Currently, chronic lower limb ischemia (CLI) remains a pressing problem in angiology and vascular surgery due to the difficulty and duration of treatment, high prevalence and high degree of disability of patients [1]. Therefore, effective treatment of patients with this pathology is extremely important from medical, social and economic points of view. Modern reconstructive vascular surgery and angiotropic pharmacotherapy can achieve positive results in a large number of patients. However, there are limitations to the capabilities of existing treatment approaches when applied to patients with diffuse lesions of the distal arterial beds, for whom long-term results of surgical treatment are not satisfactory, and pharmacotherapy is effective only in the early stages of the disease. This category of patients is the main contributor to the unsatisfactory results of treatment for CLI [3, 5].
One of the modern and new principles of action, as well as promising for further study and use of approaches in the treatment of patients with CLI, is the use of genetic engineering complexes based on vascular growth factors VEGF 165 (the drug “Neovasculgen”). The introduction of this drug into ischemic tissues ensures long-term synthesis of growth factors, leading to the development of an additional vascular network and, consequently, to an increase in tissue perfusion and a decrease in the degree of ischemia. This technique can be used both as an independent method of treatment and in combination with reconstructive vascular operations or complex conservative treatment to improve long-term results.
Currently, a certain number of both experimental and clinical studies on this problem have already been carried out in Russia and abroad [1–6].
The purpose of this work is to evaluate the clinical effectiveness and long-term results of the use of genetically engineered constructs based on the vascular growth factors VEGF165 (the drug “Neovasculgen”) in the complex treatment of patients with CLI.
Pharmacodynamics and pharmacokinetics
Pharmacodynamics
Neovasculgen belongs to gene therapy drugs and contains the human VEGF 165 gene in the form of a highly purified supercoiled plasmid, encoding the process of synthesis of vascular endothelial growth factor under the control of the DNA . This mechanism of action, which is called therapeutic angiogenesis , is based on the use of a programmed process of evolutionary formation and growth of blood vessels.
Recombinant DNA includes a large number of components. When molecules of such a plasmid penetrate into human cells, the process of production of VEGF , which stimulates endothelial cells, which in turn leads to vascularization (growth of blood vessels) in the area of administration. Endothelial cells take part in the presentation of antigens , vasoconstriction and vasodilation, and are also the most important elements of blood vessels (arteries, veins, capillaries). Activation of VEGF receptors type 1 and 2 allows various intracellular receptor signaling cascades to be involved in the process of angiogenesis .
The drug Neovasculgen was created to reduce the incidence of mortality and limb amputations in patients with diseases of the lower extremities accompanied by chronic ischemia , in particular in patients with occlusive lesions of peripheral arteries, for whom standard revascularization cannot be performed for various reasons.
Neovasculgen stimulates the formation and growth of blood collateral vessels . In turn, the creation and development of the microvasculature in the tissue of the ischemic lower limb increases their oxygen saturation, reduces pain, promotes the healing of ulcers, increases the duration of pain-free walking, and in general, reduces disability rates and improves the patient’s quality of life. The therapeutic effect of the drug lasts up to two years.
Pharmacokinetics
No data.
Results and discussion
Patient survival and limb preservation was 100%. The development of tumor, ophthalmological diseases, and complications from the cardiovascular system was not recorded.
Long-term results were assessed in the period from 6 to 18 months after the use of genetically engineered VEGF165 “Neovasculgen” constructs. Clinical effectiveness was assessed according to such criteria as pain-free walking distance, time to restore initial blood flow parameters, radioisotope studies of blood supply and perfusion of the muscles of the lower extremities, as well as assessment of quality of life.
The results of the use of genetically engineered constructs based on the vascular endothelial growth factor VEGF165 “Neovasculgen” in the complex treatment of chronic ischemia of the lower extremities are presented in Fig. 1 and 2.
Rice. 1. Results of using the drug "Neovasculgen". a — increase in pain-free walking distance; b — ankle-brachial index.
Rice. 2. Results of using the drug “Neovasculgen”. a — increase in muscle perfusion; b — quality of life index.
When assessing clinical effectiveness, a clear positive trend was established for all groups of patients. Thus, in group 1, the pain-free walking distance was 258±108 m ( p
<0.0001), and 11 out of 26 patients moved from stage IIB to stage IIA CLCI;
in the 2nd group - with a distance of 213±209 m ( p
= 0.01), of 15 patients with stage III, 7 moved to stage IIB and 3 to stage IIA, and healing of ulcerative defects was also noted in all three cases and transition 1 patient from stage IV to stage III CLI with a pain-free walking distance of 70 m.
