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Apabetalone - Resverlogix

Drug Profile

Apabetalone - Resverlogix

Alternative Names: RVX-000222; RVX-208

Latest Information Update: 31 May 2020

At a glance

  • Originator Resverlogix Corporation
  • Class Anti-inflammatories; Antidementias; Antihyperlipidaemics; Antihypertensives; Antiretrovirals; Cardiovascular therapies; Nootropics; Quinazolines; Small molecules; Urologics
  • Mechanism of Action Bromodomain and extraterminal domain protein inhibitors
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    No
  • New Molecular Entity Yes
  • Available For Licensing Yes - HIV infections

Highest Development Phases

  • Phase III Acute coronary syndromes; Atherosclerosis; Low HDL cholesterol
  • Phase II Prediabetic state
  • Preclinical Fabry's disease; HIV infections; Pulmonary arterial hypertension; Renal failure
  • Research COVID 2019 infections
  • No development reported Alzheimer's disease

Most Recent Events

  • 28 Mar 2020 Immunogenicity data from phase III BETonMACE trial in Acute coronary syndromes presented at 2020 Annual Scientific Session of the American College of Cardiology and World Congress of Cardiology (ACC-WCC-2020)
  • 28 Mar 2020 Efficacy data from phase III BETonMACE trial in Acute coronary syndromes presented at 2020 Annual Scientific Session of the American College of Cardiology and World Congress of Cardiology (ACC-WCC-2020)
  • 24 Mar 2020 Early research in COVID-2019 infections in Canada (PO)

Development Overview

Introduction

Apabetalone, a first-in-class, small-molecule that is a selective bromodomain and extraterminal domain (BET) protein inhibitor is being developed by Resverlogix for the treatment of acute coronary syndromes, atherosclerosis, COVD-2019 infections, low HDL cholesterol, pre-diabetic state, renal failure, HIV-1 infections, Fabry's disease and pulmonary arterial hypertension. BET bromodomain inhibition is an epigenetic mechanism that can regulate disease-causing genes. The drug is designed using Resverlogix’s NexVas™ technology that is selective for the second bromodomain (BD2) within BET protein called BRD4. Apabetalone also prevents vascular calcification by regulating vascular smooth muscle cell (VSMC) gene expression. Clinical development for atherosclerosis, low HDL-cholesterol and acute coronary syndromes (ACS),and pre-diabetes is underway in several countries worldwide. Preclinical development for renal failure, Fabry's disease, pulmonary arterial hypertension and HIV-1 infections is ongoing in Canada and Netherlands. Early research for COVID-2019 infections in underway in Canada.

No recent reports of development had been identified for phase I development in Alzheimer's disease in the US.

Apabetalone has emerged from Resverlogix's cardiovascular research programme [see Adis Insight Drug profile 800022214].

Resverlogix is seeking partnering opportunities for further development of apabetalone for the treatment of HIV-1 infections [1] .

As at July 2019, no recent reports of development had been identified for phase-I development in Acute coronary syndromes in New Zealand (PO, Capsule).

Company Agreements

In January 2018, Resverlogix granted exclusive rights to Medison Pharma for the commercialisation of apabetalone in Israel. Under the terms of the agreement, Medison will be responsible for all regulatory, sales and marketing costs for apabetalone in the Israel region. Resverlogix will receive double digit royalties on net sales. Further details of the agreement were not disclosed. [2]

In October 2017, Resverlogix announced that it entered into a Right of First Refusal Agreement with Hepalink USA. Under the agreement, Hepalink USA was granted a right of first refusal in connection with the licensing of the right to develop, manufacture and commercialise pharmaceutical products containing apabetalone in the US (the US Licensing Rights) until April 15, 2019. Resverlogix was paid $8 million (the “Fee”) by Hepalink USA in consideration for the right of first refusal granted. If Resverlogix and Hepalink USA enter into a license agreement with respect to the US Licensing Rights, the Fee shall be credited against any payment obligations of Hepalink USA thereunder. Upon termination of the agreement, the Fee is refundable, in whole or in part. During the first 60 day period, the agreement may only be terminated upon mutual agreement of the parties; thereafter, the agreement may be terminated by either party. In July 2015, Resverlogix closed a license agreement and formally entered into a definitive stock purchase agreement with Shenzhen Hepalink Pharmaceutical. Earlier, the former had entered into a framework agreement with Shenzhen Hepalink for an equity investment, and a license to apabetalone for all indications in China, Hong Kong, Taiwan and Macau, in April 2015. Under the license agreement, subject to achievement of certain annual sales milestones of apabetalone ranging from RMB500 million to RMB10 billion, Resverlogix will be entitled to receive sales-based milestone payments ranging from $US5 million to $US90 million from Shenzhen Hepalink. Additionally, Hepalink will pay Resverlogix a royalty based on net sales. Total sales based milestones and royalty payments have an estimated potential in excess of $US400 million. The license shall expire on a region-by-region basis on the later of the 15th anniversary of the first commercial sale in such region or the expiry date of the last-to-expire of any licensed patent. Shenzhen Hepalink will be responsible for clinical and developmental costs in the said territories, including a patient population in the planned phase III BETonMACE trial. Shenzhen Hepalink will also be granted an option to manufacture and supply products, including apabetalone, outside the territories. Under the terms of the agreement, Shenzhen Hepalink will subscribe for common shares and common share purchase warrants of Resverlogix for aggregate proceeds of approximately $CAD35 million. Following closure of the agreement, Hepalink will hold approximately 12.63% of Resverlogix's common shares, and the issued shares and warrants will have a lock in period of three years [3] [4] [5]

