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Patients, Advocates Urge FDA to Expedite Approval of ONC201 for Rare, Mutation-Defined Gliomas


NEW YORK (GenomeWeb) – Patient advocates publicly urged the US Food and Drug Administration this week to quickly approve an investigational therapy for children suffering from a kind of brain cancer with a dire prognosis that has shown promising efficacy and a far better safety profile than the current options of radiation and chemotherapy.  

Drugmaker Oncoceutics' lead product, ONC201, has shown encouraging activity in adult high-grade gliomas characterized by the H3 K27M mutation and has obtained fast-track designation from the FDA. However, the company is also exploring ONC201 in pediatric patients with H3 K27M-mutant, high-grade gliomas, since these molecularly defined brain cancers tend to impact children and young adults. Early data suggest this drug could be a substantial improvement in children over currently available options.

Brain tumors account for around 20 percent of pediatric cancers, and H3 K27M mutations characterize 24 percent of pediatric and 8 percent of adult gliomas. The mutations often occur in children with tumors in the brainstem, a type of cancer called diffuse intrinsic pontine glioma (DIPG) that has a dire prognosis. These tumors usually cannot be surgically removed and the only course of treatment is palliative radiation and chemotherapy. The median overall survival is eight to nine months, and less than 10 percent of children and young adults live two years after their diagnosis.

This week before a panel of experts tasked with advising the FDA on cancer treatments, children with H3 K27M-mutant DIPG who have benefited from ONC201, patient advocates, and the mother of a child with DIPG who died in 2014 urged the agency to approve the drug quickly, based on the encouraging results from early studies. The FDA hadn't convened the pediatric subcommittee of the Oncologic Drugs Advisory Committee to weigh in on whether the agency should approve this drug for childhood DIPG but to assess whether it would be appropriate to issue Oncoceutics a "written request” to develop ONC201 for a pediatric indication and to explore the issues related to studying the drug.

Under the Best Pharmaceuticals for Children Act, drugmakers can receive six months of additional market exclusivity for a new molecular entity if they perform certain pediatric studies and submit them to the FDA. A spokesperson from Oncoceutics said that the company appreciates the agency mentioning the "written request" option during this meeting, given the additional six months of exclusivity attached to it. "We believe that the ongoing and planned studies that were presented will lead to an approvable dataset," he said.

It was clear at the meeting that there is great interest from patients and advocates in seeing ONC201 expedited to market, given the desperate need for new drugs for DIPG. "I want to request that the FDA consider approving this drug immediately," said Al Musella, founder of the Musella Foundation, an advocacy group for brain cancer patients, noting that the real-world experience of 300 patients on the drug to date shows that it has minimal side effects and is allowing some children to live longer than expected and even return to school. "This is just something we haven't seen before."

Cancer advocacy organizations, including the Musella Foundation, xCures, and the Michael Mosier Defeat DIPG Foundation, are providing support for a compassionate use program for ONC201. So far, around 40 patients have received access through his program. "Requests [for the drug] are increasing as data like that presented [at this meeting] becomes available," said Musella, whose foundation, along with xCures, may receive a return on their investment if the drug is approved and successful on the market.

It is not possible for Musella to meet every request for ONC201, however, and he said that a few times a week, he has to decline a parent who wants access to the drug for a child. The compassionate use program is tracking patients' outcomes on the drug but he advised the FDA to grant accelerated approval based on the preliminary efficacy and safety data available and to confirm the risk/benefit profile of the treatment in the post-approval setting.

The advisory committee meeting also gave Oncoceutics a chance to  present the data it has to date on ONC201 in kids with gliomas and discuss the broader development program for the drug. Based on the activity of the drug seen in adults with aggressive gliomas and the H3 K27M mutation, the company started a Phase I study looking at the activity of the drug in five pediatric cohorts.

At the meeting, executives from Oncoceutics presented data from one of the arms that had finished enrolling 21 pediatric glioma patients who had received radiation. Outcomes data on 13 DIPG patients — 11 patients from the trial and two patients who received the drug through an expanded access protocol — were interpretable. A dozen patients had H3 K27M mutations as determined by either immunohistochemistry or RNA-seq and one patient couldn't provide a biopsy for testing.

