Collagen Turnover as a Biomarker of Hemophilia Treatment Efficacy
Over the past decades, hemophilia treatment has made significant progress—from factor therapy to prophylactic regimens and non-factor products, and even to gene therapy. Its development has greatly improved the quality of life for hemophiliacs and reduced the incidence of bleeding episodes. However, they cannot be completely eliminated, which is why further options for monitoring bleeding and joint status are still being explored. In addition to classical methods, biomarkers are attracting attention, but their practical use is still the subject of studies. A recently published work by a team of European and American experts, who assessed collagen turnover as a biomarker of treatment efficacy with rurioctocog alfa pegol, came with interesting results.
Methodology
A total of 98 patients with severe hemophilia A aged 12 to 65 years, with an annual bleeding rate (ABR) ≥ 2 and without a history or current presence of an inhibitor, were included in the evaluation. As part of the PROPEL clinical study, patients were given prophylaxis with rurioctocog alfa pegol. In the reference arm (n = 50, randomized 1:1), the target trough level was 1−3%, while in the increased arm (n = 48), the trough levels ranged between 8 and 12%. Prior to the start of the study, all patients underwent pharmacokinetic measurement, upon which the dose and frequency of prophylactic treatment administration were determined.
The study monitored biomarkers assessing basal membrane remodeling (formation of type IV collagen − PRO-C4; degradation of type IV collagen − C4M), interstitial matrix remodeling (formation of type V collagen − PRO-C5; degradation of type III collagen − C3M), and cartilage remodeling (formation of type II collagen − PRO-C2; degradation of type II collagen − C2M). Biomarker levels were measured at baseline and then at 3, 6, 9, and 12 months.
Findings
In assessing basal membrane remodeling, there was a significant reduction in the levels of the monitored biomarkers (C4M, PRO-C4), which reached statistical significance as early as the 3-month measurement. The most substantial change occurred in patients in the increased arm who had previously been on only on-demand therapy. According to available data, increased basal membrane remodeling occurs in inflammatory and degenerative arthropathies (e.g., rheumatoid arthritis), and higher levels are also seen in hemophilic patients with high ABR. The reduction in monitored biomarkers is thus a favorable sign.
Similarly, interstitial matrix remodeling showed a significant reduction in the levels of monitored biomarkers (C3M, PRO-C5), again primarily in the group with trough levels of 8−12% and previous on-demand therapy. High C3M levels correlate with high disease activity in patients with rheumatoid arthritis, suggesting that reducing C3M levels with prophylactic therapy could have a positive effect on interstitial matrix inflammation. A high PRO-C5 level was found after knee joint bleeding in laboratory rats and is also a biomarker of tissue fibrosis. Its lower level with prophylactic treatment thus suggests a positive impact on joint tissues.
Conversely, cartilage remodeling showed an increase in the levels of monitored biomarkers (C2M, PRO-C2), indicating a beneficial effect of prophylactic therapy on cartilage repair processes.
Conclusion
Prophylactic therapy with rurioctocog alfa pegol set according to the pharmacokinetic curve resulted in the gradual normalization of basal membrane and interstitial matrix remodeling, while cartilage remodeling increased. A higher effect was observed in patients with previous on-demand therapy aimed at a trough concentration of 8−12% of factor VIII. The study results suggest that collagen turnover biomarkers could serve as an early marker of joint damage compared to radiological and clinical methods, allowing for subsequent therapy optimization. However, more data are needed before this technique can be implemented in routine practice.
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Sources:
1. Manon-Jensen T., Tangada S., Bager C. et al. Evaluation of collagen turnover biomarkers as an objective measure for efficacy of treatment with rurioctocog alfa pegol in patients with hemophilia A: a secondary analysis of a randomized controlled trial. J Thromb Haemost 2024 Jan; 22 (1): 90−100, doi: 10.1016/j.jtha.2023.08.035.
2. SPC Adynovi. Available at: www.ema.europa.eu/cs/documents/product-information/adynovi-epar-product-information_cs.pdf
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