Introduction to ASTX660
ASTX660, also known as tolinapant, is a novel, orally administered, non-peptidomimetic small-molecule antagonist of cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP). Developed by Astex Pharmaceuticals, a subsidiary of Otsuka Pharmaceutical Co., Ltd., this drug candidate is being investigated for its potential in treating advanced solid tumors and lymphomas.
Mechanism of Action
ASTX660 works by inhibiting the activity of cIAP1/2 and XIAP, proteins that are often overexpressed in cancer cells and contribute to tumor growth, progression, and resistance to treatment. By blocking these proteins, ASTX660 promotes apoptosis (cell death) in cancer cells, which is a critical mechanism in cancer therapy[1][3].
Clinical Trials and Development
Phase I Study
The first-in-human phase I study of ASTX660 evaluated its safety, pharmacokinetics, and preliminary clinical activity in patients with advanced solid tumors or lymphoma. The study used a 7-day-on/7-day-off dosing schedule in a 28-day cycle. The recommended phase II dose (RP2D) was determined to be 180 mg/day, at which ASTX660 demonstrated a manageable safety profile and evidence of pharmacodynamic and clinical activity. Notably, ASTX660 suppressed cIAP1 in peripheral blood mononuclear cells, and clinical activity was observed in a patient with cutaneous T-cell lymphoma[1].
Ongoing and Future Studies
The phase II part of the study is currently enrolling patients. Additionally, ASTX660 is being investigated in combination with standard of care FOLFOX chemotherapy in metastatic colorectal cancer in a separate phase I study[3].
Regulatory Status
ASTX660 has been granted orphan drug designation by the US Food and Drug Administration (FDA) for the treatment of T-cell lymphoma, including peripheral T-cell lymphoma and cutaneous T-cell lymphoma. This designation provides seven years of marketing exclusivity in the US following product approval, along with certain tax incentives and grants[5].
Market Projection
Peripheral T-Cell Lymphoma Market
The peripheral T-cell lymphoma market is expected to grow significantly, driven by the launch of new therapies and a robust clinical pipeline. According to DelveInsight, the market size for peripheral T-cell lymphoma was approximately USD 564 million in 2021 in the 7MM (the United States, EU-4, the United Kingdom, and Japan) and is anticipated to grow at a CAGR of 4.9% by 2032. The total incident population of PTCL in the 7MM was around 18,000 in 2022 and is expected to increase during the study period[2].
Competitive Landscape
The market for peripheral T-cell lymphoma is competitive, with several companies developing novel therapies. Key players include Viracta Therapeutics, Dizal Pharmaceuticals, CStone Pharmaceuticals, and others. The emergence of new treatments, such as ADCETRIS, Azacitidine (CC-486), and COPIKTRA (Duvelisib), is expected to further drive market growth[2].
Clinical Significance and Unmet Need
T-cell lymphoma, particularly peripheral T-cell lymphoma, remains a challenging disease area with a poor prognosis and high unmet medical need. The current treatments often have limited efficacy, and there is a significant need for new therapeutic options. ASTX660, with its unique mechanism of action and promising early clinical data, represents a potential new therapeutic option for these patients[5].
Safety and Tolerability
ASTX660 has demonstrated a manageable safety profile in clinical trials. The phase I study showed that the drug was well tolerated, with no evidence of excessive weight loss or significant adverse effects at the recommended phase II dose[1].
Pharmacokinetics and Pharmacodynamics
Preclinical studies have shown that ASTX660 is orally bioavailable and distributes into tumor xenografts, with detectable levels maintained in these tumors for up to 7 days after a single oral dose. In the phase I study, ASTX660 suppressed cIAP1 in peripheral blood mononuclear cells, indicating sustained biologic activity[1].
Conclusion
ASTX660 is a promising drug candidate in the treatment of advanced solid tumors and lymphomas, particularly T-cell lymphomas. With its orphan drug designation and ongoing clinical trials, ASTX660 is poised to address a significant unmet medical need in this challenging disease area. The market projection indicates a growing demand for effective treatments in peripheral T-cell lymphoma, and ASTX660 could play a crucial role in meeting this demand.
Key Takeaways
- Mechanism of Action: ASTX660 inhibits cIAP1/2 and XIAP, promoting apoptosis in cancer cells.
- Clinical Trials: Phase I study completed; phase II study ongoing.
- Regulatory Status: Granted orphan drug designation by the FDA for T-cell lymphoma.
- Market Projection: Peripheral T-cell lymphoma market expected to grow at a CAGR of 4.9% by 2032.
- Safety and Tolerability: Manageable safety profile with no significant adverse effects.
- Pharmacokinetics and Pharmacodynamics: Orally bioavailable with sustained biologic activity.
FAQs
Q1: What is the primary mechanism of action of ASTX660?
ASTX660 works by inhibiting the activity of cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), promoting apoptosis in cancer cells.
Q2: What is the current clinical status of ASTX660?
ASTX660 has completed its phase I study and is currently in the phase II part of the clinical trial.
Q3: What regulatory designation has ASTX660 received?
ASTX660 has been granted orphan drug designation by the US FDA for the treatment of T-cell lymphoma.
Q4: How is the market for peripheral T-cell lymphoma expected to grow?
The market is expected to grow at a CAGR of 4.9% by 2032, driven by new therapies and a robust clinical pipeline.
Q5: What are the key companies involved in the development of treatments for peripheral T-cell lymphoma?
Key companies include Viracta Therapeutics, Dizal Pharmaceuticals, CStone Pharmaceuticals, and others, along with Astex Pharmaceuticals for ASTX660.
Sources
- A Phase I Study of ASTX660, an Antagonist of Inhibitors of Apoptosis ... - Clinical Cancer Research.
- Peripheral T-Cell Lymphoma Market to Observe Growth at a CAGR of 4.9% in the US by 2032 | DelveInsight - GlobeNewswire.
- Tolinapant - Drug Targets, Indications, Patents - Patsnap Synapse - Synapse.
- P53 tumour suppressor protein (Oncology) - Astex Pharmaceuticals - Astex Pharmaceuticals.
- Astex Pharmaceuticals Announces That Tolinapant (ASTX660), a ... - Astex Pharmaceuticals.