How ChadTough Defeat DIPG Helped Drive the First Treatment Approved for Recurrent H3 K27M-mutant DMG/DIPG

For more than 60 years, a DIPG diagnosis meant heartbreak and helplessness. This aggressive, inoperable brain tumor has stolen thousands of children’s lives, offering no viable treatments and virtually no hope of survival. Despite decades of medical progress, not a single drug had ever been approved—until now.

In August 2025, the FDA approved ONC201 (now known as Modeyso™) for patients with recurrent H3 K27M-mutant diffuse midline glioma (DMG), which includes DIPG. It marked the first-ever FDA-approved treatment for this devastating disease. More than a scientific milestone, it represented a turning point driven by relentless advocacy, bold philanthropy, and community-powered science.

What sets ONC201 apart is not just what was achieved but how it was achieved. In a landscape where the traditional drug development pipeline often fails children with rare diseases, ONC201’s progress defied expectations. The conventional pharmaceutical model prioritizes large markets and commercial return, leaving rare pediatric diseases grossly underserved. For decades, children diagnosed with DIPG were excluded from meaningful therapeutic innovation—not because science lacked ideas, but because the system lacked incentives.

The trajectory of ONC201 breaks that mold. It shows how families and foundations can rewrite the rules. ChadTough Defeat DIPG Foundation played an important role in ONC201’s path—funding early research and enabling expanded access when other routes stalled. To date, the foundation has invested nearly $6 million in ONC201-related efforts, representing nearly 15% of all funding awarded since the foundation’s inception. This extraordinary commitment helped maintain momentum through key milestones toward drug approval and has set the stage for the next breakthrough that will likely come from combination therapy.

Just as vital were the patients and families who chose to participate in early access programs and clinical trials, bravely stepping into the unknown to help advance science and create hope for others. Their courage and trust laid the foundation for everything that followed.

The story of ONC201 isn’t simply about drug development. It is the story of families who turned unimaginable loss into unstoppable action. It is a roadmap for how community-led science can achieve breakthroughs once thought impossible. This is what happens when love fuels science.

Let us carry this momentum forward. Let us continue to fund bold research, demand accessible care, and never lose sight of the children and families at the center of this mission. Together, we can turn hope into outcomes—and transform what it means to hear the words “your child has DIPG.” Together, we will Defeat DIPG.

A Timeline of Progress
The journey to FDA approval didn’t happen overnight. It was shaped by years of discovery, collaboration, and determination—from scientific breakthroughs and early access cases to bold philanthropy and regulatory milestones. What follows is a chronological look at the key moments that brought ONC201 to the children and families who need it most.

2012: A Mutation Changes Everything

2012: A Mutation Changes Everything

Two landmark studies published in Nature Genetics reshaped the understanding of pediatric high-grade gliomas. Led by Dr. Nada Jabado (McGill University) and Dr. Suzanne Baker (St. Jude Children’s Research Hospital), the research identified a recurrent mutation—H3 K27M—in the histone H3 genes, defining DIPG as a distinct molecular disease. This mutation, which causes epigenetic dysregulation by disrupting PRC2 function and reducing H3K27me3 levels, laid the scientific groundwork for therapies that would later include ONC201. It was the start of a new era in DIPG research.

2015–2017: Discovery and Early Trials

ONC201, developed by Oncoceutics, emerged as a novel small molecule with mitochondrial activity, targeting dopamine receptor D2 (DRD2) and activating the mitochondrial protease ClpP. Preclinical studies showed promise in H3 K27M gliomas, where DRD2 is overexpressed. First-in-human trials established a safe dose in adults, providing early validation for the drug’s potential.
 First-in-Human Trial
 Fox Chase Cancer Center

In June 2017, a 10-year-old girl with H3 K27M-mutant DIPG became the first pediatric patient treated with ONC201 under a compassionate use protocol. Within months, her neurologic symptoms improved dramatically, her tumor shrank on MRI, and she experienced no significant side effects. This case, published in the Journal of Neurosurgery: Pediatrics, provided the first real-world evidence that ONC201 could deliver meaningful clinical benefit in children with DIPG, and it helped lay the groundwork for subsequent pediatric trials.
 Journal of Neurosurgery

