Product Candidates
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VT-111 has the potential to be one of the first true anti-inflammatory drugs to market to treat cardiovascular inflammation and transplant vasculopathy. VT-111 is a 55 kDa secreted glycoprotein belonging to a superfamily of proteins called SERPINS, which share a general structure and mechanism for proteinase inhibition (1,2). VT-111 is an extremely potent inhibitor of vascular inflammation and is being used at doses much lower than most biologics on the market today (µg/kg). VT-111 dramatically reduces leukocyte recruitment to sites of inflammation at low doses in vivo and has demonstrated efficacy in over 40 animal models of disease including angioplasty, stent placement, cardiovascular bypass surgery and solid organ (heart and kidney) transplantation. VT-111 has demonstrated a favorable safety profile (safe, well tolerated in Phase I), and is currently enrolling ACS patients in a Phase IIa study with primary endpoints designed to establish safety in patients undergoing purcutaneous coronary interventions (PCI), and gather information on the drug's effects on biomarkers and intravascular ultrasound at a six month follow-up. VT-111 is currently undergoing manufacturing scale up for late stage clinical trials and market launch, and is preparing to file an IND in solid organ transplant, its second indication.
Cardiovascular indication VT-111 is currently being investigated in a Phase IIa trial in patients with ACS undergoing intervention (PCI). VT-111 has been shown to reduce atherosclerosis and increase the stability of vulnerable plaques. Reducing inflammatory cell recruitment may impart the therapeutic effects of VT-111 seen in animal models of disease. In numerous models of cardiovascular inflammation, treatment with VT-111 significantly reduced plaque growth (atherosclerosis), and early monocyte and CD2+ T lymphocyte invasion into injured tissue6.
Figure 1: Histological examination of aortas from cholesterol fed rabbits that had undergone angioplasty mediated injury (stents). Left picture identifies control treated rabbits and right identifies VT-111 treated rabbits.
VT-111 reduces monocyte invasion in multiple animal models of vascular inflammation. Microscopic examination of diseased vasculature in animal models of either transplant vasculopathy or restenosis reveals extensive monocyte infiltration in inflamed and damaged tissue. Animals treated with VT-111 show much less monocyte infiltration in these experimental models, in combination with an associated decrease in disease surrogates such as atherosclerosis, vascular lesion formation, and graft failure6,7.
Figure 2: Immunohistochemical staining for invading mononuclear cells in the adventitial layer of rate aortic allografts6.
In addition to reducing atherosclerosis, VT-111 also has a positive effect on increasing the stability of vulnerable plaques. Bot et al demonstrated this effect in a mouse model of chronic inflammation where a carotid cuff was placed on the carotid artery for 5 weeks in order to allow formation of an advanced (vulnerable) lesion. At this time, VT-111 was administered and increased both the collagen content and number of smooth muscle cells within the lesion, both characteristics suggestive of a more stable plaque morphology8. Clinical development of VT-111 aims to translate this reduction in the incidence of heart attack and stroke in patients with ACS by increasing plaque stability.
Transplant indication
VT-111 reduces chronic rejection in solid organ transplantation. Current transplantation induction therapies aim to deplete the acquired immune (T-cell) response for a short period at the time of transplantation. In contrast, VT-111 targets the innate immune response in order to combat the rampant inflammatory response that damages the vasculature. In animal models of renal, aortic and cardiac allograft transplants, VT-111 was administered once a day for 10 days by i.v. bolus injection. These studies demonstrated a marked reduction in transplant vasculopathy and scarring 8,9. These studies were performed in three different laboratories on three different organs, and all showed improvement in the chronic rejection indication. Consistent with its anti-inflammatory activity in vascular angioplasty injury models, VT-111 treatment in transplant models also resulted in a reduction of macrophage and monocyte infiltration, in this case into the vasculature of the transplanted organs9. In a rat kidney chronic allograft rejection model (F344 Rat à Lewis Rat) VT-111 significantly reduces tubular necrosis, arterial fibrinoid necrosis, and intra-graft TGF-β expression on post operative days (POD) 2 and 140 (Fig 3). This sustained anti-graft TGF-B expression on post operative days (POD) 2 and 140 (Fig 4) suggests a reduction in the basal level of organ inflammation in treated animals10.
In the solid organ transplant models, VT-111, provided along with cyclosporine A for the first 10 days post-transplant, effectively reduced chronic vasculopathy and organ scarring at 3- 5 months follow up with no further drug bolus injections. Chronic rejection, as indicated by graft vascular disease or transplant vasculopathy, accounts for 20% of patient deaths as early as two years after cardiac transplant4,6.
A model of vein graft bypass surgery was also developed (Figure 4). A segment of external jugular vein from one Lewis rat was grafted between the abdominal and left renal artery of a second Lewis rat. Treatment with VT-111 at the time of surgery reduced both plaque development and mononuclear cell infiltration into the grafted vein when measured four weeks later6
Prevention of early inflammatory cell recruitment by VT-111 prevents invasion of inflammatory cells into transplanted organs triggered by ischemia/reperfusion injury, surgical trauma as well as inflammatory responses to recurrent episodes of allograft rejection. Inhibiting this immediate organ damage and the vasculopathy that is associated with the early inflammatory response allows the organ to retain its structural integrity (i.e. reduced intimal hyperplasia and scarring) which itself could dampen subsequent inflammatory responses.
By preventing the initial inflammation that can lead to a series of compounding events with up-regulation of inflammatory cell responses and ongoing tissue damage, inhibition of these early triggers may prevent chronic inflammatory responses, thereby reducing arterial damage and occlusive plaque formation.
Safety
Viron completed its Phase I clinical trial with VT-111 in healthy volunteers in the U.S. No serious adverse events were reported and VT-111 was well tolerated at all dose levels. VT-111 elicited no adverse clinical effect on hematology, coagulation or clinical chemistry parameters, and was not immunogenic. VT-111 has undergone extensive pre-clinical testing in four species to screen for signs of toxicity. In a pivotal monkey toxicology study in which VT-111 was administered by a single daily bolus injection for 14 consecutive days at doses significantly higher than the anticipated human dose, VT-111 elicited no adverse clinical effect on body weight, food consumption, hematology, coagulation or clinical chemistry parameters, organs weights, macroscopic observations at necropsy, or tissue architecture. In a separate cardiovascular safety study in monkeys, VT-111 administration up to 50 times the proposed clinical dose (750 µg/kg) had no effect on heart rate, blood pressure or the electrocardiographic complex. All proteins have the potential to induce an immune response. Based on a comprehensive set of data, Viron believes that immunogenicity will not be a serious threat to its development compounds. Since immunogenicity would negatively affect the potency of these viral proteins, it stands to reason that viruses have evolved to produce anti-inflammatory drugs that have extremely low immunogenicity. Viral proteins, such as VT-111, have also evolved to produce highly potent anti-inflammatory signals at low doses, which will also reduce the immunogenic potential of the drug.
References
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