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ISIS-FXIRx, A Novel and Specific Antisense Inhibitor of Factor XI, Caused Significant Reduction in FXI Antigen and Activity and Increased aPTT without Causing Bleeding in Healthy Volunteers
Link
Background:
Factor XI (FXI) deficient subjects (Hemophilia C) have a low incidence of stroke and venous thromboembolism and yet do not exhibit spontaneous bleeding events, suggesting that inhibition of FXI activity (FXI:C) may be an attractive antithrombotic therapeutic strategy. We have previously demonstrated that treatment with FXI antisense oligonucleotides results in robust antithrombotic effects in multiple models of venous and arterial thrombosis without causing bleeding, validating this therapeutic approach preclinically.
Objectives:
To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics (FXI antigen, FXI:C and aPTT) of single and multiple doses of ISIS-FXIRx or placebo in healthy volunteers.
Methods:
In this double blind, single or multiple ascending-dose (SAD or MAD) study, healthy subjects aged 18 to 65 years were randomly assigned in a 3:1 ratio to receive ISIS- FXIRx or placebo (normal saline) administered as a single subcutaneous (SC) injection at 50, 100, 200 and 300 mg/kg (n=8/cohort, except 200 mg cohort n=16), or as multiple SC injections (n=12/cohort). In the MAD cohorts, subjects received 8 SC doses over 6-weeks (3 doses in Week 1 followed by once weekly dosing for 5 weeks).
Results:
In the SAD cohorts, both FXI antigen and FXI:C in the 200 and 300 mg cohorts were significantly reduced 1-week after dosing. In the MAD cohorts (interim analysis, data for 300 mg not analyzed to date), treatment with ISIS- FXIRx demonstrated a robust, sustained and dose-dependent reduction in FXI antigen and FXI:C as compared with placebo group, with maximum reduction observed 1-2 weeks post-dosing (Table). These reductions were accompanied by a concomitant increase in aPTT.
Furthermore, in the 200 mg multiple cohort, FXI:C and FXI antigen were reduced by 92% and 100% respectively in one subject after 6 weeks dosing with no symptoms, including bleeding. Significant correlation between FXI:C reduction and aPTT prolongation was observed (r=-0.8123, p=0.0078). No study drug related bleeding events were reported. ISIS- FXIRx did not cause clinically significant changes in vital signs, ECG, hepatic function, renal function or hematology. One serious AE (allergic reaction) was reported in the 200 mg single dose cohort in an ISIS-FXIRx treated subject, who recovered completely. Most AEs were mild. SC injections of ISIS-FXIRx were well tolerated with mild injection site reactions reported in 33% of the subjects vs. 10.5% in placebo group. Preliminary PK analysis indicates hepatic T1/2 of ISIS-FXIRx across doses to be ~20 days.
Conclusions:
Treatment with ISIS- FXIRx in healthy volunteers demonstrated a statistically significant and sustained reduction of FXI:C, FXI antigen and prolonged aPTT with an acceptable safety and tolerability profile. No bleeding events related to ISIS- FXIRx were found. These data provide further support for development of ISIS-FXIRx as a novel approach for the treatment and prevention of thromboembolic disorders
(see link about for data table figure)
Link
Background:
Factor XI (FXI) deficient subjects (Hemophilia C) have a low incidence of stroke and venous thromboembolism and yet do not exhibit spontaneous bleeding events, suggesting that inhibition of FXI activity (FXI:C) may be an attractive antithrombotic therapeutic strategy. We have previously demonstrated that treatment with FXI antisense oligonucleotides results in robust antithrombotic effects in multiple models of venous and arterial thrombosis without causing bleeding, validating this therapeutic approach preclinically.
Objectives:
To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics (FXI antigen, FXI:C and aPTT) of single and multiple doses of ISIS-FXIRx or placebo in healthy volunteers.
Methods:
In this double blind, single or multiple ascending-dose (SAD or MAD) study, healthy subjects aged 18 to 65 years were randomly assigned in a 3:1 ratio to receive ISIS- FXIRx or placebo (normal saline) administered as a single subcutaneous (SC) injection at 50, 100, 200 and 300 mg/kg (n=8/cohort, except 200 mg cohort n=16), or as multiple SC injections (n=12/cohort). In the MAD cohorts, subjects received 8 SC doses over 6-weeks (3 doses in Week 1 followed by once weekly dosing for 5 weeks).
