Arrowhead Pharmaceuticals Presents Preclinical Data on ARO-ALK7 for Treatment of Obesity
Arrowhead Pharmaceuticals (NASDAQ: ARWR) presented preclinical data on ARO-ALK7, its investigational RNAi therapeutic targeting ALK7 for obesity treatment, at the Keystone Symposia on Obesity and Adipose Tissue in February 2025. The company received regulatory clearance to begin a Phase 1/2a clinical trial in New Zealand, with dosing expected in Q2 2025.
Preclinical studies showed dose-dependent reductions in ALK7 mRNA in adipose tissue, with approximately 80% knockdown at 0.3 mg/kg and 91% at 1.5 mg/kg in non-human primates. In diet-induced obese mice, ARO-ALK7 suppressed body weight gain by 40% and reduced fat mass by approximately 50% while preserving lean mass.
Notably, when combined with tirzepatide (a GLP-1/GIP receptor co-agonist), ARO-ALK7 showed additive effects on weight and fat loss while ameliorating tirzepatide's lean mass reduction. The fat loss mechanism involves increased energy expenditure and lipolysis without affecting food intake. Toxicology studies in rats showed the treatment was generally well-tolerated.
Arrowhead Pharmaceuticals (NASDAQ: ARWR) ha presentato dati preclinici su ARO-ALK7, il suo terapeutico RNAi in fase di sperimentazione mirato all'ALK7 per il trattamento dell'obesità, durante le Keystone Symposia sull'Obesità e il Tessuto Adiposo nel febbraio 2025. L'azienda ha ricevuto l'autorizzazione regolatoria per avviare uno studio clinico di fase 1/2a in Nuova Zelanda, con somministrazioni previste nel secondo trimestre del 2025.
Gli studi preclinici hanno mostrato riduzioni dose-dipendenti dell'mRNA di ALK7 nel tessuto adiposo, con una riduzione di circa l'80% a 0,3 mg/kg e del 91% a 1,5 mg/kg in primati non umani. Nei topi obesi indotti dalla dieta, ARO-ALK7 ha soppressato l'aumento di peso corporeo del 40% e ridotto la massa grassa di circa il 50%, preservando la massa magra.
È interessante notare che, quando combinato con il tirzepatide (un co-agonista del recettore GLP-1/GIP), ARO-ALK7 ha mostrato effetti additivi sulla perdita di peso e di grasso, migliorando la riduzione della massa magra indotta dal tirzepatide. Il meccanismo di perdita di grasso coinvolge un aumento della spesa energetica e della lipolisi senza influenzare l'assunzione di cibo. Gli studi tossicologici sui ratti hanno mostrato che il trattamento è stato generalmente ben tollerato.
Arrowhead Pharmaceuticals (NASDAQ: ARWR) presentó datos preclínicos sobre ARO-ALK7, su terapia experimental de RNAi dirigida a ALK7 para el tratamiento de la obesidad, en las Keystone Symposia sobre Obesidad y Tejido Adiposo en febrero de 2025. La compañía recibió la autorización regulatoria para iniciar un ensayo clínico de fase 1/2a en Nueva Zelanda, con dosis esperadas en el segundo trimestre de 2025.
Los estudios preclínicos mostraron reducciones dependientes de la dosis en el ARNm de ALK7 en el tejido adiposo, con aproximadamente un 80% de reducción a 0.3 mg/kg y un 91% a 1.5 mg/kg en primates no humanos. En ratones obesos inducidos por la dieta, ARO-ALK7 suprimió el aumento de peso corporal en un 40% y redujo la masa grasa en aproximadamente un 50%, mientras preservaba la masa magra.
Notablemente, cuando se combinó con tirzepatide (un co-agonista del receptor GLP-1/GIP), ARO-ALK7 mostró efectos aditivos en la pérdida de peso y de grasa, al tiempo que mejoraba la reducción de masa magra inducida por tirzepatide. El mecanismo de pérdida de grasa implica un aumento del gasto energético y la lipólisis sin afectar la ingesta de alimentos. Los estudios de toxicología en ratas mostraron que el tratamiento fue generalmente bien tolerado.
Arrowhead Pharmaceuticals (NASDAQ: ARWR)는 2025년 2월 비만 및 지방 조직에 관한 Keystone Symposia에서 ALK7을 표적으로 하는 RNAi 치료제 ARO-ALK7에 대한 전임상 데이터를 발표했습니다. 이 회사는 뉴질랜드에서 1/2a상 임상 시험을 시작할 수 있는 규제 승인을 받았으며, 2025년 2분기에 투여가 예상됩니다.
전임상 연구에서는 지방 조직에서 ALK7 mRNA의 용량 의존적 감소가 나타났으며, 비인간 영장류에서 0.3 mg/kg에서 약 80%, 1.5 mg/kg에서 91%의 감소가 관찰되었습니다. 식이요법으로 유도된 비만 쥐에서 ARO-ALK7은 체중 증가를 40% 억제하고 지방량을 약 50% 줄이며, 제지방량은 보존했습니다.
