The landscape of cancer treatment has seen significant advancements with the emergence of targeted therapeutics. These innovative approaches aim to precisely attack cancer cells while minimizing harm to healthy tissues. This approach offers more effective, less toxic interventions than traditional treatments. Attivare Therapeutics is a company actively involved in developing such focused therapies in oncology.
Attivare Therapeutics Overview
Attivare Therapeutics is a biotechnology company developing novel drugs. The company focuses on oncology, specifically targeting aggressive and difficult-to-treat cancers. Their overarching mission involves identifying unique vulnerabilities in cancer cells and developing compounds that can selectively exploit these weaknesses. This approach aims to provide patients with more effective and tolerable treatment options.
The company’s primary drug candidate is ONC201, also known as Kevetrin. Attivare Therapeutics has positioned ONC201 as a leading investigational therapy for certain types of brain tumors, particularly those with specific genetic mutations. The development of ONC201 reflects the company’s commitment to precision medicine in cancer care.
How Their Lead Compound Works
Attivare Therapeutics’ lead compound, ONC201, operates through a dual mechanism of action. It functions as a selective antagonist of the dopamine receptor D2 (DRD2) and an agonist of the caseinolytic mitochondrial matrix peptidase proteolytic subunit (ClpP). This dual targeting disrupts processes essential for cancer cell survival and proliferation.
The antagonism of DRD2 by ONC201 leads to the inactivation of two cellular signaling pathways, Akt and ERK. This inactivation triggers programmed cell death, known as apoptosis, through a process mediated by TNF-related apoptosis-inducing ligand (TRAIL). Furthermore, ONC201’s agonistic activity on ClpP, a mitochondrial protease, induces mitochondrial dysfunction within cancer cells. Mitochondria are the powerhouses of cells, and their disruption can severely impair a cancer cell’s ability to generate energy and maintain its structure.
ONC201’s selectivity is relevant in certain cancers, such as diffuse midline gliomas with the H3 K27M mutation. In these tumors, increased DRD2 expression makes them more susceptible to ONC201’s effects. This allows ONC201 to selectively kill glioma cells while sparing normal tissues. The compound also crosses the blood-brain barrier, which is a significant advantage for treating brain tumors.
Clinical Progress and Research
ONC201 has progressed through various phases of clinical trials, primarily focusing on diffuse midline glioma (DMG) with the H3 K27M mutation. These gliomas are aggressive and often affect children, with limited effective treatments beyond radiation. Early studies have shown that ONC201 can induce durable responses in adults with recurrent H3 K27M-mutant DMG.
A Phase 1 pediatric trial evaluated the safety of ONC201 in children with DMG who had received prior radiation therapy. The adult recommended Phase II dose, scaled by body weight, was well tolerated in pediatric patients, showing a similar safety and pharmacokinetic profile to adults. This trial indicated no dose-limiting toxicity.
Further research includes a Phase 2 clinical trial that examined ONC201 as a monotherapy, reporting an overall response rate of 30% with an average duration of response around 52.7 weeks. Another patient in this trial showed stable disease for over 12 months, eventually leading to a partial response. A Phase 3 clinical trial, known as ACTION (NCT05580562), is currently evaluating the effectiveness and safety of ONC201 in individuals with this specific genetic mutation in their brain tumors. This randomized, double-blind, placebo-controlled trial assesses overall survival, progression-free survival, safety, quality of life, and biomarkers.
Ongoing research also explores ONC201 in combination with other agents. For instance, a Phase 2 trial (PNOC022) is investigating ONC201 in combination with drugs like panobinostat or paxalisib for DMG to improve outcomes. These combination studies assess the efficacy of different drug combinations and revised dosing schedules of ONC201, expanding its therapeutic applications.