The Role and Crisis of Opioids in Pain Therapy
Opioids play a pivotal role in pain management because of their potent analgesic properties, making them indispensable for treating severe pain, especially in acute, cancer-related, and palliative care settings. However, opioid uses are increasingly contributing to a global public health crisis, driven by their high potentials for addiction, adverse side effects, and misuse. Beyond these concerns, research suggests that long term opioid use may weaken the immune system and interfere with the body’s natural healing processes.
Chronic pain, defined as daily pain lasting more than three months, can lead to cognitive dysfunction, sleep impairment, reduced physical function, and work absenteeism. The widespread reliance on opioids to manage pain has exacerbated the global healthcare crisis.
Addressing the crisis of opioids overuse requires a comprehensive and multifaceted strategy. This includes developing and implementing alternative, non-opioid pain management therapies that minimize risks while maintaining effective pain relief.
Predicament of Pain Therapy
Multifaceted Dimensions of Pain:
Over millions of years of evolution, pain has developed into a highly complex and refined biological response, intricately linked to multiple mechanisms. Pain serves as a sophisticated alert system that integrates various biological systems to protect and heal the body. Most pain conditions, particularly chronic pain, are multifaceted and complex. They often involve multiple dimensions of pain and are driven by different underlying pathways.
Current Challenges:
Multimodal therapy has been shown to improve outcomes and is widely recommended as the standard of care in many therapeutic areas, including pain. To address the complexities of various painful conditions, healthcare professionals often prescribe multiple analgesics, each with a distinct mode of action. This approach frequently requires multiple prescriptions (the use of multiple drugs), raising concerns about safety, efficacy, proper dosing, and overall costs. A potential solution to these challenges is the development of fixed-dose combination drug products. However, both the use of multiple drugs and fixed-dose combination products often fail to achieve synchronized pharmacokinetics or dual-pathway targeting. These factors are essential for maintaining an optimal balance between effective pain relief and an acceptable tolerability profile. Overall, these challenges primarily arise from differences in the molecular structures of the drugs, which affect their gastrointestinal (GI) absorption and result in differences in bioavailability (BA).
Unmet Need
To effectively address the multifaceted nature of pain, innovative approaches are crucial. Integrating multiple drugs in advanced formulations to simultaneously targeting different pain pathways is essential.
Xgene Innovation
Patentable New
Chemical Entity
Through innovation, we have developed a new platform of designing dual-targeting prodrugs by chemically combining two drugs through conjugation. Within a single molecule, a dual-targeting prodrug combines the distinct actions of two drugs. For example, one component may be a cyclooxygenase (COX) inhibitor, addressing inflammation, pain, fever, and other physiological processes. Meanwhile, the other component targets the α2δ subunit of calcium channels, commonly used for treating neuropathic pain-related disorders, and central sensitization.
Upon absorption and cleavage in the bloodstream, the conjugated dual-targeting prodrug facilitates the coordinated release and synchronized pharmacokinetic profile of the parent drugs. This approach effectively and simultaneously targets multiple pain pathways, while improving the overall pharmacokinetics. By optimizing these properties to enhance efficacy, conjugation also mitigates the potential side effects associated with the parent drugs. This innovative analgesic represents a breakthrough in pain therapy, offering significant advantages over traditional multi-drug regimens or fixed-dose combinations.
Xgene’s innovative platform provides a unique multimodal approach to address the complex multifaceted dimensions of pain therapies. By leveraging medications with mechanisms of action that complement or synergistically enhance each other, Xgene aims to improve treatment outcomes while potentially reducing the complexities and risks associated with the current standard of care.
Values
Synchronized PK Profiles between Drug A and Drug B
A reduction in GI and Central Nervous System side effects (headache, dizziness, sleepiness, confusion, etc.)