특히, tirzepatide(GLP-1/GIP 수용체 공동 작용제)와 결합했을 때 ARO-ALK7은 체중 및 지방 손실에 부가적 효과를 나타내면서 tirzepatide의 제지방량 감소를 완화했습니다. 지방 손실 메커니즘은 음식 섭취에 영향을 미치지 않으면서 에너지 소비와 지방 분해가 증가하는 것을 포함합니다. 쥐에서의 독성학 연구에서는 치료가 일반적으로 잘 견디는 것으로 나타났습니다.
Arrowhead Pharmaceuticals (NASDAQ: ARWR) a présenté des données précliniques sur ARO-ALK7, sa thérapie expérimentale par RNAi ciblant ALK7 pour le traitement de l'obésité, lors des Keystone Symposia sur l'Obésité et le Tissu Adipeux en février 2025. La société a obtenu l'autorisation réglementaire pour commencer un essai clinique de phase 1/2a en Nouvelle-Zélande, avec des doses attendues au deuxième trimestre 2025.
Les études précliniques ont montré des réductions dépendantes de la dose de l'ARNm ALK7 dans le tissu adipeux, avec environ 80 % de suppression à 0,3 mg/kg et 91 % à 1,5 mg/kg chez des primates non humains. Chez des souris obèses induites par le régime, ARO-ALK7 a supprimé la prise de poids corporel de 40 % et réduit la masse grasse d'environ 50 %, tout en préservant la masse maigre.
Notamment, lorsqu'il est combiné avec le tirzepatide (un co-agoniste des récepteurs GLP-1/GIP), ARO-ALK7 a montré des effets additifs sur la perte de poids et de graisse tout en atténuant la réduction de la masse maigre induite par le tirzepatide. Le mécanisme de perte de graisse implique une augmentation de la dépense énergétique et de la lipolyse sans affecter l'apport alimentaire. Les études de toxicologie chez les rats ont montré que le traitement était généralement bien toléré.
Arrowhead Pharmaceuticals (NASDAQ: ARWR) hat im Februar 2025 auf den Keystone Symposia über Fettleibigkeit und Fettgewebe präklinische Daten zu ARO-ALK7, seiner experimentellen RNAi-Therapie zur gezielten Behandlung von ALK7 bei Fettleibigkeit, vorgestellt. Das Unternehmen erhielt die regulatorische Genehmigung, eine Phase 1/2a-Studie in Neuseeland zu beginnen, wobei die Dosis im zweiten Quartal 2025 erwartet wird.
Präklinische Studien zeigten dosisabhängige Reduktionen von ALK7-mRNA im Fettgewebe, mit einer Reduktion von etwa 80% bei 0,3 mg/kg und 91% bei 1,5 mg/kg in nichtmenschlichen Primaten. Bei diätetisch induzierten fettleibigen Mäusen unterdrückte ARO-ALK7 die Zunahme des Körpergewichts um 40% und reduzierte die Fettmasse um etwa 50%, während die fettfreie Masse erhalten blieb.
Bemerkenswert ist, dass ARO-ALK7 in Kombination mit Tirzepatid (einem GLP-1/GIP-Rezeptor-Co-Agonisten) additive Effekte auf den Gewichts- und Fettverlust zeigte und gleichzeitig die Reduktion der fettfreien Masse durch Tirzepatid abschwächte. Der Mechanismus des Fettverlusts umfasst eine erhöhte Energieverbrauch und Lipolyse, ohne die Nahrungsaufnahme zu beeinflussen. Toxikologiestudien an Ratten zeigten, dass die Behandlung im Allgemeinen gut vertragen wurde.
- Received regulatory clearance to begin Phase 1/2a clinical trial with dosing expected in Q2 2025
- Preclinical data showed 91% ALK7 mRNA knockdown at 1.5 mg/kg with 75% knockdown still present after 12 weeks
- Reduced fat mass by approximately 50% while preserving lean mass in animal models
- Showed additive effects when combined with tirzepatide (GLP-1/GIP receptor co-agonist)
- Generally well-tolerated in toxicology studies with no adverse findings in rats
- Still in preclinical/early clinical stage with no human efficacy data yet
- Potential competition from established incretin-based obesity therapies
Insights
Arrowhead Pharmaceuticals has unveiled preclinical data for ARO-ALK7, its novel RNAi therapeutic for obesity, representing a potentially significant advancement in the company's pipeline and obesity treatment landscape. The announcement of regulatory clearance to initiate a Phase 1/2a trial in New Zealand, with dosing expected in Q2 2025, marks Arrowhead's entry into the lucrative obesity market.
The preclinical results demonstrate impressive efficacy metrics: 91% knockdown of ALK7 mRNA at the highest dose with durability extending to 12 weeks in non-human primates, and approximately 50% reduction in fat mass while preserving lean mass in diet-induced obese mice. This preservation of lean mass represents a important differentiation from current GLP-1 therapies, which often cause significant muscle loss alongside fat reduction.
What's particularly compelling is ARO-ALK7's complementary mechanism to existing incretin therapies. When combined with tirzepatide (a GLP-1/GIP co-agonist), the treatment showed additive weight loss effects while mitigating tirzepatide's lean mass reduction—suggesting potential for combination approaches rather than head-to-head competition with established treatments. This positions Arrowhead to potentially capture value in the obesity market without directly challenging entrenched players like Novo Nordisk and Eli Lilly.
