Efficacy and safety of bovhyaluronidase azoximer (Longidase) in patients with post-COVID syndrome: results of an open, prospective, controlled, comparative, multicenter clinical trial DISSOLVE

Post-COVID syndrome develops after COVID-19 (COronaVIrus Disease 2019) and leads to cumulative effects in the form of shortness of breath and impaired lung function. Notably, patients with airway inflammation and COVID-19 were found to have increased concentrations of hyaluronic acid (HA). Since bovhyaluronidase azoximer (Longidase®) catalyzes the hydrolysis of HA, this drug has the potential to reduce HA levels and improve lung function in patients with post-COVID syndrome.

The aim of the DISSOLVE trial, which was conducted early in the pandemic, was to investigate the efficacy and safety of bovhyaluronidase azoximer in patients with symptoms associated with post-COVID syndrome.

Methods. An open, prospective, controlled, comparative, multicenter clinical trial (NCT04645368) included adult patients (n = 160) who had post-COVID syndrome. Patients in the treatment group (n = 81) received bovhyaluronidase azoximer, and individuals in the control group (n = 79) were followed up without intervention. The study included physical examination, evaluation of forced vital capacity (FVC), assessment of dyspnea with the Modified Medical Research Council Dyspnea Scale (mMRC), 6-minute walking test, and pulse oximetry. These indicators were measured on 3 visits, at days 1 (baseline), 75, and 180. In addition, the number of patients who experienced adverse events and serious adverse events were recorded.

Results. Baseline patient characteristics in the treatment group and the control group were similar. In the treatment group, there was a statistically significant reduction in residual pulmonary abnormalities after visit 2 (day 75) and visit 3 (day 180). In addition, FVC, pulse oximetry values, and functional exercise tolerance increased statistically significantly at days 75 and 180 compared to baseline. The mMRC scores for dyspnea decreased statistically significantly in the treatment group over 75 days. The safety profile of the drug was reported to be favorable throughout the study.

Conclusion. Treatment with bovhyaluronidase azoximer in patients with post-COVID syndrome showed improvement in FVC, pulse oximetry, functional exercise tolerance, and mMRC dyspnea.

1. Guidotti E. A worldwide epidemiological database for COVID-19 at fine-grained spatial resolution. Sci. Data. 2022; 9 (1): 1–7. DOI: 10.1038/s41597-022-01245-1.

2. World Health Organization. A clinical case definition of post COVID-19 condition by a Delphi consensus reference number, October 6, 2021. Available at: https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1

3. NIPH. Flatby A.F., Himmels J.P.W., Brurberg K.G., Gravningen K.M. COVID-19: Post COVID-19 condition-a rapid review (New edition). Oslo: Norwegian Institute of Public Health; 2022. Available at: https://www.fhi.no/globalassets/dokumenterfiler/rapporter/2022/covid-19-post-covid-19-condition-new-edition.pdf

4. Munblit D., Bobkova P., Spiridonova E. et al. Incidence and risk factors for persistent symptoms in adults previously hospitalized for COVID-19. Clin. Exp. Allergy. 2021; 51 (9): 1107–1120. DOI: 10.1111/cea.13997.

5. Korell F., Giannitsis E., Merle U., Kihm LP. Analysis of symptoms of COVID-19 positive patients and potential effects on initial assessment. Open Access Emerg. Med. 2020; 12: 451–457. DOI: 10.2147/oaem.s275983.

6. Islam N., Jdanov D.A., Shkolnikov V.M. et al. Effects of COVID-19 pandemic on life expectancy and premature mortality in 2020: time series analysis in 37 countries. BMJ. 2021; 375: e066768. DOI: 10.1136/bmj-2021-066768.

7. Torres-Castro R., Vasconcello-Castillo L., Alsina-Restoy X. et al. Respiratory function in patients post-infection by COVID-19: a systematic review and meta-analysis. Pulmonology. 2021; 27 (4): 328–337. DOI: 10.1016/j.pulmoe.2020.10.013.

8. Salem A.M., Al Khathlan N., Alharbi A.F. et al. The long-term impact of COVID-19 pneumonia on the pulmonary function of survivors. Int. J. Gen. Med. 2021; 14: 3271–3280. DOI: 10.2147/ijgm.s319436.

9. Lauer M.E., Dweik R.A., Garantziotis S., Aronica M.A. The rise and fall of hyaluronan in respiratory diseases. Int. J. Cell Biol. 2015; 2015: 712507. DOI: 10.1155/2015/712507.

10. Bai K.J., Spicer A.P., Mascarenhas M.M. The role of hyaluronan synthase 3 in ventilator-induced lung injury. Am. J. Respir. Crit. Care Med. 2005; 172 (1): 92–98. DOI: 10.1164/rccm.200405-652oc.

11. Lazrak A., Lazrak A., Creighton J. et al. Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury. Am. J. Physiol. Lung Cell Mol. Physiol. 2015; 308 (9): L891–903. DOI: 10.1152/ajplung.00377.2014.

12. Collum S.D., Molina J.G., Hanmandlu A. et al. Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in combined pulmonary fibrosis and emphysema. Dis. Model. Mech. 2019; 12 (5): dmm038711. DOI: 10.1242/dmm.038711.

13. Tesar B.M., Jiang D., Liang J. et al. The role of hyaluronan degradation products as innate alloimmune agonists. Am. J. Transplant. 2006; 6 (11): 2622–2635. DOI: 10.1111/j.1600-6143.2006.01537.x.

