Naperiglipron Trial Terminations Highlight Shifts in Oral GLP-1 Market

As of September 1, 2025, Eli Lilly has terminated two Phase 2 studies of naperiglipron (LY3549492), its next-generation oral GLP-1 receptor agonist, citing “strategic business reasons.” Each study had enrolled only one participant before being shut down. Despite this, Lilly continues development, with an active Phase 2 obesity trial (NCT06683508) and early-phase studies in Japan and China.

Clinical Trial Status (as of Aug 31, 2025)

🔬 Context and Outlook

• Structural safety overhang: Naperiglipron shares a benzimidazole-based GLP-1 agonist scaffold with Pfizer’s danuglipron (terminated Apr 2025 for liver injury) and lotiglipron (halted earlier for ALT elevations).

Figure: Comparative structures of naperiglipron, danuglipron, lotiglipron, and orforglipron

• Pipeline positioning: Orforglipron remains Lilly’s lead oral GLP-1, with Phase 3 obesity readouts showing ~12% weight loss and an FDA filing expected by end-2025. Naperiglipron was pitched as a “higher-efficacy next-gen” option, but its future now hinges on overcoming the scaffold’s baggage. Analysts (e.g., BMO, June 2025) have pointed to Lilly’s persistence as a bullish sign despite these risks. However, as highlighted in SinoDrugWatch, the rise of Chinese oral GLP-1 candidates and their strategic partnerships may influence global market dynamics and investor perspectives."
• Market competition: Novo Nordisk’s oral semaglutide (Wegovy pill) and oral amycretin are advancing, intensifying pressure on Lilly’s oral GLP-1 pipeline. Naperiglipron could have filled a potency niche, but its clinical viability is now cloudier.

Impact on the Oral GLP-1 Market

The termination of naperiglipron, alongside Pfizer’s danuglipron failure, highlights heightened scrutiny on small-molecule benzimidazole scaffolds. Peptide-based oral GLP-1s (oral semaglutide) and differentiated chemotypes like orforglipron now have a regulatory and competitive edge.

Ongoing programs will likely require extra liver-safety monitoring and longer follow-up, raising development costs. Lilly’s focus on orforglipron illustrates a broader trend of portfolio prioritization toward lower-risk, higher-confidence candidates.

Fewer global winners are expected, with incumbents dominating and other players competing on price, convenience, or niche indications. Chinese developers with differentiated chemotypes could gain local market share, but global adoption depends on convincing safety and efficacy data.

✅ Bottom Line

Lilly has pulled two early Phase 2 trials of naperiglipron after enrolling just one participant each, citing business strategy. The core obesity trial (NCT06683508) is still running, alongside Phase 1 work in Japan and China, but the program faces heightened scrutiny given its structural similarity to Pfizer’s failed oral GLP-1s.

Sources

• NCT07030868 — Phase 2 trial of naperiglipron in obesity/overweight with type 2 diabetes (terminated). ClinicalTrials.gov/study/NCT07030868
• NCT07085468 — Phase 2 safety/tolerability trial in healthy older adults (terminated). ClinicalTrials.gov/study/NCT07085468
• NCT06683508 — Phase 2 obesity/overweight trial (active, not recruiting). ClinicalTrials.gov/study/NCT06683508
• NCT06869018 — Phase 1 multiple-ascending dose study in Japanese participants (recruiting). ClinicalTrials.gov/study/NCT06869018
• NCT07073170 — Phase 1 multiple-dose escalation in Chinese participants with type 2 diabetes (not yet recruiting). ClinicalTrials.gov/study/NCT07073170
• jRCT2071240136 — Phase 1 multiple-ascending dose study in Japanese participants with type 2 diabetes and healthy volunteers (recruiting). jRCT.mhlw.go.jp/latest-detail/jRCT2071240136
• China’s Oral GLP-1 Surge — Rising amid global setbacks and intensifying competition. SinodrugWatch.com: https://www.sinodrugwatch.com/chinas-oral-glp-1-surge-rising-amid-global-setbacks-and-intensifying-competition