Product Candidates
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VT-111 is being developed as a therapeutic to prevent damage due to inflammation, in particular inflammation associated with the placement of a cardiac stent and inflammation caused by solid organ transplantation. As Viron's lead candidate, it is the first example 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. Viron recently identified the mechanism of action of VT-111 and found that the protein acts through the uPA/uPAR pathway, which is known to be a critical component of monocyte migration through vascular endothelium into inflamed tissue.
VT-111 has demonstrated a favorable safety profile in two clinical trials. In 2010, Viron completed manufacturing scale-up for late stage clinical trials and market launch. The new manufacturing process with improved yield is expected to achieve gross profit margins of over 90% even at the current 200L scale. This optimized manufacturing process has improved the drug characteristics (extended PK) which has provided a number of new IP opportunities (new composition of matter) that extend market exclusivity for the program. The optimized product, VT-111a, will enter a Phase 2b study in 2011 in patients receiving cardiovascular stents, following on the successful Phase 2a study in that same patient population.
Cardiovascular Indication
Results from a pilot Phase 2a clinical study were recently published in Circulation: Cardiovascular Interventions. VT-111 significantly reduced key cardiac enzymes, Troponin I and CKMB, at multiple time points after stent placement when administered to patients with acute coronary syndromes (UA/NSTEMI), starting just prior to stent placement (Fig.1).
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 17% MACE.
Figure 1: (Circ Cardiovasc Interv. 2010;3:543-548.)
Troponin I and CKMB are two highly validated prognostic biomarkers of cardiac tissue death. Previously published studies (n≈16,000) have shown a tight correlation between rise of Troponin I and/or CK-MB in the first 24 hours after stent placement subsequent rises in major adverse cardiac events (MACE).
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. 2), and early monocyte invasion into injured tissue6.
Figure 2: 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. 3), in combination with an associated decrease in disease surrogates such as restenosis, vascular lesion formation, and graft failure6,7.
Figure 3: 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. The clinical goal of VT-111a is to reduce procedurally driven damage that itself causes a dramatic rise in Troponin I and CKMB in about one-third of patients receiving stents. By reducing the inflammation associated with the cardiac stenting procedure, VT-111a seeks to keep Troponin I and CKMB levels low which we expect will translate into a reduction in the incidence of heart attack and stroke in patients receiving cardiovascular stents.
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 improvement in the chronic rejection indication. Given that there are currently no treatments on the market or in development 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 dampens subsequent inflammatory responses. In a cardiac allograft study, it was demonstrated that proper management of the monocyte response for ten days post transplant using VT-111 demonstrates long term improvement in graft survival and low intra-graft monocyte infiltration up to day 100. Histology endpoints also demonstrated a dramatically reduced incidence of tissue remodeling in these organs (Fig. 4).
Figure 4: VT-111/Cyclosporine (CsA) combination treatment significantly reduces inflammatory cell infiltration and prolongs graft survival in a rat cardiac allograft model.
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.
Through the Phase I and Phase 2a trials, 64 patients have received VT-111. No serious drug-related adverse events have been reported and VT-111 has been well tolerated at all dose levels. The Phase 2a study showed no difference between the treatment and placebo groups for the key safety measures, including coagulation markers and adverse events. VT-111 demonstrated no drug-related adverse events and no neutralizing antibodies (low immunogenicity) in the patient population.
VT-111 has also undergone extensive preclinical 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.
VT-111a has demonstrated an equally impressive safety profile where doses were administered once a day for seven days to rats and primates at doses that were respectively 650 and 300 fold higher than the highest clinical dose in the Phase 2a Study, with no signs of toxicity. Head to head efficacy comparisons between VT-111a and VT-111 show that VT-111a demonstrates improved efficacy at equivalent doses which is associated with the improved PK characteristics of the drug.
References
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Figure 1: VT-111 administration demonstrated a statistically-significant, dose-dependant reduction in two key cardiac biomarkers of cardiac tissue necrosis - Troponin I and CKMB - with an associated reduction of major adverse cardiac events in the high dose group compared to placebo.
