SPH3127 achieves breakthrough in upstream RAAS inhibition for hypertension

After 19 years, SPH3127 has achieved a breakthrough in upstream RAAS inhibition in the global hypertension treatment

By:DengYue International Business Division

Against the backdrop of a long-standing lack of effective interventions targeting the upstream of the renin–angiotensin–aldosterone system (RAAS) and years of structural stagnation in global hypertension treatment, China has achieved a milestone breakthrough in antihypertensive innovation.

On December 9, 2025, Shanghai Pharmaceuticals Holding Co., Ltd., in collaboration with Mitsubishi Tanabe Pharma Corporation, received approval from China’s National Medical Products Administration (NMPA) for SPH3127(brand name: Xintuoan) for the treatment of primary hypertension.

This cross-border collaboration began in 2006 and has spanned nearly 19 years, ultimately completing a full translational cycle from basic research to clinical development and commercial launch.

As the first domestically approved next-generation oral non-peptide small-molecule direct renin inhibitor, SPH3127 was approved as a Class 1 chemical innovative drug, marking China’s entry into a phase of tangible value realization in upstream RAAS-targeted innovation.

Rising Hypertension Burden: An Unmet Need for Upstream RAAS Intervention

From a global therapeutic perspective, RAAS-targeted treatments have long focused on downstream blockade strategies, primarily angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). While these therapies have significantly reduced cardiovascular risk over the past decades, issues related to compensatory RAAS activation have persisted.

Direct renin inhibitors (DRIs) have been regarded as theoretically capable of achieving more comprehensive RAAS suppression. However, due to limitations in pharmacokinetics, safety profiles, and real-world usability of early agents, this mechanism has failed to achieve large-scale clinical adoption worldwide. As a result, upstream RAAS intervention has remained a repeatedly validated yet largely unrealized therapeutic target.

Hypertension continues to be one of the most insidious yet high-risk chronic diseases globally. According to the China Hypertension Prevention and Treatment Guidelines (2024 revision), China has approximately 337 million hypertensive patients, with a treatment rate of around 46% and a blood pressure control rate of only 45%. Globally, the hypertensive population exceeds 1 billion and continues to grow.

Current first-line therapies remain dominated by ARBs, ACEIs, and calcium channel blockers (CCBs). In real-world settings, however, limited tolerability, poor long-term adherence, and complex combination regimens continue to constrain optimal blood pressure control—particularly among patients with early renal impairment or metabolic abnormalities. In this context, the question of why RAAS should be targeted at its source has regained attention in both clinical and research communities, positioning DRIs as a theoretically compelling yet historically underdeveloped therapeutic class.

Mechanism of Action: SPH3127 Redefines Upstream RAAS Modulation

Mechanistically, SPH3127 exerts its effect by directly inhibiting renin activity, blocking the generation of angiotensin I at the most upstream point of the RAAS cascade, thereby reducing downstream amplification of angiotensin II and aldosterone.

Compared with ACEIs and ARBs, which act on downstream components of the RAAS pathway, direct renin inhibition offers the theoretical advantage of more complete and stable suppression of RAAS activation, providing a more consistent biological basis for target organ protection.

Structurally, SPH3127 is designed as a non-peptide small molecule, overcoming the low bioavailability and poor oral absorption that limited earlier peptide-based renin inhibitors. This molecular optimization enables improved druggability and feasibility for long-term oral administration.

Clinical Evidence and Differentiation: Reestablishing Practical Utility Within the Class

In the pivotal Phase III confirmatory clinical study (SPH3127-301, second stage), SPH3127 met its primary endpoints, demonstrating stable antihypertensive efficacy and a favorable safety profile.

Compared with the previously approved direct renin inhibitor aliskiren, SPH3127 showed differentiation across several clinically meaningful dimensions:

● Dosing convenience: once-daily administration supporting long-term adherence

● Safety profile: adverse event incidence below 5%

● Structural optimization: non-peptide design improving oral pharmacokinetics

Notably, although aliskiren entered the Chinese market in 2010, its sales in Chinese sample hospitals totaled only approximately RMB 40,400 in 2022, highlighting inherent limitations in real-world usability and clinical acceptance of earlier-generation DRIs.

Against this backdrop, SPH3127 is not a simple replication of existing agents, but rather a systematic optimization of the direct renin inhibition strategy across molecular design, dosing practicality, and safety characteristics—positioning it as a next-generation DRI more aligned with current clinical needs.

Global Market Perspective: Structural Opportunities in Hypertension Treatment

From a global standpoint, antihypertensive drug markets remain heavily concentrated around mature mechanisms, with truly novel therapeutic approaches in short supply. In Europe and the United States, R&D activity targeting RAAS has declined, with increasing resources redirected toward heart failure and metabolic diseases.

Under these conditions, China’s breakthrough in the direct renin inhibition pathway—an area with clearly defined unmet needs but limited global validation—carries significance beyond domestic substitution. It also opens potential pathways for future international competition and outward market expansion.

Domestically, China’s antihypertensive drug market is undergoing a dual transformation characterized by scale expansion and structural upgrading. In 2023, the market exceeded RMB 50 billion, and is projected to reach RMB 145 billion by 2030, with a compound annual growth rate of approximately 6.8%. While CCBs and ARBs continue to dominate retail channels, structural opportunities for new mechanisms are emerging.

Within this landscape, the direct renin inhibitor segment has shown particularly strong growth. China’s DRI market expanded from approximately USD 800 million in 2018 to USD 1.5 billion in 2022, and is expected to exceed USD 4.25 billion by 2028, representing a CAGR of nearly 19%. The approval of SPH3127 marks the first time a domestically developed product has gained systematic competitive positioning within this target class.

Conclusion

Overall, the approval of SPH3127 represents not only the launch of a new antihypertensive drug, but also a tangible example of how Chinese pharmaceutical innovation is steadily aligning with international standards.

As the global pharmaceutical industry undergoes structural reconfiguration and innovation becomes increasingly multipolar, China’s drug development paradigm is evolving from early-stage mechanism following toward original breakthroughs in clearly defined areas of unmet clinical need.

Export-oriented pharmaceutical wholesalers, including DengYueMed, are leveraging quality, compliance, and international standards as foundational pillars to integrate Chinese innovations more systematically into the global pharmaceutical supply chain—advancing China’s role in global medicine and contributing to improved health outcomes worldwide.