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REG1 CLINICAL RESULTS

The Company conducted three phase 1 clinical studies with REG1. The studies, which enrolled 174 individuals, established REG1 was well-tolerated, exhibited predictable pharmacokinetics and demonstrated the anticipated pharmacodynamic effects in both healthy volunteers and patients with stable cardiovascular disease, while establishing an understanding of the desired dose for pegnivacogin and anivamersen for phase 2 studies.

Phase 1a3
REG1-1a was a blinded, placebo-controlled dose-escalation study. Eighty-five healthy volunteers were randomized to receive a dose of the anticoagulant pegnivacogin (aka RB006) or placebo, followed several hours later by a dose of the control agent anivamersen (aka RB007) or placebo. The study showed RB006 and RB007 were well-tolerated. In volunteers treated with RB006, rapid and dose-dependent anticoagulation was observed (Figure 1). At doses approximating a therapeutic dose of RB006, the duration of the intended anticoagulant effect was at least 24 hours. In volunteers treated with RB006 who were then administered a complete reversal dose RB007, the anticoagulation was reversed rapidly and durably, returning their blood to its normal state. This study demonstrated for the first time the anticoagulant activity of RB006 and reversal activity of RB007 in humans. It should be noted that when RB007 was administered alone it was demonstrated to have a very short half-life (~3 minutes) and no clinical effects.

Figure 1

RB006 effectively inhibits Factor IXa and prevents clotting


Phase 1b4
REG1-1b was a multi-center, double-blind, placebo-controlled study that enrolled 50 patients with stable cardiovascular disease taking commonly prescribed oral antiplatelet drugs including aspirin and clopidogrel. Patients were randomized to receive one dose of RB006 or placebo, followed several hours later by a dose of RB007 or placebo. As predicted, the reversible anticoagulant activity of the REG1 system observed in REG1-1a was observed in REG1-1b, demonstrating that the REG1 system exhibits expected pharmacodynamic effects in the target patient population. This study also showed RB006 and RB007 were well-tolerated in patients on antiplatelet therapy, demonstrating the safety to proceed to further studies of REG1 in the target patient population.

Phase 1c5
REG1-1c was a double-blind, placebo-controlled study that randomized 39 healthy volunteers to receive three consecutive RB006 - RB007 treatment cycles or placebo. The study employed a body-weight adjusted dosing strategy, whereby patients receiving RB006 had their dose prospectively determined based upon their body weight at the time of entry into the trial. The weight-adjusted dosing strategy was developed via analysis of data obtained in the phase 1a and 1b studies. Based upon this analysis, it was expected that weight-adjusted dosing of RB006 would maximally inhibit Factor IXa producing consistent pharmacodynamic responses, with low intra and inter-subject variability, and would therefore be the optimal dosing strategy for RB006 going forward. Consistent with these predictions, Regado was successful in designing a trial that demonstrated very reproducible anticoagulant effects. Two groups of volunteers were dosed with RB006 on different treatment days and then assigned to varying doses of RB007 to establish the ability of REG1 to produce a range of therapeutic anticoagulant effects. REG1-1c demonstrated that not only could RB007 neutralize completely the activity of RB006, but by adjusting the RB007 dose, physicians were able to titrate the anticoagulant effect produced by RB006 (Figure 2). It also demonstrated that RB006 was well tolerated when given as repeat doses with no loss of effect, low variability and a very predictable anticoagulant response.

Figure 2

RB006 effectively inhibits Factor IXa and prevents clotting

 

 

Phase 2a (REVERSAL-PCI)6,7
Based upon the combined results of the Company’s phase 1 clinical program, Regado initiated REVERSAL-PCI, a multi-center, open-label, randomized phase 2a clinical study that enrolled 26 stable coronary arterial disease patients undergoing elective PCI. The study was designed to assess whether REG1 could replace standard heparin therapy during a coronary balloon angioplasty dilatation and stenting procedure in patients at low risk for complications associated with therapy-related bleeding or heart attack. This study completed enrollment in October 2008. Data from this study (Figure 3) demonstrated low interpatient variability for the REG1 treated group, rapid onset and stable anticoagulant effects after a bolus injection of RB006 administered at 1 mg/kg and rapid partial or complete reversal upon administration of an appropriate dose of IV bolus RB007. Results indicated that REG1 was well-tolerated in these patients, that RB006 was an effective anticoagulant for use in PCI, that RB007 could partially or completely (depending on the dose given) reverse the anticoagulation behavior of RB006 in a predictable and rapid fashion and that planned early arterial sheath removal could be accomplished after RB006 reversal without any extraneous bleeding.

Figure 3

REVERSAL-PCI (Phase 2a) results


 

Phase 2b (RADAR)
A phase 2b study, the RADAR trial, is currently ongoing in ACS patients undergoing PCI. The study is designed as an adaptive design dose ranging study for RB007 with a fixed dose (1 mg/kg) of RB006. The dose of RB006 chosen has been shown to maximally inhibit FIXa offering the potential to improve protection during the ischemic period. The study will enroll 4 cohorts of patients receiving doses of RB007 equivalent to 25%, 50%, 75% and 100% reversal, respectively.

