Skye Bioscience Clinical Model Demonstrating Necessity of Peripheral CB1 Inhibition for Weight Loss Presented at European Congress on Obesity
Skye Bioscience (NASDAQ: SKYE) presented a clinical pharmacokinetic and pharmacodynamic model at the European Congress on Obesity that demonstrates peripheral CB1 inhibition alone is sufficient for weight loss, while central (brain) inhibition is not required. The model analyzed data from various CB1 inhibitors including nimacimab, monlunabant, and rimonabant.
The study revealed that nimacimab showed the greatest peripheral restriction compared to small molecule-based inhibitors, with minimal brain penetration while maintaining sufficient peripheral inhibition. The Phase 2 dose of nimacimab achieves peripheral CB1 engagement at >7x the inhibition threshold while remaining >600x below this threshold in the brain, suggesting a potentially superior therapeutic index with fewer neuropsychiatric side effects.
Skye Bioscience (NASDAQ: SKYE) ha presentato al Congresso Europeo sull'Obesità un modello farmacocinetico e farmacodinamico clinico che dimostra come l'inibizione periferica del CB1 da sola sia sufficiente per la perdita di peso, senza necessità di inibizione centrale (cerebrale). Il modello ha analizzato dati provenienti da diversi inibitori del CB1, tra cui nimacimab, monlunabant e rimonabant.
Lo studio ha evidenziato che nimacimab presenta la più marcata restrizione periferica rispetto agli inibitori basati su piccole molecole, con minima penetrazione cerebrale mantenendo comunque un'inibizione periferica adeguata. La dose di fase 2 di nimacimab raggiunge un coinvolgimento periferico del CB1 superiore a 7 volte la soglia di inibizione, restando oltre 600 volte al di sotto di questa soglia nel cervello, suggerendo un indice terapeutico potenzialmente superiore con meno effetti neuropsichiatrici indesiderati.
Skye Bioscience (NASDAQ: SKYE) presentó en el Congreso Europeo sobre Obesidad un modelo farmacocinético y farmacodinámico clínico que demuestra que la inhibición periférica del CB1 por sí sola es suficiente para la pérdida de peso, sin necesidad de inhibición central (cerebral). El modelo analizó datos de varios inhibidores del CB1, incluyendo nimacimab, monlunabant y rimonabant.
El estudio reveló que nimacimab mostró la mayor restricción periférica en comparación con inhibidores basados en moléculas pequeñas, con mínima penetración cerebral mientras mantenía una inhibición periférica suficiente. La dosis de fase 2 de nimacimab logra un compromiso periférico del CB1 superior a 7 veces el umbral de inhibición, permaneciendo más de 600 veces por debajo de este umbral en el cerebro, lo que sugiere un índice terapéutico potencialmente superior con menos efectos secundarios neuropsiquiátricos.
Skye Bioscience(NASDAQ: SKYE)는 유럽 비만 학회에서 임상 약동학 및 약력학 모델을 발표하며 말초 CB1 억제만으로도 체중 감소가 가능하다고 밝혔으며, 중추(뇌) 억제는 필요하지 않다고 설명했습니다. 이 모델은 니마시맙, 몬루나반트, 리모나반트를 포함한 다양한 CB1 억제제의 데이터를 분석했습니다.
연구 결과 니마시맙은 소분자 기반 억제제에 비해 가장 뛰어난 말초 제한성을 보였으며, 뇌 침투는 최소화하면서도 충분한 말초 억제를 유지했습니다. 니마시맙의 2상 용량은 억제 임계값보다 7배 이상 높은 말초 CB1 결합을 달성하는 반면, 뇌에서는 이 임계값보다 600배 이상 낮아 신경정신 부작용이 적은 잠재적으로 우수한 치료 지수를 시사합니다.
Skye Bioscience (NASDAQ : SKYE) a présenté lors du Congrès européen sur l'obésité un modèle pharmacocinétique et pharmacodynamique clinique démontrant que l'inhibition périphérique du CB1 seule suffit pour la perte de poids, alors que l'inhibition centrale (cérébrale) n'est pas nécessaire. Le modèle a analysé des données provenant de divers inhibiteurs du CB1, notamment nimacimab, monlunabant et rimonabant.
L'étude a révélé que nimacimab présentait la plus grande restriction périphérique comparée aux inhibiteurs à base de petites molécules, avec une pénétration cérébrale minimale tout en maintenant une inhibition périphérique suffisante. La dose de phase 2 de nimacimab atteint un engagement périphérique du CB1 supérieur à 7 fois le seuil d'inhibition, tout en restant plus de 600 fois en dessous de ce seuil dans le cerveau, suggérant un indice thérapeutique potentiellement supérieur avec moins d'effets secondaires neuropsychiatriques.
