Arrowhead Pharmaceuticals Conference Call Summary Company Overview - **Company**: Arrowhead Pharmaceuticals (NasdaqGS:ARWR) - **Focus**: Development of obesity therapeutics, specifically targeting the activin E ALK7 pathway and its implications for metabolic diseases Key Points from the Call Industry and Market Context - **Obesity Treatment Landscape**: The call highlighted the evolving understanding of obesity as a multifaceted disease requiring diverse treatment approaches, including pharmacotherapy, surgical options, and lifestyle changes [2][4][5] - **Unmet Needs**: There is a significant unmet need in treating obesity, particularly in patients with Type 2 diabetes, who often do not respond well to existing therapies [5][14][24] Clinical Trials and Results - **ARO-INHBE and ARO-ALK7**: The call presented interim results from Phase I and II studies of two obesity candidates, ARO-INHBE and ARO-ALK7, focusing on their efficacy and safety [2][3][30] - **Interim Results**: - ARO-INHBE demonstrated a mean maximal reduction of activin E by 85% at a 400 mg dose, leading to a 10% reduction in visceral fat and a 38% reduction in liver fat after a single dose [20][34] - In combination with tirzepatide, ARO-INHBE achieved a 9.4% weight loss in obese diabetic patients, compared to 4.8% with tirzepatide alone [25][35] - ARO-ALK7 showed an 88% mean reduction in ALK7 mRNA after a single dose, with a 14.1% placebo-adjusted reduction in visceral fat observed at week eight [32][36] Mechanism of Action - **Activin E ALK7 Pathway**: The pathway is implicated in regulating visceral adiposity, and silencing its expression may lead to improved metabolic outcomes [17][18][27] - **Combination Therapy**: The combination of ARO-INHBE with tirzepatide is seen as a promising approach to enhance weight loss and metabolic health in patients with obesity and Type 2 diabetes [24][35] Safety and Tolerability - **Safety Profile**: ARO-INHBE and ARO-ALK7 were reported to be well tolerated, with most treatment-emergent adverse events (TEAEs) being mild and no significant adverse trends in laboratory values [27][33] Future Directions - **Next Steps**: Arrowhead plans to expand its studies, including increasing patient numbers and exploring combination therapies with other GLP-1 drugs [38][39] - **Regulatory Pathway**: Discussions regarding the regulatory pathway for ARO-INHBE and ARO-ALK7 are ongoing, with a focus on combination therapies for diabetic patients [51][52] Additional Insights - **Research and Development**: Arrowhead is exploring additional targets in obesity and metabolic disorders, including liver and adipose dimers capable of silencing multiple genes with a single drug [39][40] - **Commercialization Plans**: The company is transitioning to a commercial stage with its first sales expected in the FCS patient population, with further studies planned to support label expansion [40][41] Conclusion Arrowhead Pharmaceuticals is making significant strides in the development of innovative obesity therapeutics, with promising interim results from its clinical trials. The focus on the activin E ALK7 pathway and combination therapies positions the company well in addressing the unmet needs in obesity treatment, particularly for patients with Type 2 diabetes. The safety and efficacy data presented suggest a strong potential for these candidates in future therapeutic paradigms.

ARO-INHBE Clinical Data - ARO-INHBE achieved a mean maximum reduction of 85% in serum Activin E after a single 400 mg dose, with a maximum observed reduction of 94%[80, 147] - ARO-INHBE monotherapy reduced visceral fat by 9.9% after a single dose at week 16 and 15.6% after two doses at week 24[82, 85, 147] - In obese diabetic patients, ARO-INHBE combined with tirzepatide doubled weight loss compared to tirzepatide alone, showing a 9.4% weight loss at week 16 versus 4.8% with tirzepatide alone[103, 105, 147] - Combination therapy with ARO-INHBE and tirzepatide in obese diabetic patients resulted in a 23.2% reduction in visceral fat, a 15.4% reduction in total fat, and a 76.7% reduction in liver fat, approximately a 3-fold improvement compared to tirzepatide alone across these measures[106, 107, 148] ARO-ALK7 Clinical Data - ARO-ALK7 demonstrated a mean reduction of 88% in ALK7 mRNA, confirming the TRiM platform's ability to silence adipocyte gene expression, with a maximum reduction of 94%[135, 148] - ARO-ALK7 showed a rapid dose-dependent reduction in visceral fat of up to 14% (placebo-adjusted) after a single dose[137, 148] General Summary - Both ARO-INHBE and ARO-ALK7 demonstrated favorable safety profiles in their respective monotherapy and combination therapy trials[113, 139] - The company plans to initiate Phase 2b studies as soon as possible and expand the obesity pipeline with new targets, including dimers[151] - Arrowhead's growth drivers in 2026 and beyond include potential multi-billion-dollar opportunity from Phase 3 studies of plozasiran in severe hypertriglyceridemia, first clinical readout of ARO-DIMER-PA targeting PCSK9 and APOC3 in 2H 2026, and emerging CNS pipeline with systemic delivery via SC administration[155]