The mechanistic data reveals ARO-ALK7 works through increased energy expenditure and lipolysis without affecting food intake—contrasting with GLP-1s that primarily reduce appetite. This metabolic approach addresses a different aspect of obesity pathophysiology and could potentially minimize the GI side effects common with high-dose incretin therapies.
While these results are promising, investors should recognize this program remains in early development with significant clinical hurdles ahead. The obesity therapeutic landscape is littered with preclinical successes that failed to translate to human efficacy or encountered unexpected safety issues. Arrowhead's expertise in RNAi delivery through its proprietary TRiM™ platform provides some technical de-risking, but clinical proof-of-concept remains distant.
For Arrowhead's broader business strategy, ARO-ALK7 represents expansion into a massive market opportunity while leveraging their core RNAi technology platform. Success in this program could significantly enhance Arrowhead's valuation given obesity's multi-billion dollar market potential, though investors should maintain measured expectations given the early stage and inherent development risks.
ARO-ALK7 is the first RNAi-based therapy to directly target a gene expressed in adipose tissue and highlights Arrowhead’s leadership in the delivery of siRNA to multiple tissues and cell types throughout the body utilizing its proprietary and differentiated Targeted RNAi Molecule (TRiM™) platform. Arrowhead received regulatory clearance to initiate a Phase 1/2a clinical trial of ARO-ALK7 in
“Human genetic studies support ALK7 as a promising therapeutic target for the treatment of obesity. Loss-of-function ALK7 variants have been associated with improved body composition, protection from type 2 diabetes, and reduced risk of cardiovascular disease. While incretin-based therapies are the current frontline pharmacotherapeutics for obesity and metabolic outcomes, issues concerning significant loss of lean mass, adverse GI events at high dose levels, and disproportional fat mass gain after cessation of the therapies remain a challenge for many patients,” said James Hamilton, M.D., MBA, Chief Medical Officer and Head of R&D. “In preclinical studies in rodents and non-human primates, ARO-ALK7 demonstrated dose-dependent and durable reductions in ALK7 mRNA expression in adipose tissue. Pharmacological studies in diet-induced obese mouse models demonstrate that ALK7 silencing in adipose tissue led to improved body composition, with an approximate
Select Preclinical Results:
Pharmacodynamic results in non-human primates
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Single subcutaneous doses of ARO-ALK7 led to dose-dependent and durable reductions in ALK7 mRNA in abdominal fat
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Approximately
80% knockdown achieved at 0.3 mg/kg -
Approximately
91% knockdown achieved at 1.5 mg/kg with75% knockdown still observed after 12 weeks
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Approximately
Pharmacological studies in a diet-induced obese (DIO) mouse model
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ALK7 silencing in adipose tissue suppressed body weight gain and improved body composition
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Body weight gain was suppressed by
40% relative to control -
Approximately
50% reduction in fat mass with preservation of lean mass by DEXA imaging was observed in treated animals
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Body weight gain was suppressed by
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Body fat loss in treated animals was mechanistically attributed to lipolysis and increased energy expenditure
- No change in food intake was observed
- Increased oxygen consumption and heat production were observed
- Increased levels of glycerol, NEFAs, and ketones were observed and animals exhibited upregulation in the expression of lipolytic genes
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ALK7 silencing enhanced the therapeutic benefit of tirzepatide
- Co-treatment of tirzepatide and ALK7 siRNA had additive effects on body weight and fat mass reductions
- ALK7 siRNA ameliorated the loss of lean mass observed with monotherapy treatment with tirzepatide
Toxicology results
- ARO-ALK7 was generally well-tolerated with no adverse or dose-limiting findings identified in Han Wistar rats
The poster presentation may be accessed on the Events and Presentations page in the Investors section of the Arrowhead website.
About ARO-ALK7
ARO-ALK7 is designed to silence adipocyte expression of the ACVR1C gene to reduce the production of Activin receptor-like kinase 7 (ALK7), which acts as a receptor in a pathway that regulates energy homeostasis in adipose tissue. In large genetic datasets, reduced ACVR1C expression has been associated with healthier adipose distribution and reduced risk of obesity-related metabolic complications. Treatment with investigational ARO-ALK7 has the potential to reduce visceral adiposity and improve lipid and glycemic parameters.
About the AROALK7-1001 Phase 1/2a Study
AROALK7-1001 is a Phase 1/2a first-in-human dose-escalating study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-ALK7 in up to 90 adult volunteers with obesity. Part 1 of the study is designed to assess single and multiple doses of ARO-ALK7 monotherapy, and Part 2 of the study is designed to assess ARO-ALK7 in combination with tirzepatide, a subcutaneously administered GLP-1/GIP receptor co-agonist that has been approved in
About Arrowhead Pharmaceuticals
Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing.
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Source: Arrowhead Pharmaceuticals, Inc.
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Arrowhead Pharmaceuticals, Inc.
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Source: Arrowhead Pharmaceuticals, Inc.
FAQ
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