Skye Bioscience (NASDAQ: SKYE) stellte auf dem Europäischen Kongress zur Adipositas ein klinisches pharmakokinetisches und pharmakodynamisches Modell vor, das zeigt, dass eine periphere CB1-Hemmung allein für Gewichtsverlust ausreicht, während eine zentrale (Gehirn-) Hemmung nicht erforderlich ist. Das Modell analysierte Daten verschiedener CB1-Inhibitoren, darunter nimacimab, monlunabant und rimonabant.
Die Studie ergab, dass nimacimab im Vergleich zu kleinen Molekül-Inhibitoren die stärkste periphere Einschränkung aufweist, mit minimaler Gehirndurchdringung bei gleichzeitig ausreichender peripherer Hemmung. Die Phase-2-Dosis von nimacimab erreicht eine periphere CB1-Bindung von über dem 7-fachen des Hemmschwellenwerts, während sie im Gehirn mehr als 600-fach unter diesem Schwellenwert bleibt, was auf einen potenziell überlegenen therapeutischen Index mit weniger neuropsychiatrischen Nebenwirkungen hinweist.
- Nimacimab demonstrates superior peripheral restriction compared to competitors
- Phase 2 dose achieves 7x peripheral inhibition threshold with minimal brain exposure
- Model validates the company's therapeutic approach for weight loss
- Potential for better safety profile due to minimal brain penetration
- Still in early clinical stages with no proven efficacy in humans yet
- Competitive market with established players like Novo Nordisk and Sanofi
Insights
Skye's data strengthens nimacimab's position in obesity treatment by demonstrating peripheral CB1 inhibition alone drives weight loss without brain-related side effects.
Skye Bioscience has presented a compelling pharmacokinetic/pharmacodynamic model at the European Congress on Obesity that provides critical differentiation for their lead candidate nimacimab in the competitive obesity drug landscape. The model confirms that peripheral CB1 inhibition outside the brain is sufficient for weight loss efficacy, while central (brain) inhibition is unnecessary and associated with neuropsychiatric side effects.
This finding represents a significant advantage for nimacimab, an antibody-based CB1 inhibitor that shows minimal brain penetration compared to small-molecule competitors like monlunabant (Novo Nordisk) and rimonabant (Sanofi). The data revealed that rimonabant at low doses (5mg) reached the brain but had insufficient peripheral activity, resulting in minimal weight loss. Conversely, monlunabant showed similar weight loss across doses despite increasing brain penetration, confirming peripheral activity drives efficacy.
Nimacimab's therapeutic index (ratio of effective dose to toxic dose) appears superior because it achieves peripheral CB1 engagement at 7× the inhibition threshold while remaining 600× below the threshold in the brain. This exceptional brain/periphery separation addresses the historical challenge that derailed rimonabant's commercialization – neuropsychiatric side effects including anxiety and depression.
The model integrates published clinical data from competitors' trials with nimacimab's Phase 1 data, strengthening the scientific foundation for Skye's approach. This pharmacological validation comes at a crucial time as the company prepares for Phase 2 trials, potentially positioning nimacimab as a differentiated entrant in the rapidly expanding GLP-1-dominated obesity market. The antibody approach offers a mechanistically distinct alternative that could complement or compete with existing therapies.
• This model demonstrates that central inhibition of CB1 is not required for weight loss
• Anti-CB1 inhibiting antibody, nimacimab, showed greatest peripheral restriction compared with monlunabant and rimonabant, small molecule-based CB1 inhibitors, which both exhibited increasing dose-dependent brain penetration
• This model predicts nimacimab’s potentially superior therapeutic index, which is dependent on minimal brain exposure while maintaining sufficient peripheral inhibition
SAN DIEGO, May 13, 2025 (GLOBE NEWSWIRE) -- Skye Bioscience, Inc. (Nasdaq: SKYE) (“Skye”), a clinical-stage biotechnology company focused on unlocking new therapeutic pathways for obesity and other metabolic health disorders, presented a clinical pharmacokinetic (“PK”) and pharmacodynamic (“PD”) model that underscores the fundamental relationship between biodistribution and efficacy of CB1 inhibitors at the annual European Congress on Obesity meeting. This model demonstrated that achieving strong peripheral CB1 inhibition is sufficient to achieve efficacy, including weight loss. In contrast, blocking CB1 in the brain (central inhibition), which is associated with neuropsychiatric side effects, is not enough on its own to achieve weight loss.