Results:
In the SAD cohorts, both FXI antigen and FXI:C in the 200 and 300 mg cohorts were significantly reduced 1-week after dosing. In the MAD cohorts (interim analysis, data for 300 mg not analyzed to date), treatment with ISIS- FXIRx demonstrated a robust, sustained and dose-dependent reduction in FXI antigen and FXI:C as compared with placebo group, with maximum reduction observed 1-2 weeks post-dosing (Table). These reductions were accompanied by a concomitant increase in aPTT.
Furthermore, in the 200 mg multiple cohort, FXI:C and FXI antigen were reduced by 92% and 100% respectively in one subject after 6 weeks dosing with no symptoms, including bleeding. Significant correlation between FXI:C reduction and aPTT prolongation was observed (r=-0.8123, p=0.0078). No study drug related bleeding events were reported. ISIS- FXIRx did not cause clinically significant changes in vital signs, ECG, hepatic function, renal function or hematology. One serious AE (allergic reaction) was reported in the 200 mg single dose cohort in an ISIS-FXIRx treated subject, who recovered completely. Most AEs were mild. SC injections of ISIS-FXIRx were well tolerated with mild injection site reactions reported in 33% of the subjects vs. 10.5% in placebo group. Preliminary PK analysis indicates hepatic T1/2 of ISIS-FXIRx across doses to be ~20 days.
Conclusions:
Treatment with ISIS- FXIRx in healthy volunteers demonstrated a statistically significant and sustained reduction of FXI:C, FXI antigen and prolonged aPTT with an acceptable safety and tolerability profile. No bleeding events related to ISIS- FXIRx were found. These data provide further support for development of ISIS-FXIRx as a novel approach for the treatment and prevention of thromboembolic disorders
(see link about for data table figure)
ISIS-FXIRx , a Potent Antisense Inhibitor of Factor XI, Suppresses FXI Activity and Elevates Aptt without Increased Risk of Bleeding in Cynomolgus Monkeys Following 13 Weeks of Treatment
Link
Complications associated with increased bleeding risk are the main limitations with current anticoagulant therapy. Inhibition of factor XI (FXI), a component of the intrinsic coagulation pathway, has received considerable interest because of the potential to produce sufficient anticoagulant activity without bleeding .
The objective of these studies were to characterize the efficacy and safety of ISIS-FXrx and to assess the bleeding risk associated with FXI depletion under experimental surgical settings in cynomolgus monkeys.
ISIS-FXIRx was selected from a series of 2nd-generation (2’-O-methoxyethyl) antisense oligonucleotides (ASOs) targeted to FXI which were evaluated for both tolerability and efficacy in cynomolgus monkeys (25 mg/kg twice per week for 13 weeks, SC). ISIS-FXIRx emerged as the most efficacious among the FXI ASOs evaluated, producing marked reductions of FXI RNA in liver, and FXI protein and activity levelsin plasma with a good tolerability profile. A more extensive dose-response evaluation of ISIS-FXrx (4,8,12 and 40 mg/kg/wk, SC) was conducted over a 13-week treatment period in cynomolgus monkeys to further assess tolerability and activity.
ISIS-FXIRx produced a dose-dependent reduction in plasma FXI activity (>80% at 4 weeks of treatment at 40 mg/kg) with a concomitant increase in aPTT (33%). No effects on PT, platelets and no evidence of bleeding were observed after 13 weeks of treatment with ISIS-FXrx. ASO treatment was well tolerated at all doses tested and only produced changes typical for this chemical class of ASOs (e.g., basophilic granules in multiple tissues due do drug accumulation). ISIS-FXIRx (20 mg/kg, SC for 6 weeks) was also evaluated for bleeding risk in two experimental surgical models in cynomolgus monkeys; a tail amputation model and gum laceration model. Enoxaparin (2 mg/kg), known to increase the risk of bleeding, produced a statistically significant (p<0.05) increase in bleeding time and blood volume loss compared to saline control animals in both the tail amputation and the gum laceration models. Animals treated with ISIS-FXIRx displayed no increase in bleeding parameters compared to control animals.
