Breakthrough Clinical Results
Harmony Biosciences announced positive preclinical data for BP1.15205, a novel orexin 2 receptor (OX2R) agonist, demonstrating significant wake-promoting and cataplexy-suppressing effects in a mouse model of narcolepsy type 1. The data, presented at SLEEP 2025, showed BP1.15205 to be a highly potent and selective OX2R agonist with a favorable safety profile in preclinical toxicology studies. A first-in-human study is planned for the second half of 2025, with topline data expected in 2026. The company is pursuing regulatory approvals in both the US and Europe.
Key Highlights
- Significant wake-promoting and cataplexy-suppressing effects observed in a mouse model of narcolepsy.
- BP1.15205 is a highly potent and selective OX2R agonist with >600-fold selectivity over OX1R.
- Favorable safety and tolerability profile observed in preclinical toxicology studies.
- First-in-human study planned for 2H 2025, with topline data anticipated in 2026.
Incidence and Prevalence
Narcolepsy Prevalence:
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A meta-review published in 2023 found that narcolepsy occurs in 0.87-1.21% of the world population. This review pooled incidence and prevalence rates reported in 30 countries or from 209 sets of data and specifically investigated narcolepsy type 1 (NT1).
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A 2008 review reported a prevalence of narcolepsy with cataplexy between 25 and 50 per 100,000 people.
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A US health care claims database study (2008-2010) found a higher prevalence of 79.4 per 100,000, with 65.4 per 100,000 without cataplexy and 14.0 per 100,000 with cataplexy. This study noted a higher prevalence in females and those in their early 20s, with regional variations within the US.
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Another US claims database study (2013-2016) showed an increase in narcolepsy prevalence from 38.9 to 44.3 per 100,000. This study also observed higher prevalence in commercially insured individuals compared to Medicare/Medicaid recipients, and lower prevalence in the Northeast US.
Narcolepsy Incidence:
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The 2023 meta-review reported a pooled incidence rate of 1.58 in vaccinated samples for NT1. This highlights the impact of the H1N1 pandemic vaccines on narcolepsy incidence.
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The 2008 review reported a limited incidence of narcolepsy with cataplexy at 0.74 per 100,000 person-years.
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The US health care claims database study (2008-2010) estimated an average annual incidence between 4.87 and 7.67 per 100,000 person-years, depending on the criteria used. The incidence of narcolepsy without cataplexy was several times higher than that with cataplexy.
Important Considerations:
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Underdiagnosis and Underreporting: Narcolepsy is often underdiagnosed, particularly in ethnic/racial and gender minorities, as well as in children with narcolepsy type 2. Comorbid conditions can also mask symptoms, delaying diagnosis.
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Impact of H1N1 Vaccine: The 2023 meta-review highlights the increased incidence of NT1 in vaccinated samples, emphasizing the role of the H1N1 pandemic vaccine in narcolepsy development.
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Data Limitations: Variations in study methodologies and data sources contribute to the range of reported prevalence and incidence rates. Further research is needed to refine these estimates and better understand the global burden of narcolepsy.
Mechanism of Action
Modafinil, while approved for narcolepsy, has been investigated in trials for other conditions where it ultimately did not receive approval. Some of the most common mechanisms of action explored in these trials, though not necessarily the only ones, include:
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Dopamine and Norepinephrine Reuptake Inhibition: This mechanism is central to modafinil's wake-promoting effects in narcolepsy. It was also explored in trials for conditions like Attention Deficit Hyperactivity Disorder (ADHD), where modafinil showed efficacy in some studies, even comparable to methylphenidate. However, concerns about dermatological toxicity and the availability of other established treatments contributed to its non-approval for ADHD.
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Cytochrome P450 Isoenzyme Modulation: Modafinil's interaction with these enzymes affects drug metabolism, a factor considered in trials for conditions like cocaine addiction. While some studies explored whether modafinil could alter the metabolism of cocaine or reduce cravings, inconsistent results and small sample sizes prevented definitive conclusions and subsequent approval.
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Unknown Mechanisms with Placebo Effects: In several conditions, including traumatic brain injury, major depressive disorder, schizophrenia, post-polio fatigue, and multiple sclerosis, modafinil demonstrated a substantial placebo effect on outcomes like fatigue and sleepiness. However, it did not show benefits beyond placebo, hindering its approval. The exact mechanisms underlying these placebo responses remain unclear, but they highlight the complex interplay of neurochemical and psychological factors in these conditions.
It's important to note that these are not exhaustive, and modafinil's actions are still not fully understood. Furthermore, the reasons for non-approval are often multifaceted, involving not only efficacy but also safety, existing treatment options, and regulatory considerations.
Drug used in other indications
BP1, also known as DLX4, is a homeobox transcription factor, and its isoform, BP1, is primarily studied in the context of cancer, particularly breast cancer. While the provided text mentions pitolisant as a treatment for narcolepsy, there is no mention of BP1 or DLX4 being trialled for this condition.
BP1 in Cancer Research:
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Breast Cancer: BP1 is overexpressed in about 80% of invasive ductal breast carcinomas and is associated with aggressive phenotypes, poor prognosis, and estrogen receptor negativity, leading to resistance to anti-estrogen therapies. Studies have shown that BP1 overexpression promotes cell growth, estrogen-independent tumor formation, and increased proliferation in breast cancer cells, suggesting its potential as a biomarker and therapeutic target.
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Other Malignancies: The provided text also mentions that BP1's role is being investigated in four other unspecified malignancies. Further information would be needed to determine the specific types of cancer and the nature of these investigations.
Intervention Models in BP1-Related Cancer Trials (Hypothetical):
Since the provided text does not detail specific trials involving BP1, the following are hypothetical examples of intervention models that might be employed in such trials:
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Targeted Therapy: Developing drugs that specifically inhibit BP1 activity to reduce tumor growth and progression. This could involve small molecule inhibitors or other targeted approaches like RNA interference. Phase I trials would focus on dose-finding and safety, while later phases would evaluate efficacy in specific cancer types.
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Combination Therapy: Combining BP1 inhibitors with existing chemotherapy or other targeted therapies to enhance treatment efficacy and overcome resistance mechanisms. Trials would investigate different combinations and schedules to optimize treatment outcomes.
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Biomarker-Driven Trials: Using BP1 expression levels as a biomarker to select patients most likely to benefit from BP1-targeted therapies. This could involve basket trials that enroll patients with different cancer types but share the common biomarker of BP1 overexpression.
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Immunotherapy: Exploring the potential of combining BP1-targeted therapies with immunotherapy approaches like checkpoint inhibitors to enhance anti-tumor immune responses.
It's important to note that these are just examples, and the actual intervention models used in BP1-related trials would depend on the specific cancer type, stage of disease, and available therapeutic options.