Results of 5-year observation of patients with diseases of peripheric arteries after gene therapy

Deev R.V.^1,2, Plaxa I.L.¹, Boso I.Y.¹, Mzhavanadze N.D.², Suchkov I.A.², Chervyakov Yu.V.³, Staroverov I.N.³, Kalinin R.E.², Isaev A.A.¹, Matveev S.A.⁴

This study included patients who were in a clinical study evaluating the safety and efficacy of gene therapy with pl-VEGF165 in patients with chronic ischemia of the lower extremities of atherosclerotic origin (ClinicalTrials.gov: NCT03068585). In just 5 years the study included 36 patients who received a gene therapy drug and 12 patients in the control group. Patients were registered for adverse events, as well as an assessment of the pain-free walking distance (PWD), ankle-brachial index (ABI), transcutaneous oxygen pressure (TcPO2). There were no side effects associated with the use of pl-VEGF165. Differences in the incidence of adverse cardiovascular events (pl-VEGF165 5/36 versus 2/12 in control, P=0,85), oncological diseases (pl-VEGF165 1/36 vs 0/12 in control, P=0,38) and visual impairment (not recorded in both groups) over the 5-year follow-up period did not reach statistical significance. The safety of the target limb was 95% in the clinical group and 67% in the control group. The PWD in the clinical group increased by 288% by the end of the fifth year (from 105,7±16,5 m to 384±39 m). The greatest increase in PWD from 24,3±5,3 m to 378±73,1 m was determined in the III stage of the disease. Also positive dynamics of the ABI and TcPO₂ was established.

Therefore, the use of pl-VEGF165 should be considered safe. The therapeutic effect of gene induction of angiogenesis persists for five years, with a maximum increase by the end of 3 years and is most pronounced in patients with stage III disease.

1. Deev, R.V. Klinicheskie rezul’taty primeneniya genno-inzhenernyh tekhnologij indukcii angiogeneza v kompleksnom lechenii pacientov s hronicheskoj ishemiej nizhnih konechnostej / R.V. Deev, R.E. Kalinin, Yu.V. Chervyakov i dr. // Vestnik nacional’nogo mediko-hirurgicheskogo centra im. N.I. Pirogova. — 2011. — T. 6, № 4. — S. 20-25.

2. Deev, R.V. Effektivnost’ primeneniya gena VEGF165 v kompleksnom lechenii pacientov s hronicheskoj ishemiej nizhnih konechnostej 2A-3 stadii / R.V. Deev, I.Ya. Bozo, N.D. Mzhavanadze i dr. // Angiologiya i sosudistaya hirurgiya. — 2014. — T. 20, № 2. — S. 38-48.

3. Deev, R.V. Otdalennye rezul’taty primeneniya pl-VEGF165 pri hronicheskoj ishemii nizhnih konechnostej vsledstvie obliteriruyushchego ateroskleroza / R.V. Deev, R.E. Kalinin, Yu.V. Chervyakov i dr. // Kardiologiya i serdechno-sosudistaya hirurgiya. — 2015. — T. 4. — S. 43-49.

4. Kalinin, R.E. Effektivnost’ preparata dlya terapevticheskogo angiogeneza v kompleksnom lechenii pacientov s saharnym diabetom i kriticheskoj ishemiej nizhnih konechnostej / R.E. Kalinin, I.A. Suchkov, A.S. Pshennikov i dr. // Kazanskij medicinskij zhurnal. — 2016. — T. 97, № 5. — S. 674-680.

5. Kalinin, R.E. Gennaya indukciya angiogeneza u neoperabel’nyh pacientov s aterosklerozom i saharnym diabetom / R.E. Kalinin, I.A. Suchkov, R.V. Deev i dr. // Angiologiya i sosudistaya hirurgiya. — 2018. — T. 24, — № 2. — S. 33-39.

6. Nacional’nye rekomendacii po vedeniyu pacientov s patologiej arterij nizhnih konechnostej // Angiologiya i sosudistaya hirurgiya. — 2013. — T. 19, № 2 (Prilozhenie). — C. 1-67.