2018: Families Fund Access

In mid-2018, Mark and Jenny Mosier, then co-founders of the Michael Mosier Defeat DIPG Foundation, first heard about ONC201. Mark learned about ONC201’s promising initial results at the ISPNO meeting, and Jenny heard about ONC201 from a friend at the NIH. Recognizing its potential, the Mosiers and their foundation—alongside the Musella Foundation and The Cure Starts Now—initiated funding for a formal Expanded Access Program (EAP) with Oncoceutics to bring ONC201 to children and young adults with DIPG. Unlike traditional research grants, this was about direct access: families funding real-time treatment.
 Cancer Commons EAP News

2019: Hope, Tension, and Advocacy

With the help of Cancer Commons and xCures, Oncoceutics officially opened the ONC201 EAP in early 2019. The intermediate-size Expanded Access Program gave options to patients who did not qualify for clinical trials. 

Cancer Commons EAP News

On May 17, 2019—DIPG Awareness Day—Kansas State student Jace Ward was diagnosed with DIPG. He quickly learned about a promising new treatment: ONC201. He did not qualify for existing clinical trials. Jace eventually gained access through the EAP thanks to the determination of his mother, Lisa, and support from the foundations funding the EAP. Jace bravely shared his treatment journey publicly, becoming one of the most visible advocates for ONC201 and helping elevate awareness of both the treatment and the urgent needs of DIPG patients.

On June 20, 2019, Jenny Mosier, then Executive Director of Michael Mosier Defeat DIPG Foundation, delivered emotional testimony before the FDA. She highlighted the dire prognosis of H3K27M-mutant gliomas and emphasized the promise of ONC201, reminding regulators that families had no time to wait.

Jenny Mosier Statement to the FDA

By late 2019, Michael Mosier Defeat DIPG Foundation and The ChadTough Foundation began receiving research proposals specifically tied to ONC201. Recognizing the potential, the foundation (based on direction from its Scientific Advisory Council) awarded two New Investigator Grants—one to Dr. James Stafford (University of Vermont) and one to Dr. Matthew Dun (University of Newcastle). This marked the foundation’s first investment in scientific research focused on ONC201 and laid the groundwork for future discoveries.

Stafford New Investigator Grant

Dun New Investigator Grant

2020: Momentum Grows and the Innovative DMG-ACT Trial Platform Launches

Although data from DMG-ACT did not inform the FDA’s approval of ONC201, the Michael Mosier Defeat DIPG Foundation and The ChadTough Foundation played a pivotal role in launching this groundbreaking initiative—one that is now positioned to support future breakthroughs. Recognizing the urgent need for a more unified and innovative approach to clinical research, the foundations jointly invested in building the infrastructure for what would become DMG-ACT (Diffuse Midline Glioma – Adaptive Combinatorial Trial). Rather than a single trial, DMG-ACT is a collaborative clinical trial framework designed to accelerate the evaluation of promising treatments for DMG, including ONC201, through adaptive, multi-arm studies across multiple institutions. This early support positioned the foundation as a founding partner in a new model of research that breaks through traditional barriers in pediatric cancer and lays the groundwork for sustained progress.

Funding DMG-ACT

PNOC’s DMG ACT

In February 2020, Jace Ward delivered the closing remarks at the inaugural DIPG Advocacy Briefing to Congress in Washington, D.C. He shared his personal journey with ONC201 and urged lawmakers to act on behalf of children battling DIPG. His message—“I can’t die, I’m busy”—resonated deeply and helped bring national attention to the urgent need for research funding and access to promising therapies.

Jace Ward Remarks

Again working with Onoceutics, Michael Mosier Defeat DIPG Foundation, The ChadTough Foundation and Dragon Master Foundation committed $250,000 to support the opening of an additional Expanded Access Program for ONC201 in response to growing demand. Dozens of children gained access who otherwise had no treatment options.
 Additional Round of Expanded Access

Chimerix Expanded Access

2021: Strategic Consolidation and Commercial Turning Point

Michael Mosier Defeat DIPG Foundation and The ChadTough Foundation officially merged to form the ChadTough Defeat DIPG Foundation, combining leadership, networks, and strategic vision to strengthen their collective impact. The merger unlocked new levels of influence and fundraising capacity, enabling deeper, more coordinated investments in high-impact research—particularly around ONC201. Just as importantly, it marked a philosophical shift: an open invitation for other families to join the movement. The merged foundation embraced the idea that defeating this disease would take a united community, welcoming Family, Research & Navigator Partners into the fold. This inclusive model continues to grow, accelerating progress through collaboration, shared resources, and a steadfast commitment to change.

