Acellular Tissue Engineered Vessel

SYMVESS™ is an acellular tissue engineered vessel indicated for use in adults as a vascular conduit for extremity arterial injury when urgent revascularization is needed to avoid imminent limb loss, and autologous vein graft is not feasible. SYMVESS™ is an acellular tissue engineered vessel indicated for use in adults as a vascular conduit for extremity arterial injury when urgent revascularization is needed to avoid imminent limb loss, and autologous vein graft is not feasible. ( 1 )

SYMVESS is an acellular tissue engineered vessel composed of organized extracellular matrix (ECM) proteins. SYMVESS is implanted using standard surgical techniques as a vascular construct to replace a patient’s damaged extremity artery after injury. SYMVESS has dimensions of 6 mm in inner diameter and 42 cm in length (approximately 40 cm of usable length). Since the length of SYMVESS to be implanted is dependent on the surgical needs, it is cut to length by the surgeon in the operating room [see Administration (2.3 steps 5 and 6) ] . SYMVESS is an acellular tissue engineered vessel composed of organized extracellular matrix (ECM) proteins. It has dimensions of 6 mm in inner diameter and 42 cm in length (approximately 40 cm of usable length). ( 3 )

DO NOT use SYMVESS in patients who have a medical condition that would preclude long-term antiplatelet therapy (such as aspirin or clopidogrel) after resolution of acute injuries. DO NOT use SYMVESS in patients who have a medical condition that would preclude long-term antiplatelet therapy (such as aspirin or clopidogrel) after resolution of acute injuries.

Graft Rupture. ( 5.1 ) Anastomotic Failure. ( 5.2 ) Thrombosis. ( 5.3 ) Transmission of Infectious Diseases ( 5.4 )

5.1 Graft Rupture Vascular graft rupture has occurred in patients treated with SYMVESS [see Clinical Trials Experience (6.1) ] . Advise patients that arterial bleeding can be life-threatening and to seek emergent medical evaluation for any signs or symptoms of graft rupture such as bleeding, pain and swelling in the extremity, or signs of extremity ischemia. Follow appropriate procedures for handling and administering SYMVESS [see Dosage and Administration (2) ] .

5.2 Anastomotic Failure Anastomotic failure has occurred in patients treated with SYMVESS [see Clinical Trials Experience (6.1) ] . In clinical studies of SYMVESS, anastomotic failure occurred within the first 36 days post-implantation. Monitor patients for signs of anastomotic failure such as pain and swelling at the surgical site, decreasing hemoglobin or other signs and symptoms of bleeding. Advise patients to seek urgent medical evaluation if they have any signs or symptoms that may be indicative of anastomotic failure such as bleeding, swelling or worsening pain at the surgical site or changes in color of overlying skin. Follow appropriate procedures for handling and administering SYMVESS [see Dosage and Administration (2) ] .

5.3 Thrombosis Thrombosis has occurred in patients treated with SYMVESS [see Clinical Trials Experience (6.1) ] . In clinical trials of SYMVESS, patients received antiplatelet therapy following implantation of SYMVESS to reduce the risk of thrombosis. The risk of thrombosis may increase in patients who discontinue antiplatelet therapy. Anti-platelet therapy is recommended following treatment with SYMVESS.

5.4 Transmission of Infectious Diseases SYMVESS is manufactured using cells and reagents that may transmit infectious diseases or infectious agents. The cells used in the manufacture of SYMVESS are derived from a donor who met the donor eligibility requirements for transmissible infectious diseases which includes screening and testing of risks associated with human immunodeficiency virus 1 (HIV-1), human immunodeficiency virus 2 (HIV-2), hepatitis B virus (HBV), hepatitis C virus (HCV), and syphilis ( Treponema pallidum) . The cell banks are tested negative for human and animal viruses, retroviruses, bacteria, fungi, yeast, and mycoplasma. While all animal-derived reagents are tested for animal viruses, bacteria, fungi, and mycoplasma before use, these measures do not eliminate the risk of transmitting these or other transmissible infectious diseases and disease agents. Fetal bovine serum is sourced to minimize the risk of transmitting a prion protein that causes bovine spongiform encephalopathy and the cause of a rare fatal condition in humans called variant Creutzfeldt-Jakob disease. No transmissible agent infections have been reported during clinical testing.

The most common adverse reactions (incidence ≥3%) were thrombosis, fever, pain, anastomotic stenosis, rupture or anastomotic failure, and infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Humacyte Global, Inc. at 1-833-591-0081 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a product cannot be directly compared to adverse reaction rates in clinical trials of other products, and they may not reflect the rates observed in real-world clinical practice. The safety data described in this section reflect exposure to SYMVESS in one single arm, open-label study in patients requiring vascular replacement or reconstruction for life or limb threatening vascular trauma, Study 1 (CLN-PRO-V005; NCT03005418). A total of 54 adults received extremity implantation of SYMVESS as a vascular conduit. The patient population ranged in age from 18 to 72 years (mean age 33 years). Each patient received a SYMVESS implant ranging in length from 1 to 35 cm (mean length 10.1 cm). The most frequently occurring adverse reactions are shown in Table 1 . Table 1 Adverse Reactions Occurring with a Frequency of ≥3% in Study 1 Adverse Reaction Adverse Reaction Frequency based on up to 3 years follow-up data [median 191 days (range 1-1134 days)] Extremity Patients (%) Extremity patients are with arterial repair in upper or lower limbs (n=54) Vascular graft thrombosis 15 (28%) Pyrexia (fever) 9 (17%) Pain 8 (15%) Anastomotic stenosis 5 (9%) Vascular graft rupture or anastomotic failure 4 (7%) Vascular graft infection 3 (6%) Long term follow-up of up to 36 months in Study 1 is ongoing. At the data cut-off date, 7 out of 54 patients in the extremity group have completed the study (i.e., completed 36 months of follow-up). The safety of SYMVESS beyond 36 months was not evaluated in the clinical studies for this indication.

8.1 Pregnancy Risk Summary The limited clinical data that are available with SYMVESS use in pregnant women are insufficient to inform a drug-associated risk. No animal reproductive and developmental toxicity studies have been conducted with SYMVESS to assess whether it can cause harm to the mother or fetus when administered to a pregnant woman. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2 Lactation Risk Summary There is no information regarding the transmission of antibodies or any components of SYMVESS in human milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SYMVESS and any potential adverse effects on the breastfed infant from SYMVESS or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of SYMVESS in pediatric patients (0 to 17 years old) have not been established.

8.5 Geriatric Use Two (2) patients out of the 54 Extremity Group implanted with SYMVESS as a conduit in Study 1 were aged ≥65 years. The number of patients aged ≥65 years was not sufficient to determine whether they responded differently than younger patients to SYMVESS.

SYMVESS is an acellular tissue engineered vessel composed of human extracellular matrix (ECM) that exhibits mechanical and biological activity. Product testing results have shown that SYMVESS can withstand the forces associated with the arterial blood flow and suturing during implantation. Product testing results have also demonstrated that SYMVESS ECM can support cell binding and proliferation. However, the exact mechanism of action has not been established.

12.2 Pharmacodynamics The pharmacodynamic effects of SYMVESS are not known.