At the same time, in terms of the dynamics of the ankle-brachial index, statistically significantly better results were obtained only in the 1st group of patients with stage IIB of chronic ischemia.
Data obtained from assessing muscle perfusion in 38 patients using radioisotope research methods, conducted before the administration of the drug "Neovasculgen" and again 6 months after, show an increase in muscle perfusion by an average of 450±72% ( p
<0.05) and by 490±94% (
p
<0.05) in patients of groups 1 and 2, respectively.
In terms of quality of life, statistically significantly better results were obtained in all groups.
Clinical example 1
Patient K.
, 66 years old. Diagnosis: widespread atherosclerosis with predominant damage to the arteries of the lower extremities. Stenosis of the common iliac, common femoral, deep and superficial femoral arteries. Femoropopliteal bypass with a synthetic prosthesis in March 2012. Type 2 diabetes mellitus.
From the anamnesis: he considers himself sick since 2010, when he first noticed the appearance of pain in the calf muscles, mainly on the right, when walking a distance of 300 meters. Subsequently, the disease progressed, and in March 2012, the pain-free walking distance was 50 m. In March 2012, femoral-popliteal bypass surgery was performed with a synthetic prosthesis on the right lower limb with a positive effect - an increase in the pain-free walking distance to 200 m. However, in February 2013 g., the distance was again 50 m, in connection with which he turned to the Russian Scientific Center for Surgery named after. B.V. Petrovsky for examination and adoption of further treatment tactics.
From the examination: according to duplex scanning of the arteries of the lower extremities, the patient has stenosis of both common and external iliac arteries up to 60%, stenosis of the common femoral artery on the right up to 55%, on the left up to 60%; stenosis of the deep femoral artery on the right up to 45%, on the left up to 50%; stenosis of the superficial femoral artery on the right up to 80%, condition of femoropopliteal bypass, the bypass is passable; left stenosis up to 65%; stenosis of the popliteal arteries up to 60%; the arteries of the leg are occluded, the blood flow is of collateral type. ABI indices: 0.35 on the right; 0.3 on the left.
Duplex scanning data were confirmed by multislice computed tomography data of the arteries of the lower extremities with intravenous contrast and angiography (Fig. 3).
Rice. 3. Patient K. Angiogram performed before therapy with Neovasculgen.
According to the treadmill test conducted at a speed of 2 km/h, the initial distance of pain-free walking was 40 m.
03/04/13 in the Department of Vascular Surgery of the Russian Scientific Center for Surgery named after. B.V. Petrovsky RAS, an intramuscular injection of 5.0 ml of the drug “Neovasculgen” was performed into the calf muscle of the left lower limb according to the accepted technique. The patient tolerated the drug well; no local or systemic reactions were noted. On March 18, 2013, the drug was re-injected in a volume of 5.0 ml into the left lower limb.
On 05/17/13, during a control treadmill test at a speed of 2.0 km/h, an increase in the pain-free walking distance to 80 m was noted. On 09/09/13, the pain-free walking distance was 210 m.
On 12/24/13 and 01/10/14, an intramuscular injection of 5.0 ml of the drug “Neovasculgen” was performed into the calf muscle of the right lower limb according to the accepted technique. The patient tolerated the drug well.
On June 16, 2014, the pain-free walking distance during the treadmill test at a speed of 2 km/h was 750 m. The control duplex scan showed an increase in the ABI index to 0.5 on the right and 0.45 on the left.
Clinical example 2
Patient S.,
69 years old. Diagnosis: widespread atherosclerosis with predominant damage to the arteries of the lower extremities. Stenosis of the common iliac, common femoral, deep arteries. Occlusion of the right superficial femoral artery, occlusion of the right popliteal artery. Hypertension stage II, degree 3, risk 4.
From the anamnesis: she considers herself sick since 2006, when she first noticed the appearance of pain in the calf muscles of the right lower limb when walking a distance of 450 m. Subsequently, the disease progressed, and in 2010 pain appeared in the left lower limb, the pain-free walking distance began to be 150 m. Repeatedly underwent courses of conservative treatment at the place of residence without a positive effect. In June 2013, the pain-free walking distance began to be 50 m, and therefore she contacted the Russian Scientific Center for Surgery named after. B.V. Petrovsky for examination and adoption of further treatment tactics.