These results further support the conclusion that targeting FXI is an effective and safe strategy for development of novel antithrombotic agents with minimal increase in bleeding risk. ISIS-FXIRx is currently under evaluation in Phase 1 studies.
Link
Complications associated with increased bleeding risk are the main limitations with current anticoagulant therapy. Inhibition of factor XI (FXI), a component of the intrinsic coagulation pathway, has received considerable interest because of the potential to produce sufficient anticoagulant activity without bleeding .
The objective of these studies were to characterize the efficacy and safety of ISIS-FXrx and to assess the bleeding risk associated with FXI depletion under experimental surgical settings in cynomolgus monkeys.
ISIS-FXIRx was selected from a series of 2nd-generation (2’-O-methoxyethyl) antisense oligonucleotides (ASOs) targeted to FXI which were evaluated for both tolerability and efficacy in cynomolgus monkeys (25 mg/kg twice per week for 13 weeks, SC). ISIS-FXIRx emerged as the most efficacious among the FXI ASOs evaluated, producing marked reductions of FXI RNA in liver, and FXI protein and activity levelsin plasma with a good tolerability profile. A more extensive dose-response evaluation of ISIS-FXrx (4,8,12 and 40 mg/kg/wk, SC) was conducted over a 13-week treatment period in cynomolgus monkeys to further assess tolerability and activity.
ISIS-FXIRx produced a dose-dependent reduction in plasma FXI activity (>80% at 4 weeks of treatment at 40 mg/kg) with a concomitant increase in aPTT (33%). No effects on PT, platelets and no evidence of bleeding were observed after 13 weeks of treatment with ISIS-FXrx. ASO treatment was well tolerated at all doses tested and only produced changes typical for this chemical class of ASOs (e.g., basophilic granules in multiple tissues due do drug accumulation). ISIS-FXIRx (20 mg/kg, SC for 6 weeks) was also evaluated for bleeding risk in two experimental surgical models in cynomolgus monkeys; a tail amputation model and gum laceration model. Enoxaparin (2 mg/kg), known to increase the risk of bleeding, produced a statistically significant (p<0.05) increase in bleeding time and blood volume loss compared to saline control animals in both the tail amputation and the gum laceration models. Animals treated with ISIS-FXIRx displayed no increase in bleeding parameters compared to control animals.
These results further support the conclusion that targeting FXI is an effective and safe strategy for development of novel antithrombotic agents with minimal increase in bleeding risk. ISIS-FXIRx is currently under evaluation in Phase 1 studies.
Antisense Oligonucleotide Mediated Depletion of Factor XI Prevents Vascular Occlusion in An Experimental Thrombosis Model in Primates
Link
It has recently been demonstrated that the intrinsic pathway is an important contributor to pathologic intravascular thrombosis, suggesting that targeting this pathway may yield effective antithrombotic agents. Furthermore, FXI deficiency is not associated with spontaneous bleeding in humans, and deficiency of a contact factor does not cause abnormal bleeding. We have previously shown that treatment with FXI Antisense Oligonucleotides (ASOs) produces potent, dose-dependent antithrombotic activity in various venous and arterial murine thrombosis models. In the current study we characterize the antithrombotic effects of FXI ASOs in a non-human primate model.
Subcutaneous administration of FXI ASOs in cynomologus monkeys resulted in a dose-and time-dependant decrease in FXI mRNA levels in liver (up to 90%), decreased FXI protein and activity levels measured in plasma, and prolonged activated partial thromboplastin times (aPTT). Importantly, FXI depletion in monkeys was not associated with an increased risk of bleeding. Recent studies demonstrated that complete inhibition (>99%) of FXI by a monoclonal antibody reduced thrombin generation and prevented vascular occlusion in a collagen-coated graft inserted into a baboon arteriovenous shunt (Tucker et al., Blood 2009). In the present study, we set out to determine the relationship between FXI levels and antithrombotic activity, and in particular, the minimal level of FXI reduction required to produce an antithrombotic effect in a baboon thrombosis model. Using the FXI monoclonal antibody, we demonstrate that ~50% inhibition of FXI levels produces antithrombotic activity in baboons. Next we applied baboon-specific FXI ASOs and demonstrated reductions in FXI protein levels and activity, with corresponding increases in aPTT levels. Baboons were then treated with FXI ASOs in a manner that would produce ~50% reduction of FXI protein levels and measured anti-thrombotic activity. Similar to the antibody approach, ASO-mediated reduction of FXI plasma levels ≥ 50% resulted in a potent antithrombotic effect. Furthermore, reductions in FXI levels do not increase bleeding times in baboons.