An active control group receiving heparin will complete the study (Figure 4). The study will compare the bleeding effects between the heparin and RB007 arms. It is also designed to estimate an effect of REG1 versus heparin on ischemic events. All endpoints are adjudicated independently. Study design including endpoints, sample size, dosing and statistical analysis plan have been discussed and agreed with the FDA at an end-of-phase-2a meeting in March 2009. Upon completion, Regado expects to have verified the RB006 dose and identified the dose or dose range of RB007 that yields the optimal combination of improved safety (reduced bleeding) and maximized therapeutic outcomes. In discussions with FDA, it has been agreed that this study will be adequate to serve as the basis for the design of a phase 3 program and that it will be supportive to the pivotal studies. The trial was initiated in September 2009 and is expected to complete enrollment in about 16 months (4Q10) including ~800 subjects in 7 countries.  Top-line data is projected to be available in early 1Q2011.

Figure 4

RADAR (phase 2b) design and milestones



REG2 CLINICAL RESULTS

The Company has conducted one phase 1 clinical study to date with REG2. The study enrolled 36 individuals to evaluate subcutaneously administered RB006 with and without IV bolus administered RB007 compared to placebo. REG2 was easy to inject, well-tolerated and exhibited predictable pharmacokinetics and pharmacodynamic effects in healthy volunteers. The characteristics of REG2 in this initial clinical study were consistent with those desirable for use in venous thrombosis applications.8

Phase 1a9
REG2-1a was a partially blinded, placebo-controlled 5-arm dose escalation study involving 36 healthy volunteers. In each of three arms, 6 subjects received RB006 and 2 received placebo. The subjects were then followed for 10 days. In the remaining 2 arms, subjects received open label RB006, one arm with a prolonged follow-up (8 weeks), the other with predefined doses of RB007 reversal and a 10 day follow-up. As shown in Figure 5, injection of RB006 resulted in an intermediate onset of action with anticoagulation beginning at about 8-12 hours, a peak effect at ~48 hours and a long duration of action with a half-life of approximately 7 days. Injection of RB007 resulted in the reversal of plasma RB006 concentration and anticoagulant effect, which defines a pattern for active control of RB006 for future use. The study was the first study of aptamers using a subcutaneous formulation in humans and demonstrated that RB006 can be easily used and is well tolerated in healthy volunteers.

Phase 1b
A partially blinded, placebo-controlled, multiple dose escalation study in adult volunteers is presently undergoing design and is planned for initiation in the first half of 2011.


 Figure 5

Mean Relative Activated Partial Thromboplastin Time T1/2=6-7 days

         

 

 

Bibliography

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  2. Kuliczkowski W, Floyd J, Malinin E, Serebruany V, 2010, “Aptamers: the emerging class of future anticoagulation for vascular disease”, Expert Rev. Cardiovasc Ther  8(4), 503-507.
  3. Dyke CK, Steinhubl SR, Kleiman NS, Cannon RO, Aberle LG, Lin M, Myles SK, Melloni C, Harrington RA, Alexander JH, Becker RC, Rusconi CP. 2006, “First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity”, Circulation 114, 2490-2497.
  4. Chan MY, Cohen MG, Dyke CK, Myles SK, Aberle LG, Lin M, Walder J, Steinhubl SR, Gilchrist IC, Kleiman NS, Vorchheimer DA, Chronos N, Melloni C, Alexander JH, Harrington RA, Tonkens RM, Becker RC, Rusconi CP. 2008, ”Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease”, Circulation 117, 2865-74.
  5. Chan MY, Rusconi CP, Alexander JH, Tonkens RM, Harrington RA, Becker RC. 2008, “A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor”, Journal of Thrombosis Haemostasis 6, 789-96.
  6. Cohen MG, Purdy DA, Rossi JS, Grinfeld LR, Aberle LH, Greenbaum AB, Fry ET, Alexander JH, Rusconi CP, Becker RC. 2009, “First clinical application of an actively reversible direct factor IXa inhibitor in elective percutaneous coronary intervention”, European Heart Journal 30, 101.
  7. Cohen MG, Purdy DA, Rossi JS, Grinfeld LR, Myles SK, Aberle LH, Greenbaum AB, Fry E, Chan MY, Tonkens RM, Zelenkofske SL, Alexander JH, Harrington RA, Rusconi CP, Becker RC. 2010, “First Clinical Application of an Actively Reversible Direct Factor IXa Inhibitor as an Anticoagulation Strategy in Patients Undergoing Percutaneous Coronary Intervention”, Circulation 122: 614 - 622.
  8. Eikelboom JW, Zelenkofske SL, Rusconi CP. 2010, “Coagulation Factor IXa as a target for treatment and prophylaxis of venous thromboembolism”, Arterioscler Thromb Vasc Biol 30(3), 382-387.
  9. Zelenkofske SL, Rusconi CP, Damiento CM, Wargin W, Medlock M, Becker R. 2010, “Subcutaneous RB006, a direct FIXa inhibitor provides prolonged anticoagulation with rapid reversal; the first clinical experience with the REG2 system”, Presented at Atherothrombosis and Vascular Biology meeting, April 2010.