From the examination: according to duplex scanning of the arteries of the lower extremities, the patient had stenosis of both common and external iliac arteries up to 75%, stenosis of the common femoral artery on the right - up to 70%, on the left - up to 60%; stenosis of the deep femoral artery on the right - up to 45%, on the left - up to 50%; occlusion of the right superficial femoral artery; left stenosis - up to 80%; occlusion of the right popliteal artery, left stenosis - up to 80%; the arteries of the leg are occluded, the blood flow is of collateral type. ABI indices: 0.25 on the right; 0.5 on the left.
Duplex scanning data were confirmed by multislice computed tomography data of the arteries of the lower extremities with intravenous contrast.
According to the initial scintigraphy of the muscles of the lower extremities, there was a predominance of volumetric blood flow in the left leg, on average 42% relative to the level of this indicator in the right leg. Local hyperfixation of the radiotracer in the middle of the right calf muscles indicates a pronounced inflammatory reaction.
According to the initial treadmill test, performed at a speed of 1.5 km/h, the pain-free walking distance was 55 m.
06/15/13 in the Department of Vascular Surgery of the Russian Scientific Center for Surgery named after. B.V. Petrovsky RAS, an intramuscular injection of 5.0 ml of the drug “Neovasculgen” was performed into the calf muscle of the right lower limb according to the accepted technique. The patient tolerated the drug well; no local or systemic reactions were noted. On June 29, 2013, the drug was re-injected in a volume of 5.0 ml into the right lower limb.
On September 10, 2013, during a control treadmill test at a speed of 1.5 km/h, an increase in the distance of pain-free walking to 100 m was noted.
The control scintigram of the muscles of the lower extremities shows a predominance of volumetric blood flow in the right leg by 74% (in contrast to the original study, where R
On March 16, 2014, the pain-free walking distance during the treadmill test at a speed of 1.5 km/h was 550 m. The control duplex scan showed an increase in the ABI index to 0.35 on the right. According to scintigraphy of the muscles of the lower extremities dated September 17, 2014, a predominance of volumetric blood flow in the right leg was noted by 105%.
Neovasculgen, instructions for use (Method and dosage)
Neovasculgen is administered after skin treatment intramuscularly at a dosage of 1.2 mg twice with an interval of 14 days to a place close to the ischemic area. Administer the drug fractionally in several injections with the maximum possible infiltration of the entire muscle mass of the affected area with the solution. The lyophilisate is dissolved in 1.2 ml of water for injection. The drug should completely dissolve. The solution should be at room temperature before administration.
The drug is administered in a hospital or on an outpatient basis under the supervision of doctors.
Material and methods
We analyzed 155 patients with CLI of various stages, who were treated with various genetic engineering constructs to stimulate angiogenesis in the Department of Vascular Surgery of the Russian Scientific Center for Surgery named after. B.V. Petrovsky. Complex treatment of 41 patients (27 men and 14 women) aged from 37 to 79 years (average age 64±9 years) with genetically engineered constructs based on the vascular endothelial growth factor VEGF165 (the drug "Neovasculgen") with stage IIB-IV CLI was carried out. according to the Fontaine-Pokrovsky classification. The main disease in 38 patients was widespread atherosclerosis, in 3 patients - nonspecific aortoarteritis. In 3 cases, trophic disorders of the soft tissues of the lower extremities were noted. All patients included in this study had pronounced diffuse changes in the arteries of the lower extremities (up to occlusion of large-caliber arteries).
All patients are divided into two groups. In the 1st ( n
=26) included patients with stage IIB CLIN, the 2nd stage (
n
=15) included patients with stage III-IV critical ischemia according to the Fontaine-Pokrovsky classification. The initial distance of pain-free walking in the 1st group was 135±53 m, in the 2nd group - 43±14 m. In 3 patients with stage IV ischemia, pain at rest and the presence of ulcerative defects of the soft tissues of the foot were noted. All patients underwent a double injection of 1.2 mg of the drug “Neovasculgen” into the lower leg muscles of the affected limb with an interval between procedures of 14 days. Stimulation of angiogenesis was performed both as an independent method of treatment (24 patients) and in combination with reconstructive vascular operations: femoropopliteal bypass (8), aortofemoral bypass (7), and plastic surgery of the deep femoral artery (2).
Long-term treatment results were studied over a period of 6 to 18 months (average 11 months). Pain-free walking distance, ankle-brachial index, treadmill test results, muscle perfusion according to radioisotope research methods, and quality of life index were used as criteria for assessing treatment results.
Statistical analysis of mean scores was performed using t
-Student's t-test.
The level of statistical significance of differences was taken to be p
<0.05.
