Ono Ends ONO-1110 in Psychiatry But Chases Pain After Missed Endpoints

Ono Pharma Discontinues ONO-1110 Development for Depression and Social Anxiety

Ono Pharma has announced the discontinuation of its endocannabinoid modulator ONO-1110 for depression and social anxiety disorder after the drug failed to show efficacy signals in five Phase 2 trials. Despite these setbacks, the Japanese company plans to continue developing ONO-1110 for three pain indications: postherpetic neuralgia (PHN), fibromyalgia (FM), and Hunner-type interstitial cystitis (HIC). This decision comes even though the pain studies also missed their primary endpoints, with Ono citing encouraging improvements in pain scores as a basis for further clinical trials. The news, alongside the discontinuation of a Phase 1 candidate ONO-4578 for non-small cell lung cancer, impacted sentiment for the drugmaker despite product sales of approximately $431 million in the fiscal second quarter.

• Ono Pharma has ceased development of ONO-1110 for depression and social anxiety disorder. This decision follows the drug's failure to demonstrate efficacy signals across five distinct Phase 2 clinical trials, indicating a lack of therapeutic benefit in these neuropsychiatric conditions. The company offered limited specific details regarding the nature of these failures beyond the absence of positive efficacy data.
• Despite ONO-1110 missing its primary endpoints in three separate Phase 2 pain studies, Ono Pharma remains committed to exploring its potential in pain indications. The company reported observing encouraging improvements in pain scores for postherpetic neuralgia, fibromyalgia, and Hunner-type interstitial cystitis, prompting plans for additional clinical trials to further investigate the drug's utility in these areas.
• In addition to the ONO-1110 developments, Ono Pharma also announced other pipeline changes. The company discontinued a Phase 1 candidate, ONO-4578, for non-small cell lung cancer. However, ONO-4578 will continue its development path in a Phase 3 trial for gastric cancer and a Phase 2 trial for colorectal cancer, indicating a strategic refocusing of this asset.

The Persistent Hurdles in Depression Treatment Development

Current treatments for major depressive disorder are limited by delayed benefit, incomplete response, and poor long-term durability. Although antidepressant medications are effective in about 50-70% of patients with major depressive disorder (MDD), latency, resistance, relapse, and tolerability continue to constrain outcomes.

• Delayed onset of therapeutic effect prolongs impairment and risk. The latency prolongs the impairments associated with depression, leaves patients vulnerable to an increased risk of suicide, increases the likelihood that a patient will prematurely discontinue therapy, and increases medical costs associated with severe depression.

• Treatment-resistant depression is common and definitionally heterogeneous. A consensus definition of TRD with demonstrated predictive utility does not currently exist, while the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition, and a significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment).

• Remission is frequently not sustained and relapse increases burden. Seventy percent (32 of 46) of participants entered remission the week following Stanford Neuromodulation Therapy (SNT), while after 12 weeks of treatment, 15 of 46 (33%) participants remained in remission. Relapse was defined as suicide attempts, psychiatric hospitalization, mental health-related emergency department (ED) visit, use of electroconvulsive therapy, or reinitiation of treatment after a gap ≥6 months, with patients with relapse having significantly higher rates of hospitalization (16.6% vs 8.5%) and ED visits (54.8% vs 34.7%) and total costs ($12,594 vs $10,445).

• Tolerability limits adherence and long-term recovery. SSRIs and SNRIs can still cause nausea, headache, sleep disturbances, dry mouth, weight gain and sexual dysfunction, and traditional antidepressant therapies are associated with adverse events, such as sexual side effect, weight gain, which could limit their use in patients with multiple sclerosis (MS). Long-term tolerability is important in facilitating adherence to treatment and thereby maintaining control over depressive symptoms.

• Co-morbidity increases severity and complicates treatment selection. Depression and anxiety disorders frequently co-occur, a type of co-morbidity associated with higher severity, suicidality, chronicity and treatment resistance, while available treatment guidelines mainly focus on treatment for singular disorders. In MDD with comorbid post-traumatic stress disorder, current suicide risk was associated with concurrent PTSD (OR = 3.58, 95%CI:1.30-9.91), and high rates of co-occurring psychiatric disorders may explain in part the difficulty providers have treating patients with co-occurring opioid use disorder and chronic pain.

• Trial evidence has limited generalizability and early signals are unreliable. Less than one in seven depressed patients would be eligible to participate in antidepressant clinical trials, with depressed patients who are suicidal or who score higher than 30 on the 17-item HAM-D excluded, and differences in times to onset have been shown in studies not specifically designed to detect differences in onset of action (post-hoc analysis). Early improvement is not a reliable outcome predictor in TRD, with very early improvement showing sensitivity = 0.52 and AUC = 0.67, and early improvement showing sensitivity = 0.87, specificity = 0.71 and AUC = 0.76.

ONO-1110's New Path: Targeting Chronic Pain Indications

The knowledge base does not have sufficient information to answer this question.

Endocannabinoid Modulation: A Broader Look Beyond ONO-1110

The knowledge base does not have sufficient information to answer this question.

Ono's Endocannabinoid Pivot: A High-Stakes Bet on Pain

Ono Pharma's recent portfolio adjustments signal a strategic recalibration, particularly concerning its endocannabinoid modulator, ONO-1110. The decision to halt development for depression and social anxiety disorder, following a lack of efficacy signals in Phase 2 trials, reflects the persistent challenges in translating the promise of endocannabinoid system modulation into effective treatments for complex psychiatric conditions. Research indicates that while the endocannabinoid system plays a crucial role in mood and stress response, and compounds like palmitoylethanolamide show potential, clinical translation for mood disorders remains limited and complex.

Conversely, the company's commitment to ONO-1110 for postherpetic neuralgia (PHN), fibromyalgia (FM), and Hunner-type interstitial cystitis (HIC), despite these pain studies also missing primary endpoints, represents a high-stakes bet. Ono cites 'encouraging improvements in pain scores' as the rationale for continuation. This strategy, however, introduces significant clinical development risk. Relying on secondary or exploratory endpoints to justify further investment can be precarious, as these signals may not consistently translate into successful outcomes in larger, pivotal trials required for regulatory approval.

Moreover, ONO-1110 faces a formidable competitive landscape in these pain indications:

• Postherpetic Neuralgia (PHN): This market is well-served by established therapies like pregabalin, which has demonstrated efficacy in reducing pain and improving sleep. Emerging treatments such as botulinum toxin A, methylene blue infusions, and neuromodulation techniques like spinal cord stimulation also offer effective alternatives, creating a crowded field for any new entrant.

• Fibromyalgia (FM): This indication is notoriously difficult, with some analgesics, including nortriptyline, failing to show superiority to placebo. ONO-1110 would need to demonstrate a compelling and consistent efficacy profile to differentiate itself.

• Hunner-type Interstitial Cystitis (HIC): While a high unmet need exists, novel approaches like low-energy shock wave therapy combined with botulinum toxin A instillation and systemic ozone therapy are showing promise, indicating a dynamic treatment landscape.

Ono's pivot underscores the ongoing industry challenge of optimizing R&D portfolios. While the discontinuation of the NSCLC candidate ONO-4578 is a setback, the strategic focus on ONO-1110 in pain suggests a deep conviction in the endocannabinoid mechanism for these specific conditions. Success will hinge on robust trial design, clear demonstration of clinical benefit, and a strong differentiation strategy to navigate these competitive and challenging therapeutic areas.