These results further support the development of FXI ASOs for antithrombotic therapy with the potential for a superior safety profile compared to currently available anticoagulants.
Link
It has recently been demonstrated that the intrinsic pathway is an important contributor to pathologic intravascular thrombosis, suggesting that targeting this pathway may yield effective antithrombotic agents. Furthermore, FXI deficiency is not associated with spontaneous bleeding in humans, and deficiency of a contact factor does not cause abnormal bleeding. We have previously shown that treatment with FXI Antisense Oligonucleotides (ASOs) produces potent, dose-dependent antithrombotic activity in various venous and arterial murine thrombosis models. In the current study we characterize the antithrombotic effects of FXI ASOs in a non-human primate model.
Subcutaneous administration of FXI ASOs in cynomologus monkeys resulted in a dose-and time-dependant decrease in FXI mRNA levels in liver (up to 90%), decreased FXI protein and activity levels measured in plasma, and prolonged activated partial thromboplastin times (aPTT). Importantly, FXI depletion in monkeys was not associated with an increased risk of bleeding. Recent studies demonstrated that complete inhibition (>99%) of FXI by a monoclonal antibody reduced thrombin generation and prevented vascular occlusion in a collagen-coated graft inserted into a baboon arteriovenous shunt (Tucker et al., Blood 2009). In the present study, we set out to determine the relationship between FXI levels and antithrombotic activity, and in particular, the minimal level of FXI reduction required to produce an antithrombotic effect in a baboon thrombosis model. Using the FXI monoclonal antibody, we demonstrate that ~50% inhibition of FXI levels produces antithrombotic activity in baboons. Next we applied baboon-specific FXI ASOs and demonstrated reductions in FXI protein levels and activity, with corresponding increases in aPTT levels. Baboons were then treated with FXI ASOs in a manner that would produce ~50% reduction of FXI protein levels and measured anti-thrombotic activity. Similar to the antibody approach, ASO-mediated reduction of FXI plasma levels ≥ 50% resulted in a potent antithrombotic effect. Furthermore, reductions in FXI levels do not increase bleeding times in baboons.
These results further support the development of FXI ASOs for antithrombotic therapy with the potential for a superior safety profile compared to currently available anticoagulants.
Target TMPRSS6 for the Treatment of Hereditary Hemochromatosis
Link
Hereditary hemochromatosis (HH) is a genetic disorder in which hyperabsorption of dietary iron leads to accumulation of iron in multiple tissues including liver and heart. A common clinical manifestation in HH patients is cirrhosis and hepatocellular carcinoma as a result of iron-mediated injury in liver. The most prevalent genetic defect for HH is the failure to up-regulate hepcidin, a peptide hormone that inhibits the absorption of iron in duodenum and the release of iron from intracellular iron storage such as macrophages. Mutations in a number of genes have been identified as the cause for HH, including hepcidin itself. However, the most common mutation is C282Y mutation in HFE, which is a positive regulator for hepcidin expression. C282Y mutation represents about 85% of the HH population. HFE C282Y HH is an autosomal recessive disease with a ~50% penetrance. Currently, the only treatment available for iron overload is phlebotomy which will continue throughout the patient’s life.
Hepcidin is mainly expressed and secreted by the liver and its expression is regulated predominantly at the transcription level. TMPRSS6, a transmembrane serine protease mutated in iron-refractory, iron-deficient anemia, is a major suppressor for hepcidin expression. It’s been demonstrated that hepcidin expression is significantly elevated in Tmprss6-/- mice and reduction of TMPRSS6 in Hfe-/- mice could ameliorate the iron overload phenotype (Du et al. Science 2008; Folgueras et al. Blood 2008; Finberg KE et al., Blood, 2011).