Analogs
Level 4 ATC code matches: Cystamine
Lymphomyosot
Galium-Hel
Spascuprel
Ammonia
Mucosa Compositum
Coenzyme Compositum
Ubiquinone Compositum
Dimephosphone
Oscillococcinum
Dantinorm Baby
Coryzalia
Longidaza
Homeovox
Neovasculgen has no analogues.
Reviews about Neovasculgen
According to reviews from doctors, the use of Neovasculgen in the complex treatment of patients with chronic ischemia of the lower extremities significantly increases the effectiveness of the treatment process and leads to regression of pathological symptoms.
the vegf 165 gene construct is well tolerated by patients and is safe. There are extremely few reviews among patients. In addition to its high effectiveness, patients complain about the extremely high cost of the drug.
Neovasculgen® is the first Russian gene therapy drug developed by JSC HSCI for the treatment of ischemia of the lower extremities of atherosclerotic origin (chronic ischemia of the lower extremities /CLI/, including critical ischemia /CLI/)
Video: TV Expert about the drug Neovasculgen
Video: Dmitry Medvedev about the drug Neovasculgen
Dmitry Medvedev at a meeting in Skolkovo about the breakthrough innovative Russian drug Neovasculgen.
Video: Method of administering the drug “Neovasculgen”
An educational film that shows in detail the method of administering an innovative drug for the treatment of lower extremity ischemia.
Neovasculgen® passed all the necessary preclinical and clinical studies, and based on their results, on September 28, 2011, it was included in the state register of medicines for medical use of the Russian Federation. The registration certificate for the drug was received by the Company on December 7, 2011 (RU No. LP-000671).
Certification of the first batches of Neovasculgen® was completed at the end of September 2012, and the drug entered the Russian market as a prescription finished medicinal product (lyophilisate for solution preparation, course - 2 injections /2 packs/) through a network of distributors.
In the future, it is possible to include the drug in federal and regional programs for financing drug assistance to the population. After successful implementation of the promotion program, income from the sale of Neovasculgen® should occupy a significant place in the Company's revenue structure.
The production of Neovasculgen® is carried out on the basis of the Hematological Research Center (FSBI State Scientific Center) of the Ministry of Health of the Russian Federation.
In the future, Neovasculgen® is planned to be introduced to the CIS markets, as well as to the US and Chinese markets. In February 2013, a registration certificate for Neovasculgen® was received in Ukraine.
The innovative drug Neovasculgen® is intended for the treatment of patients with chronic lower limb ischemia (CLI). The disease is caused by clinical manifestations of atherosclerotic lesions of the vessels of the legs (narrowing of the lumen of blood vessels and a decrease in their patency). In Russia, about 1.5 million people suffer from it. Every year, in 145 thousand people, the disease is diagnosed in a severe form, threatening the need for amputation and in 25% of cases resulting in death - the so-called critical ischemia of the lower extremities (CLI). Limb amputation is performed on 35-40 thousand patients every year. Some patients with CLI are inoperable, and for them, the use of Neovasculgen® can become the main method of treatment, which would significantly improve the quality of life, and also, if possible, avoid amputation in the future.
Neovasculgen® is an original, innovative, “first in class” drug that opens up a new approach in the treatment of ischemia - the use of an evolutionarily programmed process of formation and growth of blood vessels. This mechanism of action is called therapeutic angiogenesis.
The drug is a circular DNA (plasmid) carrying the human VEGF 165 gene, encoding the synthesis of vascular endothelial growth factor (VEGF - Vascular Endothelial Growth Factor). By stimulating the formation and growth of collateral vessels, Neovasculgen® is designed to provide a long-term therapeutic effect and improve the quality of life of patients. The development of the microvasculature in the ischemic tissue of the lower limb contributes to the saturation of tissues with oxygen, healing of ulcers, and increases the distance of pain-free walking*. According to clinical studies, the therapeutic effect after a course of Neovasculgen® lasts up to 3 years. The results of 3-year observations of the results of treatment with Neovasculgen® in patients with CLI/CINK were announced at professional conferences and also published (N.I. Pirogov journal “Surgery” (No. 4, 2014). See also the results of a two-year observation It is assumed that the mechanism of action of the drug can provide a longer-lasting effect - observations of patients with CLI/CLI who participated in clinical trials and underwent treatment with Neovasculgen® will continue in the future. * Information is intended for medical and pharmaceutical professionals. Before prescribing the drug, it is necessary Read the text of the full instructions.
