Summary of Alnylam Pharmaceuticals (ALNY) Update / Briefing - August 30, 2025 Company Overview - **Company**: Alnylam Pharmaceuticals (ALNY) - **Key Product**: Zalbesiran, a novel treatment for uncontrolled hypertension - **Collaboration**: Partnership with Roche for the development of Zalbesiran Industry Context - **Focus Area**: Cardiovascular disease, specifically hypertension - **Global Burden**: Cardiovascular disease is the leading cause of death worldwide, with approximately 20 million deaths annually attributed to it, primarily due to high blood pressure [11][12] - **Treatment Gap**: Less than 40% of women and 30% of men achieve adequate blood pressure control, highlighting a significant unmet need in hypertension management [13] Core Points and Arguments Clinical Development and Results - **CARDIA Trials**: The presentation focused on the results of the CARDIA three trial, which evaluated Zalbesiran in patients with uncontrolled hypertension and high cardiovascular risk [27][38] - **Efficacy**: - CARDIA one showed a significant reduction in blood pressure of 15 mmHg as monotherapy [28] - CARDIA two demonstrated reductions of -19 mmHg with a diuretic, -10 mmHg with amlodipine, and -7 mmHg with olmesartan [29] - CARDIA three results indicated a placebo-adjusted reduction of -5 mmHg and -3.3 mmHg for the 300 mg and 600 mg doses, respectively, at three months [34][38] - **Safety Profile**: The safety profile was encouraging, with low rates of serious adverse events and manageable instances of hyperkalemia and kidney dysfunction [36] Mechanism of Action - **RNA Interference Technology**: Zalbesiran utilizes RNA interference to silence genes associated with hypertension, allowing for infrequent dosing (once every six months) [4][5] - **Blood Pressure Control**: The drug aims to provide consistent blood pressure control, addressing both daytime and nighttime variability, which is crucial for reducing cardiovascular risk [17][21] Market Opportunity - **Patient Population**: There are approximately 219 million patients with hypertension in major markets, with 62 million currently uncontrolled [40] - **Unmet Need**: Patients with uncontrolled hypertension and high cardiovascular risk represent a significant unmet need, particularly those with comorbidities like diabetes and chronic kidney disease [40] Future Directions - **Phase Three Trial (Zenith)**: The upcoming Zenith trial will enroll 11,000 patients with uncontrolled hypertension and established cardiovascular disease, focusing on cardiovascular outcomes [43][45] - **Regulatory Engagement**: The protocol for the Zenith trial has been filed with multiple regulators, with plans to activate sites soon [45] - **Commercial Strategy**: Alnylam and Roche are developing strategies for the commercialization of Zalbesiran, including potential additional indications [46][47] Important but Overlooked Content - **Adherence Issues**: The challenge of treatment adherence in chronic diseases like hypertension is significant, with about 40% of patients not taking their medications as prescribed [22][23] - **Long Duration of Action**: The six-month duration of action for Zalbesiran is highlighted as a major advantage in improving adherence and overall treatment outcomes [24][51] - **Synergistic Effects with Diuretics**: The potential for Zalbesiran to work synergistically with diuretics is noted, as diuretics can upregulate the renin-angiotensin system, enhancing the effectiveness of Zalbesiran [60][63] Conclusion - **Transformational Potential**: Zalbesiran is positioned as a potentially paradigm-shifting therapy for hypertension, with the ability to improve blood pressure control and cardiovascular outcomes significantly [55][56]