14. Yuan S., Hollinger M., Lachowicz-Scroggins M.E. et al. Oxidation increases mucin polymer cross-links to stiffen airway mucus gels. Sci. Transl. Med. 2015; 7 (276): 276ra27. DOI: 10.1126/scitranslmed.3010525.

15. Ontong P., Prachayasittikul V. Unraveled roles of hyaluronan in severe COVID-19. EXCLI J. 2021; 20: 117–125. DOI: 10.17179/excli2020-3215.

16. Yang S., Ling Y., Zhao F. et al. Hymecromone: a clinical prescription hyaluronan inhibitor for efficiently blocking COVID-19 progression. Signal Transduct. Target. Ther. 2022; 7 (1): 91. DOI: 10.1038/s41392022-00952-w.

17. Li W., Yang S., Xu P. et al. SARS-COV-2 RNA elements share human sequence identity and upregulate hyaluronan via namirna-enhancer network. eBioMedicine. 2022; 76: 103861. DOI: 10.1016/j.ebiom.2022.103861.

18. Nekrasov A.V., Ivanova A.S., Puchkova N.G. et al. Preparation for treatment of connective tissue pathological state. Patent RU № 971103034/14А. October 06, 1998. Bulletin. 1998 (24). Available at: https://yandex.ru/patents/doc/RU2112542C1_19980610 (in Russian).

19. Novikova L.N., Zakharova A.S., Dzadzua D.V. et al. Effects of longidaza in patients with idiopathic pulmonary fibrosisъ. Doktor.RU. 2011; (6): 50–54. Available at: https://cyberleninka.ru/article/n/rezultaty-primeneniya-longidazy-u-bolnyh-idiopaticheskim-fibroziruyuschim-alveolitom/viewer (in Russian).

20. Laszlo G. Standardisation of lung function testing: Helpful guidance from the ATS/ERS task force. Thorax. 2006; 61 (9): 744–746. DOI: 10.1136/thx.2006.061648.

21. Hsu K.Y., Lin J.R., Lin M.S. et al. The modified Medical Research Council dyspnoea scale is a good indicator of health-related quality of life in patients with chronic obstructive pulmonary disease. Singapore Med. J. 2013; 54 (6): 321–327. DOI: 10.11622/smedj.2013125.

22. Rajala K., Lehto J.T., Sutinen E. et al. mMRC dyspnoea scale indicates impaired quality of life and increased pain in patients with idiopathic pulmonary fibrosis. ERJ Open Res. 2017; 3 (4): 00084-2017. DOI: 10.1183/23120541.00084-2017.

23. Siddiq M.A., Rathore F.A., Clegg D., Rasker J.J. Pulmonary rehabilitation in COVID-19 patients: a scoping review of current practice and its application during the pandemic. Turk. J. Phys. Med. Rehabil. 2020; 66 (4): 480–494. DOI: 10.5606/tftrd.2020.6889.

24. Jiang D., Liang J., Noble P.W. Hyaluronan as an immune regulator in human diseases. Physiol. Rev. 2011; 91 (1): 221–264. DOI: 10.1152/physrev.00052.2009.

25. Evanko S.P., Potter-Perigo S., Bollyky P.L. et al. Hyaluronan and versican in the control of human T-lymphocyte adhesion and migration. Matrix Biol. 2012; 31 (2): 90–100. DOI: 10.1016/j.matbio.2011.10.004.

26. Dicker K.T., Gurski L.A., Pradhan-Bhatt S. et al. Hyaluronan: a simple polysaccharide with diverse biological functions. Acta Biomater. 2014; 10 (4): 1558–1570. DOI: 10.1016/j.actbio.2013.12.019.

27. Cowman M.K., Schmidt T.A., Raghavan P., Stecco A. Viscoelastic properties of hyaluronan in physiological conditions. F1000Res. 2015; 4: 622. DOI: 10.12688/f1000research.6885.1.

28. Nettelbladt O., Tengblad A., Hällgren R. Lung accumulation of hyaluronan parallels pulmonary edema in experimental alveolitis. Am. J. Physiol. 1989; 257 (6, Pt 1): L379–384. DOI: 10.1152/ajplung.1989.257.6.l379.

29. Hellman U., Karlsson M.G., Engstrom-Laurent A. et al. Presence of hyaluronan in lung alveoli in severe COVID-19: an opening for new treatment options? J. Biol. Chem. 2020; 295 (45): 15418–15422. DOI: 10.1074/jbc.ac120.015967.

30. Cui X., Chen W., Zhou H. et al. Pulmonary edema in COVID-19 patients: mechanisms and treatment potential. Front. Pharmacology. 2021; 12: 664349. DOI: 10.3389/fphar.2021.664349.

31. Vaz de Paula C.B., Nagashima S., Liberalesso V. et al. COVID-19: Immunohistochemical analysis of TGF-P signaling pathways in pulmonary fibrosis. Int. J. Mol. Scie. 2021; 23 (1): 168. DOI: 10.3390/ijms23010168.

32. Solomon J.J., Heyman B., Ko J.P. CT of post-acute lung complications of COVID-19. Radiology. 2021; 301 (2): E383–395. DOI: 10.1148/radiol.2021211396.

33. Fumagalli A., Misuraca C., Bianchi A. et al. Pulmonary function in patients surviving to COVID-19 pneumonia. Infection. 2020; 49 (1): 153–157. DOI: 10.1007/s15010-020-01474-9.