7. Chervyakov, YU.V. Otdalennye rezul’taty do 3 let ispol’zovaniya nepryamyh sposobov revaskulyarizacii u bol’nyh s hronicheskoj ishemiej nizhnih konechnostej // Yu.V. Chervyakov, I.N. Staroverov, A.V. Borisov i dr. // Vestnik hirurgii im. I.I. Grekova. — 2015. — T. 147, № 2. — S. 84-88.

8. Chervyakov, Yu.V. Pyatiletnie rezul’taty lecheniya bol’nyh hronicheskoj ishemiej nizhnih konechnostej s ispol’zovaniem gennoj terapiej // Yu.V. Chervyakov, I.N. Staroverov, O.N. Vlasenko i dr. // Angiologiya i sosudistaya hirurgiya. — 2016. — T. 22, № 4. — S. 38-45.

9. Yudin, M.A. Ocenka sistemnogo raspredeleniya i angiogennnogo effekta pl-VEGF165 v modeli ishemii konechnostej / M.A. Yudin, I.L. Plaksa, N,D. Mzhavanadze i dr. // Patologiya krovoobrashcheniya i kardiohirurgiya. — 2015. — T. 19, № 2-4. — S. 33-42.

10. Cooke, J.P. Modulating the Vascular Response to Limb Ischemia / J.P. Cooke, D.W. Losordo // Angiogenic and Cell Therapies Circ. Res. — 2015. — V. 116. — P. 1561-1578.

11. Efficacy and Safety of AMG0001 in Subjects With Critical Limb Ischemia (AGILITY). NCT02144610.

12. Deev, R. pCMV-vegf165 intramuscular gene transfer is an effective method of treatment for patients with chronic lower limb ischemia / R. Deev, I. Bozo, N. Mzhavanadze et al. // J. Cardiovasc. Pharmacol. Ther. — 2015. — V. 20, № 5. — R. 473-482.

13. Deev, R. Results of an International Postmarketing Surveillance Study of pl-VEGF165 Safety and Efficacy in 210 Patients with Peripheral Arterial Disease / R. Deev, I. Plaksa, I. Bozo, A. Isaev // Am. J. Cardiovasc. Drugs. — 2017. doi: 10,1007/s40256-016-0210-3.

14. Goodney, P.P. National trends in lower extremity bypass surgery, endovascular interventions, and major amputations / P.P. Goodney, A.W. Beck, J. Nagle et al. // J. Vasc. Surg. — 2009. — V. 50, № 1. — R. 54-60.

15. Goodney, P.P. Relationship between regional spending on vascular care and amputation rate / P.P. Goodney, L.L. Travis, B.S. Brooke et al. // JAMA Surg. — 2014. — V. 149, № 1. — R. 34–42.

16. Gupta, R. Human Studies of Angiogenic Gene Therapy / R. Gupta, J. Tongers, D.W. Losordo // Circ. Res. — 2009. — V. 105, № 8. — 724–736.

17. Hedman, M. Eight-year safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer / M. Hedman, K. Muona, A. Hedman et al. // Gene Therapy. — 2009. — V. 16. — P. 629–634.

18. Morishita, R. Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy / R. Morishita, S. Nakamura, S. Hayashi et al. // Hypertension. — 1999. — V. 33. — P. 1379—1384.\

19. Muona, K. 10-year safety follow-up in patients with local VEGF gene transfer to ischemic lower limb / K. Muona, K. Mäkinen, M. Hedman et al. // Gene Ther. 2012. — V. 19, № 4. — R. 392-395.

20. Nikol, S. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia / S. Nikol, I. Baumgartner, E. Van Belle et al. // Mol. Ther. — 2008. — V. 16. — P. 972— 978.

21. Safety and Efficacy Study Using Gene Therapy for Critical Limb Ischemia. NCT01064440.

22. Yla-Herttuala, S. Angiogenic gene therapy in cardiovascular diseases: dream or vision? / S. Yla-Herttuala, C. Bridges, M.G. Katz et al. European Heart J. — 2017; V. 38, № 18/ — P. 1365-1371.