Expanding indications beyond
the parent drug
Driven by a patient-centric approach to R&D, our efforts begin by addressing difficult-to-treat, unmet patient needs through non-opioid, dual-targeting conjugated drugs. Our commitment is to advance a robust and sustainable portfolio of medicines aimed at overcoming these obstacles. The innovated medicines have the potential to significantly reduce, if not eliminate, the reliance on opioids for managing various painful conditions. Leveraging the collective expertise of our researchers and partners, Xgene is developing best-in-class and first-in-class solutions. We put particular emphasis on next-generation treatments in the pain management field, targeting substantial market opportunities. Through precision-driven strategies, we are progressing a comprehensive pipeline that spans all stages of development, from discovery through late-stage clinical trials.
PRODUCT CANDIDATE
DISCOVERY
PRECLINICIAL
PHASE 1
PHASE 2
PHASE 3
RIGHTS
ACUTE PAIN
XG005
Oral Tablet
Dual-targeting prodrug conjugate of an NSAID and a gabapentinoid completed II/III trial following 505(b)1 FDA regulatory pathway in the US, demonstrating statistically significant and clinically meaningful analgesic efficacy and improved safety profile, in the acute post-surgical pain following bunionectomy.
Global
CHRONIC PAIN
XG005
Oral Tablet
Dual-targeting prodrug conjugate of an NSAID and a gabapentinoid completed phase II trial following Class 1 regulatory pathway in China, demonstrating statistically significant and clinically relevant results in the chronic pain due to osteoarthritis.
Global
CHRONIC PAIN
XG004
Topical Gel
Dual-targeting prodrug conjugate of an NSAID and a gabapentinoid with high transdermal penetration properties. A Phase Ib/IIa trial, including exploratory analgesic endpoints, in patients with Osteoarthritis of the knee has been completed in Australia with a positive analgesic signal and statistically significant improvement in sleep quality.
Global
CHRONIC PAIN, METASTATIC BONE PAIN
XG2002
Novel Target
TRPM8 channel blocker successfully completed phase I trial in Australia.
Global Excluding Japan
XG045
Patent-pending dual mechanism of action NCE
Global
XG046
Patent-pending dual mechanism of action NCE
Global
Regulatory status of XG005 drug conjugate
NMPA : Recognized it as Class 1 Innovative Drug
U.S. FDA: Designated as NCE with the 505(b)1 development pathway
Clinical development pathway has the potential for acceleration
NMPA directly allows simultaneous development of XG005 for two indications
XG005 entered directly from Phase 1 into first potentially pivotal trial in the US
Pipeline
ACUTE PAIN
XG005
Oral Tablet
Phase 3
Dual-targeting prodrug conjugate of an NSAID and a gabapentinoid completed II/III trial following 505(b)1 FDA regulatory pathway in the US, demonstrating statistically significant and clinically meaningful analgesic efficacy and improved safety profile, in the acute post-surgical pain following bunionectomy.
Global rights
CHRONIC PAIN
XG005
Oral Tablet
Phase 2
Dual-targeting prodrug conjugate of an NSAID and a gabapentinoid completed phase II trial following Class 1 regulatory pathway in China, demonstrating statistically significant and clinically relevant results in the chronic pain due to osteoarthritis.
Global rights
CHRONIC PAIN
XG004
Topical Gel
Phase 1b/2a
Dual-targeting prodrug conjugate of an NSAID and a gabapentinoid with high transdermal penetration properties. A Phase Ib/IIa trial, including exploratory analgesic endpoints, in patients with Osteoarthritis of the knee has been completed in Australia with a positive analgesic signal and statistically significant improvement in sleep quality.
Global rights
CHRONIC PAIN, METASTATIC BONE PAIN
XG2002
Novel Target
Discovery/Pre-clinical has been finished
TRPM8 channel blocker successfully completed phase I trial in Australia.
Global Excluding Japan rights
Pain Discovery Program
XG045
Discovery
Patent-pending dual mechanism of action NCE
Global rights
Pain Discovery Program
XG046
Discovery
Patent-pending dual mechanism of action NCE
Global rights