Oncoceutics—the small biotech company that had led the early development of ONC201—was acquired by Chimerix, Inc., a publicly traded biopharmaceutical company. This acquisition was a major turning point for the drug. Chimerix brought expanded infrastructure, regulatory expertise, and financial stability that strengthened the path toward FDA approval. The transition to a larger company meant that ONC201 could progress more rapidly through the later stages of development, gain broader access to regulatory engagement, and prepare for commercial scale. The acquisition helped ensure that the promise of ONC201 would not stall, but continue moving forward toward patients.
 Chimerix Acquires Oncoceutics – Press Release

The infrastructure developed through the DMG-ACT initiative led to the launch of its first clinical trial: PNOC022. This innovative, multi-arm study was designed to evaluate ONC201 in combination with other promising agents in children and young adults with H3 K27M-mutant diffuse midline gliomas, including DIPG. The trial opened to enrollment in November 2021, marking a critical milestone for the collaborative model established by DMG-ACT. It represented the first tangible realization of the foundation-supported effort to transform the clinical research landscape for DMG, moving from fragmented, single-agent studies toward a coordinated, adaptive framework capable of accelerating progress.

 PNOC022 Launch

2022: Scientific Momentum

Building on the success of PNOC022, the DMG‑ACT infrastructure enabled the initiation of PNOC023, an open-label Phase 1 and target validation study evaluating ONC206 in children and young adults with newly diagnosed or recurrent diffuse midline glioma (DMG), along with other recurrent malignant CNS tumors. The trial opened for enrollment in September 2022 at the University Children’s Hospital Zurich—becoming the first ONC206-based study launched under the DMG‑ACT model.

 PNOC023 Launch

That same year, ChadTough Defeat DIPG Foundation awarded a Game Changer Grant to Dr. Richard Lu, whose lab focused on uncovering epigenetic mechanisms behind therapy resistance and sensitivity in DMG. His work offered vital insights into the molecular landscape that determines ONC201 response, supporting smarter trial design and biomarker development.
 2022 Game Changer Grant – Dr. Richard Lu

2023: Scientific Breakthroughs and Global Collaboration

ChadTough Defeat DIPG Foundation doubled down on its commitment to empowering the next generation of researchers. It awarded three research fellowships to Drs. Erik Peterson, Ryan Duchatel, and Akash Deogharkar—each focused on exploring how ONC201 works and why resistance may develop. Their investigations ranged from tumor heterogeneity to therapeutic sequencing and mitochondrial stress response.

Erik Peterson – 2023 Predoctoral Fellowship
 Ryan Duchatel – 2023 Postdoctoral Fellowship
 Akash Deogharkar – 2023 Postdoctoral Fellowship

Meanwhile, the DMG-ACT clinical trial platform continued to expand its global reach and impact. By 2023, more than 40 trial sites worldwide were participating in studies launched under the DMG-ACT infrastructure. The flagship trial, PNOC022, added new treatment arms to evaluate ONC201 in combination with additional investigational agents, furthering its adaptive approach to testing promising therapies for children and young adults with diffuse midline glioma. In parallel, PNOC023, launched under the same umbrella, advanced early-phase evaluation of ONC206, a next-generation imipridone. The continued growth of DMG-ACT reflects the strength of the collaborative model it was built on—bringing together researchers, institutions, and foundations to drive smarter, faster clinical progress against one of the most devastating pediatric brain cancers.

