Seeking Alpha • Aug 23
Chimerix: Advancement For Rare Brain Cancer Drug Targeting Specific Mutation
Initiation of phase 3 ACTION study using ONC201 for treatment of glioma patients who harbor the H3 K27M mutation is expected in the 2nd half of 2022.
Interim results from the ACTION study are expected in early 2025, with final results expected in 2026.
Proof of concept data using ONC201 has already been established in two phase 2 studies; in patients with H3 K27M mutation gliomas and neuroendocrine tumors.
Additional imipridones being developed in the pipeline are ONC206 and ONC212 for oncology indications; CMX521 being advanced as prophylactic and treatment for Covid-19.
Chimerix, Inc. (CMRX) is a great speculative biotech that should be on your radar. While it is still a risky longer-term play, I believe it could have value based on established proof of concept using ONC201 for the treatment of patients with H3 K27M-mutant glioma. In a phase 2 study, it showed to improve overall survival rates in this specific population, which I will show below. The only downside is that the first interim analysis is not expected until early 2025 with final data not coming out until 2026. However, ONC201 is also being explored in a phase 2 study in neuroendocrine tumors. Such neuroendocrine tumors being explored are Pheochromocytoma/paraganglioma. Initial data was revealed which established some proof of concept of the mechanism of action. Even then, it is working on a second generation imipridone known as ONC206 which is much improved compared to 1st generation ONC201.
It is believed that ONC206 provides greater anti-tumor activity compared to ONC201 and thus it is also being advanced in the pipeline. The biotech also entered into an agreement with Emergent BioSolutions ((EBS)) for the sale of worldwide rights to TEMBEXA for a $225 million upfront payment, potential milestone payments and double-digit royalties on net sales as well. It is important to note that this agreement is still in the process of being completed. This agreement relies on additional items being executed. If the agreement goes through with EBS, then the biotech will have enough cash into 2027. Lastly, it is in the process of developing an improved oral formulation of CMX521 as a prophylactic and treatment of SARS-CoV-2 (Covid-19) in collaboration with the Rapidly Emerging Antiviral Drug Development Initiative ((READDI)).
While early in the process and already many approved treatments in this space, I believe it could still act as a catalyst if it is successfully advanced. It is believed that animal data will be released in the 2nd half of 2022 on such an improved oral formulation for CMX521 for Covid-19. With a growing pipeline, plus some established proof of concept of ONC201 in a rare brain glioma and neuroendocrine tumors, I believe it is a great speculative biotech play to look into.
Imipridone ONC201 Could Possibly Greatly Improve Overall Survival Rates For Rare Gliomas
The main drug in Chimerix's pipeline would be ONC201, which is being developed for the treatment of patients with gliomas who harbor the H3 K27M mutation. What occurs with respect to this specific type of glioma? What occurs is the H3K27M mutation itself puts in a new amino acid known as H3, which promotes a gene expression that enable tumor growth to occur. Patients with this type of glioma have poor prognosis and definitely need new types of treatments to be approved.
Before diving into ONC201 clinical results, it's important to understand what the drug actually is. Again, it is an imipridone which targets G protein-coupled receptors (GPCRs) and mitochondrial caseinolytic protease p (ClpP), resulting in cancer death. Cell death happens with the induction of the integrated stress response and upregulation pathway of apoptotic (cell death) factors, such as tumor necrosis factor ((TNF)) related apoptosis-inducing ligand ((TRAIL)). More specifically, it selectively induces cell death by binding and altering activity of DRD2 (Selectively coupled G-protein receptor) and ClpP. This is further established with the following action:
DRD2 antagonism is responsible for inhibiting Ras signaling pathway that cancer has
ClpP degrades excess amount of mitochondrial proteins which are important for the cancer cell to be viable
Remember above when I stated that H3 K27M mutation uses amino acid H3 to promote gene expression for the cancer? Well, ONC201 was established to alter this gene expression making it sensitive to the drug itself. All these actions are what are put in place to specifically treat glioma patients who harbor the H3 K27M mutation.
Moving onto the program advancement at hand, the company intends to initiate a phase 3 study in the 2nd half of 2022 known as ACTION. This is going to be a randomized late-stage study using ONC201 for the treatment of newly diagnosed diffuse glioma patients whose tumors harbor the H3 K27M mutation. It is expected that about 450 patients will be randomized 1:1:1 to receive doses as followed:
625 mg ONC201 once per week
625 mg ONC201 twice per week
Placebo
The primary endpoint of this study is overall survival ((OS)). Patients will first be treated with radiation and then be randomized to one of the dosing groups noted directly above. As far as catalysts go for this study, it could be quite some time to see data. It is said that the first interim analysis for results is not expected until 2025. From there, final data from this ACTION study is not expected until 2026.
The thing is that it may be a good market to tap into despite the fact how rare the H3 K27M mutation glioma is. Chimerix believes it can earn above $500 million in sales annually should it ultimately get ONC201 to market for this specific population. Despite results taking time to come out, it's important to note that there is a great shot at clinical success. That's because ONC201 monotherapy was able to achieve an overall response rate ((ORR)) of 30% by RANO HGG and/or LGG by dual reader BICR. Even better, is what those treated with this drug obtained in terms of overall survival rates. For the H3 K27M recurrent glioma patients given ONC201, overall survival at 12 months and 24 months was 57% and 35%, respectively, whereas historical control at 12 months and 24 months was 27.5% and 6.4%, respectively. What does this show? This shows that with the biotech specifically targeting patients with this H3 K27M mutation by using ONC201, it can improve overall survival for them.
Proof Of Concept For ONC201 In Treatment Of Patients With Neuroendocrine Tumors
In addition to some proof of concept being established in a phase 2 study with ONC201 in patients with H3 K27M mutated gliomas, the drug had also seen some mechanism of action in patients with neuroendocrine tumors. One neuroendocrine tumor being explored is paraganglioma. A paraganglioma is a type of neuroendocrine tumor that forms near certain blood vessels and nerves outside of the adrenal glands. The adrenal glands being affects is not a very good thing, considering they are responsible for making hormones which control many functions in the body. In an open-label phase 2 investigator-initiated study with 30 patients, treatment with ONC201 performed pretty well. The cohort of paraganglioma patients who were dosed with ONC201 once a week performed better than the other cohort of patients dosed twice a week with ONC201. For these patients who were dosed once weekly with ONC201, the outcome was as follows:
5 out of 10 patients (50%) achieved a partial response ((PR))
2 out of 10 patients achieved stable disease ((SD))
The other neuroendocrine tumor also being evaluated with the use of this drug is Pheochromocytoma, which is a hormone secreting tumor that can occur in the adrenal glands.
Additional Shots On Goal With Imipridones ONC206 And ONC212