Using second generation antisense technology, we identified antisense oligonucleotides (ASOs) targeting mouse TMPRSS6 for the treatment of HH. These compounds were first identified through in vitro screens in mouse primary hepatocytes. After 4 weeks of treatment in C57BL/6 mice on normal chow, we observed an 80% to 90% reduction of liver TMPRSS6 mRNA with a subsequent 2-3 fold induction of liver hepcidin mRNA. Serum iron and transferrin saturation levels were reduced by ~50%. These ASOs are currently being evaluated in a diet-induced iron overload model and an Hfe-/- iron overload model. Our preliminary results demonstrate that targeting TMPRSS6 is a viable approach for the treatment of hereditary hemochromatosis and possibly other iron-loading diseases associated with suppressed hepcidin levels.
Link
Hereditary hemochromatosis (HH) is a genetic disorder in which hyperabsorption of dietary iron leads to accumulation of iron in multiple tissues including liver and heart. A common clinical manifestation in HH patients is cirrhosis and hepatocellular carcinoma as a result of iron-mediated injury in liver. The most prevalent genetic defect for HH is the failure to up-regulate hepcidin, a peptide hormone that inhibits the absorption of iron in duodenum and the release of iron from intracellular iron storage such as macrophages. Mutations in a number of genes have been identified as the cause for HH, including hepcidin itself. However, the most common mutation is C282Y mutation in HFE, which is a positive regulator for hepcidin expression. C282Y mutation represents about 85% of the HH population. HFE C282Y HH is an autosomal recessive disease with a ~50% penetrance. Currently, the only treatment available for iron overload is phlebotomy which will continue throughout the patient’s life.
Hepcidin is mainly expressed and secreted by the liver and its expression is regulated predominantly at the transcription level. TMPRSS6, a transmembrane serine protease mutated in iron-refractory, iron-deficient anemia, is a major suppressor for hepcidin expression. It’s been demonstrated that hepcidin expression is significantly elevated in Tmprss6-/- mice and reduction of TMPRSS6 in Hfe-/- mice could ameliorate the iron overload phenotype (Du et al. Science 2008; Folgueras et al. Blood 2008; Finberg KE et al., Blood, 2011).
Using second generation antisense technology, we identified antisense oligonucleotides (ASOs) targeting mouse TMPRSS6 for the treatment of HH. These compounds were first identified through in vitro screens in mouse primary hepatocytes. After 4 weeks of treatment in C57BL/6 mice on normal chow, we observed an 80% to 90% reduction of liver TMPRSS6 mRNA with a subsequent 2-3 fold induction of liver hepcidin mRNA. Serum iron and transferrin saturation levels were reduced by ~50%. These ASOs are currently being evaluated in a diet-induced iron overload model and an Hfe-/- iron overload model. Our preliminary results demonstrate that targeting TMPRSS6 is a viable approach for the treatment of hereditary hemochromatosis and possibly other iron-loading diseases associated with suppressed hepcidin levels.
Thrombin Supports Colitis and Colitis-Associated Cancer Pathogenesis
Link
Chronic inflammation has been recognized as a major factor in the development and progression of multiple cancers. A prime example of this is the strong association between colitis and colon cancer. However, the specific factors that regulate disadvantageous immune processes in the context of inflammation-associated cancers remain poorly defined. Growing evidence suggests that hemostatic system components, traditionally associated with the maintenance of vascular integrity and prevention of blood loss, also directly regulate inflammatory processes. Furthermore, thrombin and several thrombin targets (e.g., PARs, fibrinogen, factor XIII) have been shown to regulate tumor cell proliferation and apoptosis, support metastasis, and protect tumor cells from innate immune surveillance mechanisms in other experimental contexts. A logical extension of these findings is the hypothesis that thrombin, as a master regulator of both inflammatory processes and tumor cell biology, is a major determinant of the progression of inflammation-driven cancers such as colitis-associated colon cancer (CAC).