At a median follow-up of 13 months, 69 percent of patients were alive for a year, and median overall survival and progression-free survival hadn’t yet been reached for the whole study. Historically, between 40 percent and 50 percent of DIPG patients are alive for a year after diagnosis. The company highlighted the experience of a seven-year-old girl named Emerson who was diagnosed with H3 K27M-mutated DIPG last year, and after six months of receiving ONC201, saw dramatic tumor shrinkage.

Emerson's mother, Amy Hogendorn, told the advisory committee that after receiving initial radiation and chemotherapy treatment, her daughter's tumor had actually increased in size. Luckily, Emerson got a spot on an ONC201 clinical trial at the University of Michigan in September 2018. "It is very likely that Emerson would not be here today if not for ONC201," she said, noting that her last scan in May showed that her tumor had shrunk by 23 percent.

In the study data presented, the safety profile also appeared more favorable than that of radiation and chemotherapy. Patients have had low-grade nausea and headache, which researchers feel could be due to the drug in some of them. One patient had grade 3/4 increased aspartate aminotransferase, which may indicate liver damage, and researchers said this could be related to ONC201.

Hogendorn attested to the safety profile of the drug based on her daughter's experience. "ONC201 allows Emerson to live a fully normal life outside of the hospital," she said, describing how her daughter goes swimming, participates in gym class, has a full schedule of summer activities planned and graduated from first grade a few weeks ago. "Emerson is able to be herself again, with no side effects from the medication."

Oncoceutics in April published in the Journal of Neurosurgery the experience of a 10-year-old girl with H3 K27M-mutant DIPG who received ONC201 on a compassionate use basis after getting radiation treatment. Her tumors completely shrank for almost a year upon receiving Oncoceutics' drug, allowing her to return to school.

Oncoceutics discovered that its drug might work especially well in high-grade glioma patients with H3 K27M mutations thanks to an extraordinary responder in one of its early studies involving adults with recurrent glioblastoma. ONC201 shrank this patient's tumor and more than three years later, she is still on the drug. Molecular analysis of her tumor revealed an H3 K27M mutation.

Researchers then used RNA-seq to analyze additional patient samples and to understand why ONC201 worked well in this patient and found that gliomas with H3 K27M mutations overexpress the dompamine receptor D2 (DRD2) and have suppressed DRD5 expression. ONC201 is designed to block DRD2, which plays a part in controlling pathways involved in cancer growth.

At the meeting, Jenny Mosier, whose six-year-old son Michael died in 2015 of DIPG and did not have the option to try ONC201, described how the brain stem tumor paralyzed him and how he continued to gain weight on steroids. "At the end of Michael's life, he could not move any part of his body or speak," Mosier said. "Michael fought for eight-and-a-half months and he suffered tremendously. He did not make it to his seventh birthday."

Mosier started the Michael Mosier Defeat DIPG Foundation, which funds research for DIPG and provided support for the development of ONC201. Given the toll current DIPG treatments take on children, the "FDA should use all tools available to expedite development on ONC201 for DIPG," Mosier told the agency and the advisory committee.

The pediatric subcommittee of FDA's Oncologic Drugs Advisory Committee told the agency that ONC201 could be the subject of a "written request" in H3 K27M-mutant high-grade gliomas and that Oncoceutics should try to improve understanding of the drug's mechanism of action and identify other cancers that respond to it.

The committee added that children with cancers that have spread to the brain who are otherwise eligible for partaking in the ONC201 trials shouldn't be excluded. Experts also felt that based on the relatively mild toxicity profile of the drug, children younger than two years could also be enrolled in studies of the drug. They suggested that Oncoceutics develop liquid formulations of ONC201 for younger children who can't swallow pills.

Oncoceutics is studying the drug in the ongoing Phase I study in several other patient groups, and in Phase II studies in patients with newly diagnosed DIPG and H3 K27M-mutant gliomas. "We have been [working], and we will continue to work closely with the FDA to define the requirements for an approval," the spokesperson from Oncoceutics said.

The company expects that based on the unmet need in DIPG and the committee's support for the development plan for ONC201, accelerated approval is possible. "We also hope that based on the benefit experienced by patients, with little risk on the safety side, and [based on] the convenient oral intake, especially given the absence of effective therapies, that ONC201 will be a priority for approval," the spokesperson said.