Due to the fact that the action of Neovasculgen® is aimed at treating tissue ischemia by stimulating angiogenesis, the drug has the potential to treat other conditions where the development of collateral circulation is required. Therefore, HSCI aims to expand the indications for the use of the drug. The company plans to work in the field of treatment of coronary heart disease (CHD), and is also considering the possibility of using Neovasculgen® for the treatment of diabetic foot syndrome (DFS) and traumatic injuries of peripheral nerves. In addition, work is underway to create tissue-engineered products using Neovasculgen®.
The Company also plans to work towards the creation of new gene therapy drugs based on other constructs and genes, maintaining its status as a leader in the development and promotion of gene therapy in the pharmaceutical market.
According to published pharmacoeconomic calculations, the total social effect from the introduction of Neovasculgen® will be about 4 million rubles per patient. The amount of 3.93 million rubles obtained as a result of assessing the cost-effectiveness of the drug Neovasculgen® is added up taking into account the savings from prescribing the drug and the benefits from improving the patient’s quality of life. Experts have concluded that the widespread use of the drug within the hospital budget has clinical and economic advantages (see: Scientific and practical journal “Bulletin of the North-Western State Medical University named after I.I. Mechnikov” (No. 2, 2014) – https ://neovaskulgen.info/stati-otsenka-stoimosti-efektivnosti-genoterapevticheskogo-preparata-Neovaskulgen-v-lecheni-hronicheskoj-ishemi-nizhnih-konechnostej, as well as Clinical and economic assessment of the effectiveness of using Neovasculgen in the treatment of chronic ischemia of the lower extremities - www .remedium.ru/drugs/detail.php?ID=63731).
Film: mechanism of action of Neovasculgen®
Article: Pathohistological assessment of the state of skeletal muscle after direct gene therapy of vegf165 in patients with chronic occlusive diseases of the arteries of the lower extremities
Article: Cost-effectiveness assessment of the gene therapy drug "Neovasculgen" in the treatment of chronic ischemia of the lower extremities
Article: Gene therapy in Russia: three years of experience
All publications
News from April 6, 2015 The results of the use of the innovative Russian drug Neovasculgen have passed international examination
News from March 12, 2015 The Russian drug Neovasculgen increases the growth of blood vessels in the muscles in patients with ischemia of the lower extremities
News from January 20, 2015 ASI approved HSCI programs on gene therapy and genetic diagnostics
News from December 1, 2014 Vascular surgeons will talk about their experience of using gene therapy in clinical practice
News from November 19, 2014 Gene therapy will be discussed at the All-Russian Congress of Cardiovascular Surgeons
News from August 7, 2014 The world's first gene drug for the treatment of vascular diseases of the legs will save the Russian budget about 4 million rubles per patient
News from July 04, 2014 A Russian innovative drug for the treatment of ischemia was approved by the Council of Biotechnological Societies of Maryland (USA)
News from June 26, 2014 At the Annual Conference of the Russian Society of Angiologists and Vascular Surgeons, an innovative method of treating lower extremity ischemia will be discussed
News from June 4, 2014 Pandemic of lower extremity ischemia - a new challenge to the Russian economy
News from May 14, 2014 Modern methods of treating vascular diseases will be discussed in Kiev
News from September 24, 2013 Leading surgeons from Russia, the USA and Finland will discuss the use of gene and cell technologies in the treatment of cardiovascular diseases in St. Petersburg
News from August 8, 2013 Experts are sounding the alarm: the number of people suffering from ischemia of the lower extremities has exceeded 200 million people
News from July 31, 2013 The innovative drug Neovasculgen® is included in the National recommendations for the treatment of patients with vascular pathologies
Press release dated April 23, 2013 HSCI held the School of Angiology in Kiev and announced the entry into the Ukrainian market of an innovative gene drug for the treatment of ischemia
Press release dated March 26, 2013 HSCI signed a contract for the supply of the Russian innovative drug Neovasculgen®
Press release dated September 21, 2012 The first Russian innovative drug for the treatment of ischemia enters the market
Press release dated September 19, 2012 The innovative drug developed by HSCI was highly appreciated by the Government of the Russian Federation
Press release dated July 5, 2012 An innovative domestic drug for the treatment of ischemia was highly praised by specialists
News from April 25, 2012 Nature magazine about an innovative treatment method developed by the Human Stem Cell Institute
Press release dated March 20, 2012 HSCI begins registration of the Russian innovative drug Neovasculgen® in Ukraine
Press release dated December 7, 2011 HSCI received a registration certificate for Neovasculgen®, a Russian innovative drug for the treatment of lower extremity ischemia
Electronic magazine ANGIOLOGIA . ru , No. 1/2011 Theoretical and practical aspects of the use of a drug based on nucleic acid encoding endothelial vascular growth factor (“Neovasculgen”)