To test this hypothesis, we induced CAC in mice carrying prothrombin levels 50% of normal (fII+/-) and WT mice in parallel using an established two step protocol consisting of azoxymethane (AOM) and dextran sodium sulfate (DSS) exposure. The modest diminution in prothrombin levels imposed by the fII+/- genotype resulted in a dramatic diminution in the number of colonic adenomas formed after AOM/DSS challenge relative to WT mice. In order to determine if the diminution in adenoma formation observed in fII+/- mice was coupled to thrombin function, wildtype mice challenged with AOM/DSS were treated with daily i.p. injections of hirudin, a direct thrombin inhibitor, or saline carrier. Similar to the finding in mice with a genetically-imposed diminution in circulating prothrombin, hirudin treatment significantly blunted adenoma formation. To determine if reduction of thrombin generation improved the inflammation preceding the development of colonic adenomas, we used a novel, highly-specific factor XI antisense oligonucleotide “gapmer” (ISIS Pharmaceuticals) to inhibit hepatic factor XI synthesis prior to DSS challenge. Gapmer-mediated diminution of fXI levels to ~15% of normal resulted in a dramatic improvement in colitis related symptoms. Gapmer-treated mice had less intestinal bleeding and weight loss associated with DSS challenge relative to mice treated with a control oligonucleotide. Consistent with these gross observations, microscopic analyses of colonic tissue showed that fXI gapmer treatment significantly limited mucosal ulceration. Factor XI gapmer treatment also significantly diminished local levels of several inflammatory cytokines known to play a role in colon cancer progression (i.e., IL-6, IL-1β, IL-12).
These results demonstrate that thrombin is a crucial driver of the pathogenesis of colitis-associated colon cancer and suggest that therapies directed at thrombin or thrombin generation could treat or prevent inflammation-driven colon cancer. As pathological inflammation has been estimated to account for as many as 1 in 5 cancer-related deaths, thrombin-directed therapies could have broad applicability to multiple malignancies.
Link
Chronic inflammation has been recognized as a major factor in the development and progression of multiple cancers. A prime example of this is the strong association between colitis and colon cancer. However, the specific factors that regulate disadvantageous immune processes in the context of inflammation-associated cancers remain poorly defined. Growing evidence suggests that hemostatic system components, traditionally associated with the maintenance of vascular integrity and prevention of blood loss, also directly regulate inflammatory processes. Furthermore, thrombin and several thrombin targets (e.g., PARs, fibrinogen, factor XIII) have been shown to regulate tumor cell proliferation and apoptosis, support metastasis, and protect tumor cells from innate immune surveillance mechanisms in other experimental contexts. A logical extension of these findings is the hypothesis that thrombin, as a master regulator of both inflammatory processes and tumor cell biology, is a major determinant of the progression of inflammation-driven cancers such as colitis-associated colon cancer (CAC).
To test this hypothesis, we induced CAC in mice carrying prothrombin levels 50% of normal (fII+/-) and WT mice in parallel using an established two step protocol consisting of azoxymethane (AOM) and dextran sodium sulfate (DSS) exposure. The modest diminution in prothrombin levels imposed by the fII+/- genotype resulted in a dramatic diminution in the number of colonic adenomas formed after AOM/DSS challenge relative to WT mice. In order to determine if the diminution in adenoma formation observed in fII+/- mice was coupled to thrombin function, wildtype mice challenged with AOM/DSS were treated with daily i.p. injections of hirudin, a direct thrombin inhibitor, or saline carrier. Similar to the finding in mice with a genetically-imposed diminution in circulating prothrombin, hirudin treatment significantly blunted adenoma formation. To determine if reduction of thrombin generation improved the inflammation preceding the development of colonic adenomas, we used a novel, highly-specific factor XI antisense oligonucleotide “gapmer” (ISIS Pharmaceuticals) to inhibit hepatic factor XI synthesis prior to DSS challenge. Gapmer-mediated diminution of fXI levels to ~15% of normal resulted in a dramatic improvement in colitis related symptoms. Gapmer-treated mice had less intestinal bleeding and weight loss associated with DSS challenge relative to mice treated with a control oligonucleotide. Consistent with these gross observations, microscopic analyses of colonic tissue showed that fXI gapmer treatment significantly limited mucosal ulceration. Factor XI gapmer treatment also significantly diminished local levels of several inflammatory cytokines known to play a role in colon cancer progression (i.e., IL-6, IL-1β, IL-12).
These results demonstrate that thrombin is a crucial driver of the pathogenesis of colitis-associated colon cancer and suggest that therapies directed at thrombin or thrombin generation could treat or prevent inflammation-driven colon cancer. As pathological inflammation has been estimated to account for as many as 1 in 5 cancer-related deaths, thrombin-directed therapies could have broad applicability to multiple malignancies.
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