Published clinical PK and potency data coupled with Phase 2 (“P2”) and Phase 3 efficacy data from Novo Nordisk’s monlunabant and Sanofi’s rimonabant, respectively, as well as Phase 1 data from nimacimab were used to develop a model to determine whether peripheral CB1 inhibition alone is sufficient for weight loss, or if central inhibition is also required for optimal efficacy. The results showed that central inhibition of CB1 alone was not sufficient for weight loss with P2 data for monlunabant, and demonstrated that increasing drug levels in the brain did not improve efficacy. Relatedly, monlunabant’s Ph2 dose range established that all doses achieved significant peripheral inhibition, resulting in significant but similar weight loss. The model also showed that a 5 mg dose of rimonabant that had significant levels in the brain but not peripherally was not effective, leading to only minimal weight loss.
“This model meaningfully advances our understanding of how CB1 inhibitors work, demonstrating that peripheral and not central target engagement is foundational to achieving efficacy including weight loss. Moreover, it clarifies how the therapeutic index of CB1 inhibitors is tied to the relationship between receptor inhibition in the brain, or centrally, versus peripherally--and the widest therapeutic index is associated with the greatest peripheral restriction,” said Punit Dhillon, CEO. “Our clinical model, together with Skye’s recent mouse diet-induced obesity studies, highlights that nimacimab can potentially achieve significant weight loss with a molecule uniquely restricted to tissues outside the brain. We believe nimacimab’s highly favorable therapeutic index sets our antibody-based drug apart from small-molecule CB1 inhibitors.”
Beyond the relationship with weight loss, using reported safety data from the same clinical trials allowed the model to provide further insight into the therapeutic index of different CB1 inhibitors. Unlike weight loss, neuropsychiatric adverse events such as anxiety and mood changes became present and escalated as CB1 inhibition in the brain increased. While nimacimab has been shown to be virtually undetectable in the brain, penetration into the brain is a challenge small molecule CB1 inhibitors such as rimonabant and monulunabant continue to face.
Dr. Chris Twitty, Chief Scientific Officer added, “While the sufficiency of peripheral CB1 inhibition, as it relates to metabolic gains including weight loss, has been demonstrated preclinically in tissue-specific knock-out systems, our modeling provides a clinical lens that demonstrates parallel findings. Our data show that nimacimab’s Phase 2 dose achieves peripheral CB1 engagement at more than seven times the inhibition threshold, while remaining over 600 times below this threshold in the brain. We remain confident in our belief that the Phase 2 dose of nimacimab will be safe and effective, with potent inhibition and a favorable PK profile in the periphery with very little presence in the brain.”
The poster can be accessed on Skye’s Spotlight page.
About Skye Bioscience
Skye is focused on unlocking new therapeutic pathways for metabolic health through the development of next-generation molecules that modulate G-protein coupled receptors. Skye's strategy leverages biologic targets with substantial human proof of mechanism for the development of first-in-class therapeutics with clinical and commercial differentiation. Skye is conducting a Phase 2 clinical trial (ClinicalTrials.gov: NCT06577090) in obesity for nimacimab, a negative allosteric modulating antibody that peripherally inhibits CB1. This study is also assessing the combination of nimacimab and a GLP-1R agonist (Wegovy®). For more information, please visit: www.skyebioscience.com. Connect with us on X and LinkedIn.
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FORWARD-LOOKING STATEMENTS
This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. In some cases, forward-looking statements can be identified by terminology including “anticipated,” “plans,” “goal,” “focus,” “aims,” “intends,” “believes,” “can,” “could,” “challenge,” “predictable,” “will,” “would,” “may” or the negative of these terms or other comparable terminology. These forward-looking statements include, but are not limited to: (i) statements regarding the superior safety and tolerability profile of nimacimab relative to other small molecule CB1 inhibitors, (ii) statements relating to any expectations regarding the efficacy and therapeutic potential of nimacimab as a monotherapy or in combination with a GLP-1 targeted drug, including expectations based on clinical models of rimonabant and monlunabant and nimacimab , (iii) statements regarding nimacimab’s potential to achieve significant weight loss, and (iv) statements regarding superior potency of nimacimab to other small molecule CB1 inhibitors based on nimacimab’s mechanism of action. Such statements and other statements in this press release that are not descriptions of historical facts are forward-looking statements that are based on management’s current expectations and assumptions and are subject to risks and uncertainties. If such risks or uncertainties materialize or such assumptions prove incorrect, our business, operating results, financial condition, and stock price could be materially negatively affected. We operate in a rapidly changing environment, and new risks emerge from time to time. As a result, it is not possible for our management to predict all risks, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements the Company may make. Risks and uncertainties that may cause actual results to differ materially include, among others, our capital resources, uncertainty regarding the results of future testing and development efforts and other risks that are described in the Company’s periodic filings with the Securities and Exchange Commission, including in the “Risk Factors” section of Skye’s most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q. Except as expressly required by law, Skye disclaims any intent or obligation to update these forward-looking statements.
FAQ
What did Skye Bioscience's (SKYE) clinical model reveal about CB1 inhibition and weight loss?
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