Critical to the eventual FDA approval, a landmark paper led by Drs. Carl Koschmann and Sriram Venneti (Cancer Discovery, Aug 2023) reported significant survival benefit in ONC201–treated children with H3 K27M DMG (median overall survival of ~22 months vs ~12 months historically). The study linked clinical outcomes to metabolic and epigenetic activity—including restored H3K27me3 and altered TCA cycle metabolites—strengthening both the scientific rationale and regulatory momentum for ONC201. It also uncovered EGFR/FOXG1-driven resistance mechanisms, guiding future combination strategies.

  Koschmann et al., Cancer Discovery (2023)

2024: Scaling the Platform, Preparing for Approval

By 2024, DMG-ACT had grown into a global research engine, driving progress across dozens of institutions and rapidly generating data that informed treatment decisions in real time. The PNOC022 trial, supported under the DMG-ACT umbrella, had more than 32 active sites, with multiple ONC201 arms enrolling patients at all stages of the disease—from newly diagnosed to recurrent. This adaptive model not only produced critical clinical insights, but also dramatically expanded access to ONC201 for families facing DIPG who had previously struggled to obtain the drug.

Recognizing the importance of this infrastructure, the ChadTough Defeat DIPG Foundation continued to provide core operating support for DMG-ACT while playing a leading role in regulatory engagement, scientific advocacy, and patient access efforts. The foundation worked closely with researchers, regulators, and company leadership to ensure that families could benefit from emerging science as quickly—and equitably—as possible.

Throughout the year, real-world data from trials like PNOC022 and expanded use programs added weight to the growing body of evidence supporting ONC201. These efforts helped bridge the gap between early-phase trial results and the FDA’s threshold for accelerated approval. In December 2024, Chimerix submitted its New Drug Application (NDA) for ONC201 in recurrent H3 K27M-mutant diffuse midline glioma, marking a pivotal step forward in what had long been considered an untreatable disease.

2025: Approval Achieved, Momentum Sustained

In February 2025, the FDA accepted Chimerix’s New Drug Application (NDA) seeking accelerated approval for ONC201 (dordaviprone) to treat patients with recurrent H3 K27M-mutant diffuse midline glioma. The application was granted Priority Review and assigned a Prescription Drug User Fee Act (PDUFA) target action date of August 18, 2025. ONC201 had previously received Orphan Drug, Fast Track, and Rare Pediatric Disease designations, reinforcing the urgency and promise of the therapy.
 FDA Acceptance & Priority Review

In March, it was announced that Jazz Pharmaceuticals would acquire Chimerix, signaling a major milestone in the drug’s commercial trajectory. The acquisition brought the resources and global infrastructure needed to support ONC201’s broad clinical adoption and future development.
 Jazz Acquires Chimerix

Then, on August 6, 2025, the long-awaited moment arrived: The FDA granted accelerated approval of ONC201 (now known as Modeyso™) for patients with recurrent H3 K27M-mutant diffuse midline glioma—making it the first-ever FDA-approved treatment for DMG/DIPG. The decision marked a historic turning point in pediatric neuro-oncology, validating years of research, collaboration, advocacy, and philanthropic investment.
 FDA Approval Announcement

What’s Next

With ONC201 now FDA-approved for recurrent H3 K27M-mutant diffuse midline glioma, the focus turns to what comes next—and the DMG-ACT platform is at the center of that momentum. As Dr. Carl Koschmann noted, “This is the first drug approved for H3K27M-mutant DMG, and work through DMG-ACT will now receive a huge amount of focus from families and clinicians to establish optimal combinations with ONC201 to be the next step to test in clinical trials.”

The approval unlocks new possibilities: It allows drug developers testing combination therapies under DMG-ACT to pursue FDA approval of their agents in combination with ONC201—a regulatory path that wasn’t possible before. Trials like PNOC022 are already evaluating multiple ONC201-based combinations, and those data will be critical in defining the next generation of treatment.

This approval is not the finish line. It’s the starting gate. For the first time ever, we have an FDA-approved therapy for DMG/DIPG. But one drug is not enough. Now is the moment to accelerate progress—to fund the trials that will unlock powerful combinations, expand access at diagnosis, and deliver real hope to every family facing this disease. The path forward is clear, the infrastructure is in place, and the momentum is on our side. With your support, we can go faster and farther than ever before. Donate today.

Thank you to Dr. Misha Mehta for her contributions to this article.