Product Candidates
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VT-111 is being developed as a therapeutic to prevent damage due to inflammation, in particular cardiovascular inflammation and inflammation caused by solid organ transplantation. As Viron's lead candidate, it is the first example from its pipeline of a viral anti-inflammatory protein being successfully adapted into a therapeutic for the treatment of human disease.
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 monocyte migration during vascular inflammation at doses much lower (in µg/kg doses) than most biologics on the market today. VT-111 dramatically reduces leukocyte recruitment to sites of inflammation at low doses in vivo and has demonstrated efficacy in more than 40 animal models of disease including those for angioplasty, stent placement, cardiovascular bypass surgery and solid organ (heart and kidney) transplantation.
VT-111 has demonstrated a favorable safety profile in two clinical trials. The drug is currently undergoing manufacturing sacle-up for late stage clinical trials and market launch, and preparations to file an IND in solid organ transplant, its second indication.
Cardiovascular Indication
Viron recently reported positive Phase IIa data evaluating VT-111 for the treatment of vascular inflammation in patients with Acute Coronary Syndrome demonstrating that VT-111 significantly reduces key cardiac enzymes, Troponin I and CKMB, at multiple time points after stent placement.
A statistically significant, dose-dependent reduction in levels of the cardiac damage biomarker Troponin I was associated with VT-111 treatment at eight, 16, 24, and 54 hours following the initial dose. The VT-111 treated patients also showed a statistically significant reduction in the cardiac damage biomarker creatine kinase myocardial biomarker (CKMB) at eight, 16, and 24 hours.
VT-111 also showed strong trends toward reducing Major Adverse Cardiac Events (MACE, a clinical endpoint comprised of myocardial infarction, revascularization, coronary artery bypass graft (CABG) or death) in the higher dose group, with no MACE events at the six month follow-up, compared to the placebo group, which had >18% MACE.
Previously published studies have shown that a reduction in the rise of Troponin I and/or CK-MB in the first 24 hours after stent placement is predictive of whether a patient will experience a subsequent clinical event.
The 48-patient placebo-controlled study (3:1 treated versus control) enrolled patients at seven sites across North America.
Treated patients were placed in one of two dose cohorts, 5 µg/kg or 15 µg/kg. Each treated patient received three consecutive daily doses of VT-111, plus standard of care. The first dose was administered immediately preceding the PCI procedure.
In earlier preclinical models, VT-111 has been shown to reduce restenosis 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 (Fig 1), 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 cardiovascular restenosis reveals extensive monocyte infiltration in inflamed and damaged tissue. Animals treated with VT-111 show much less monocyte infiltration in these experimental models (Fig 2), in combination with an associated decrease in disease surrogates such as restenosis, vascular lesion formation, and graft failure6,7.
Figure 2: Immunohistochemical staining for invading mononuclear cells in the adventitial layer of rat aortic allografts6.
In addition to reducing cardiovascular restenosis, VT-111 also has a positive effect on increasing the stability of vulnerable plaques. Bot et al (2003) 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 is also being developed to reduce 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 attenuate the rampant inflammatory response that damages the vasculature. Studies were performed in three different laboratories on three different organs, and all showed improvment in the chronic rejection indication. Given that there are currently no treatments in development or on the market targeting monocyte/macrophage infiltration and/or chronic rejection, VT-111 has the potential to be a first in class treatment in solid organ transplantation.
In animal models of renal, aortic and cardiac allograft transplants, VT-111 was administered once a day for up to 10 days by intravenous bolus injection. These models demonstrated VT-111 is an extremely effective way of preventing an over-reaction of the inflammatory cell response (in particular monocyte/macrophage migration), triggered by surgical trauma and ischemia reperfusion. This acute response of immune cells contributes to organ damage that ultimately leads to loss of graft function; also known as chronic rejection. By preventing monocyte/macrophage infiltration into the transplanted organ, VT-111 has demonstrated a dramatic reduction in histological markets of organ damage with a corresponding improvement in graft survival.
Prevention of early inflammatory cell recruitment by VT-111 prevents invasion of inflammatory cells into transplanted organs triggered by ischemia/reperfusion injury, surgical trauma or 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.
VT-111 prevents the initial inflammation that can lead to a series of compounding events with up-regulation of inflammatory cell responses and on-going tissue damage. Preclinical data suggests that inhibition of these early triggers can prevent chronic inflammatory responses, thereby reducing arterial damage and occlusive plaque formation over the long term.
Safety Through the Phase I and Phase IIa trials, 64 patients have received VT-111. No seriouos drug-related adverse events have been reported and VT-111 has been well tolerated at all dose levels. The Phase IIa study showed no difference between the treatment and placebo groups for the key safety measures, including coagulation markers and adverse events. The in-stent plaque area and lumen area, as assessed by intravascular ultrasound at six months, were similar for both groups. VT-111 demonstrated no drug-related adverse events and no neutralizing antibodies (low immunogenicity) in the patient population.
VT-111 has also 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 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 proteins 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.
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