Background Excessive production of reactive oxygen species (ROS), particularly superoxide anion (<InlineEquation ID="IEq1"> <EquationSource Format="TEX">${\text{O}}_{2}^{ \cdot - }$</EquationSource> <EquationSource Format="MATHML"><math> <msubsup> <mtext>O</mtext> <mrow> <mn>2</mn> </mrow> <mrow> <mo>·</mo> <mo>-</mo> </mrow> </msubsup> </math></EquationSource> </InlineEquation>), is a key mechanism in diseases such as cancer, inflammatory disorders, neurodegenerative conditions, and metabolic diseases. Evidence also suggests that microgravity-induced oxidative stress, primarily driven by elevated <InlineEquation ID="IEq2"> <EquationSource Format="TEX">${\text{O}}_{2}^{ \cdot - }$</EquationSource> <EquationSource Format="MATHML"><math> <msubsup> <mtext>O</mtext> <mrow> <mn>2</mn> </mrow> <mrow> <mo>·</mo> <mo>-</mo> </mrow> </msubsup> </math></EquationSource> </InlineEquation> levels, may contribute to the adverse physiological effects observed in astronauts during extended space missions. Superoxide dismutase (SOD) is critical for mitigating oxidative stress, and exogenous SOD supplementation offers a potential therapeutic strategy. Methods This randomized, double-blind, placebo-controlled Phase I study evaluated the safety, tolerability, and pharmacokinetics of recombinant human Cu/Zn-SOD (rhSOD, SOD1) following subcutaneous administration of 40 mg every 12 hours in 16 healthy volunteers. Eight subjects were enrolled each in the single-dose (SD) and multiple-dose (MD) cohorts. Study assessments, including pharmacokinetic sampling, were performed for 72 (SD) or 92 hours (MD). Injection site erythema was objectively assessed using the innovative Standardized Erythema Value (SEV) method, derived from photographs taken with Scarletred®Vision software (SCARLETRED Holding GmbH). Results No serious adverse events occurred, and all treatment-related adverse events were mild. Injection site erythema was objectively assessed using the innovative standardized erythema value (SEV) method, derived from photographs taken with Scarletred® Vision software (SCARLETRED Holding GmbH). The Visual Analog Scale scores and SEV* assessments were comparable between the rhSOD and placebo groups. Beyond safety and tolerability, pharmacokinetic analysis revealed that the volume of distribution, clearance, and half-life at presumed steady state were 129 ± 66.3 L, 5.97 ± 1.25 L/h, and 15.0 ± 6.69 h, respectively. Compared with the rapid systemic elimination after intravenous administration of SOD, subcutaneous administration resulted in a favorable plasma concentration-time profile. Conclusions These findings suggest that subcutaneous rhSOD may be a promising therapeutic candidate for conditions characterized by excessive <InlineEquation ID="IEq3"> <EquationSource Format="TEX">${\text{O}}_{2}^{ \cdot - }$</EquationSource> <EquationSource Format="MATHML"><math> <msubsup> <mtext>O</mtext> <mrow> <mn>2</mn> </mrow> <mrow> <mo>·</mo> <mo>-</mo> </mrow> </msubsup> </math></EquationSource> </InlineEquation> exposure or diminished endogenous SOD activity. Further clinical studies are warranted to assess its anti-inflammatory potential in relevant patient populations. EudraCT Number: 2022-000173-11.

Randomized, Double-Blind, Phase I Pharmacokinetic Study of Subcutaneous Recombinant Human Superoxide Dismutase (rhSOD) in Healthy Volunteers

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2025年10月18日

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Valentin al Jalali,
Martin Bauer,
Anselm Jorda,
Felix Bergmann,
Michael Wölfl-Duchek,
Richard Partl,
Brigitta Vcelar,
Dietmar Katinger,
Rawad Bashur,
Harald Schnidar,
Markus Zeitlinger

摘要

Background

Excessive production of reactive oxygen species (ROS), particularly superoxide anion ( ${\text{O}}_{2}^{ \cdot - }$ $O_{2}^{\cdot -}$ ), is a key mechanism in diseases such as cancer, inflammatory disorders, neurodegenerative conditions, and metabolic diseases. Evidence also suggests that microgravity-induced oxidative stress, primarily driven by elevated ${\text{O}}_{2}^{ \cdot - }$ $O_{2}^{\cdot -}$ levels, may contribute to the adverse physiological effects observed in astronauts during extended space missions. Superoxide dismutase (SOD) is critical for mitigating oxidative stress, and exogenous SOD supplementation offers a potential therapeutic strategy.

Methods

This randomized, double-blind, placebo-controlled Phase I study evaluated the safety, tolerability, and pharmacokinetics of recombinant human Cu/Zn-SOD (rhSOD, SOD1) following subcutaneous administration of 40 mg every 12 hours in 16 healthy volunteers. Eight subjects were enrolled each in the single-dose (SD) and multiple-dose (MD) cohorts. Study assessments, including pharmacokinetic sampling, were performed for 72 (SD) or 92 hours (MD). Injection site erythema was objectively assessed using the innovative Standardized Erythema Value (SEV*) method, derived from photographs taken with Scarletred®Vision software (SCARLETRED Holding GmbH).

Results

No serious adverse events occurred, and all treatment-related adverse events were mild. Injection site erythema was objectively assessed using the innovative standardized erythema value (SEV*) method, derived from photographs taken with Scarletred^® Vision software (SCARLETRED Holding GmbH). The Visual Analog Scale scores and SEV* assessments were comparable between the rhSOD and placebo groups. Beyond safety and tolerability, pharmacokinetic analysis revealed that the volume of distribution, clearance, and half-life at presumed steady state were 129 ± 66.3 L, 5.97 ± 1.25 L/h, and 15.0 ± 6.69 h, respectively. Compared with the rapid systemic elimination after intravenous administration of SOD, subcutaneous administration resulted in a favorable plasma concentration-time profile.

Conclusions

These findings suggest that subcutaneous rhSOD may be a promising therapeutic candidate for conditions characterized by excessive ${\text{O}}_{2}^{ \cdot - }$ $O_{2}^{\cdot -}$ exposure or diminished endogenous SOD activity. Further clinical studies are warranted to assess its anti-inflammatory potential in relevant patient populations.

EudraCT Number: 2022-000173-11.