is not diagnosis. "Patients with high-grade gliomas often have symptoms such as epilepsy, headache, and fatigue. Magnetic resonance imaging (MRI) can be performed. If the diagnosis is brain cancer, biopsy is performed and the tumor tissue is observed under a microscope to confirm the diagnosis. "Unfortunately, early detection of high-grade gliomas does not really change the results. Even if surgical resection or other treatments are performed, it almost always recurs.

Due to the lack of effective treatment, high-grade gliomas are daunting. In the past 20 years, only the VEGF inhibitor Avastin (bevacizumab), which inhibits vascular proliferation, has received accelerated approval from the US FDA for relapsed / refractory patients. Unfortunately, further data analysis showed that Avastin did not improve survival time much. Therefore, even if you continue to use this drug, you can not rely on it to significantly prolong the survival of patients.

In the confrontation with high-grade gliomas, a large wave of drugs have been defeated. The cold reality has made many patients, doctors and interested pharmaceutical companies full of frustration.

So many drugs have encountered "Waterloo", where is the problem? An important factor is: it is too difficult to find "drug target" of high-grade glioma! First, it is difficult to find such a target, which can provide corresponding pathways and mechanisms to achieve therapeutic effects; second, even if such pathways or mechanisms can be identified, it is difficult to find related compounds; and finally, even if it is found Such compounds, they are often too toxic, or unable to maintain a sufficiently high concentration in patients for a long time.

Difficult to enter the brain to kill tumors is another obstacle to the development of related therapies. Because they cannot pass the blood-brain barrier-the barrier exists to protect the brain from harmful substances (such as infectious pathogens, toxins, and other compounds circulating in the blood). As a result, many originally promising drugs produced very good data in in vitro and animal models, but when tested in the clinical environment, they eventually failed.

Things are not over yet, there is another hateful thing about high-grade gliomas, which is its heterogeneity. Therefore, even if a certain treatment has an effect on some cancer cells, it is not effective for all cancer cells.

However, no matter whether it is a strong opponent or a lesson from the loser, Oncoceutics has not stopped, the patient's voice makes them upstream, and developed a potential drug candidate-ONC201.

Targeting histone H3 K27M mutation

ONC201 is a small molecule drug that can effectively cross the blood-brain barrier and does not damage normal cells while killing cancer cells. Studies have shown that this drug is particularly effective in patients with specific gene mutations in gliomas, namely histone H3 K27M mutations. At present, the prognosis of H3 K27M mutant glioma is extremely poor, and there is a lack of effective treatment after relapse.

ONC201 uses a unique mechanism of action: by antagonizing the dopamine receptor D2 (DRD2). Dopamine is an important neurotransmitter in the human body. It mainly functions by binding to its receptors. The dopamine D2 receptor is a member of the dopamine receptor family and plays a positive role in the proliferation of glioma cells. DRD2's antagonism has been shown to activate integrated stress response and inhibit Ras signaling pathways, both of which have been shown to have clinical effects in oncology. For example, an integrated stress response can lead to the termination of cell division and promote cell apoptosis. "Dopamine effectively" nourishment "this type of cancer, blocking the dopamine receptors, and to a certain extent, blocking the development of cancer." After receiving ONC201 treatment, many patients' tumors shrank significantly.

It is worth noting that ONC201 only binds to DRD2. It does not block all dopamine receptors. In the nearly 400 patients receiving ONC201 treatment, the side effects of excessive blocking of dopamine have not been found, such as Parkinson ’s disease. Symptoms. In addition, this medicine only needs to be taken orally once a week, which is very convenient. In December 2018, ONC201 was granted fast-track qualification by the US FDA. The indication is adult patients with recurrent H3 K27M mutant high-grade glioma.

It is worth mentioning that, according to Oncoceutics' plan, ONC201 will not only meet the needs of adult patients, but also bring benefits to pediatric patients. The development of medicines for children is under double pressure: first, they need to be careful about the dosage; second, they need to consider that the tumor growth of children is different.

Another headache is that, according to FDA practice, conducting a study on survival requires a control arm, which means that half of the patients take the drug and the other half do not. It's difficult to put it on children, because almost no parents will accept the fact that their children participated in a trial, where they are half likely to get a placebo!

As a response, Oncoceutics has collaborated with the Children ’s Oncology Group and developed an algorithm to find the right dose for children based on the child ’s weight, body surface area and adult dose. In addition, they are also in deeper communication and cooperation with FDA.

Currently, ONC201 is undergoing single-agent testing, but Oncoceutics also plans to combine radiotherapy for first-line treatment of high-grade gliomas. In addition to ONC201, Oncoceutics is also developing two compounds, namely ONC206 and ONC212, which have the same tricyclic core structure as ONC201. Oncoceutics hopes to make a difference in combating other diseases, such as leukemia.