In March 2015, Resverlogix Corporation announced its collaboration with Emerald Logic for use of Emerald's Fast Collective Evolution Technology (FACET) in identifying factors that cause variable drug response and major adverse cardiac events (MACE) in patients enrolled in the phase II trials [6] .

Resverlogix Corporation established RVX Therapeutics in July 2005, a wholly owned subsidiary for business and strategic objectives. Resverlogix retains its primary asset, the NexVas™ technology, whereas RVX Therapeutics holds non-core assets including TGF-Beta Shield™ technology [7] . In April 2013, the subsidiary RVX Therapeutics was spun-out from the parent company to split the apabetalone programme from its epigenetics platform; Resverlogix Corporation will continue clinical development of apabetalone and the Apo A-1 programme [8] .

In January 2005, Resverlogix began an international research collaboration with the Cedars-Sinai Medical Center and Dr PK Shah, Director of the Atherosclerosis Research Center [9] . The programme was expanded in July 2005 to include the acute as well as the chronic aspects of cardiovascular disorders, as a result of favourable preclinical testing [10] .

Key Development Milestones

In June 2018, Resverlogix received confirmation from the US FDA that the phase III BETonMACE study, if successful, will support the filing and approval of an NDA for apabetalone. In July 2017, Resverlogix received a positive Type C written response from the Division of Metabolism and Endocrinology Products of the US FDA which allowed inclusion of the US in the phase III studies including the BETonMACE trial [11] [12] .

COVID-2019 infections

In preclinical studies, apabetalone suppressed bromodomain and extra terminal domain (BET) the specialised protein that interacts with the SARS-CoV-2 viral protein [13] .

Cardiovascular disorders (acute coronary syndrome, atherosclerosis and low HDL-cholesterol)

In September 2019, Resverlogix announced that the phase III BETonMACE trial did not meet its primary endpoint of reduction of major adverse events in cardiovascular events. In October 2015, the company had initiated the trial in high-risk type 2 diabetes mellitus (T2DM) patients with coronary artery disease (CAD) and low high-density lipoprotein (HDL), to determine if apabetalone increases the time to major adverse cardiovascular events (MACE) (RVX222-CS-015; NCT02586155; EudraCT2015-002040-14). The primary outcome measure is the time to occurrence of narrowly defined MACE. The first patient was dosed in November 2015. In March 2018, the double-blind, randomised, parallel group, placebo-controlled trial surpassed the planned enrolment target of over 2 425 patients in the US, Argentina, Australia, Belgium, Bulgaria, Croatia, Germany, Hungary, Israel, Mexico, Poland, Netherlands, Serbia and Slovakia. In October 2015, Resverlogix received initial approval from the regulatory authority and ethics committee in Belgium, Hungary and Israel. The company's phase III clinical trial plan was approved by a European regulatory authority, in June 2015. The company reported in August 2015 that an international Clinical Steering Committee (CSC) was formed for this trial. The CSC will advise on the trial design, provide overall supervision, have oversight on protocol, any protocol amendments and to provide advice to the investigators on all aspects of the trial. In July 2017, Resverlogix randomised the first patient in the Taiwan or China portion of the trial. As a result of the randomisation, Hepalink is now responsible for the first $CAD1 million payment to Resverlogix. In January 2018, the US FDA accepted the protocol amendments of the trial and the company announced that the trial will be expanded to North America, including the US. In February 2018, the DSMB completed a sixth safety review and recommended that the study should continue as planned without any modifications. The DSMB reviewed available study data and noted that no safety or efficacy concerns were identified, and will conduct additional periodic reviews. In July 2018, the independent Data and Safety Monitoring Board (DSMB) completed a seventh safety review and no safety or efficacy concerns were identified. DSMB recommended to continue the study as planned without any modifications. In December 2018, Resverlogix announced completion of eighth pre-specified review of safety data for treated patients in the trial by the independent Data Safety Monitoring Board (DSMB). In the review, DSMB concluded the trial safe and recommended continuation of the trial without any modification. In March 2019, the independent Data and Safety Monitoring Board (DSMB) completed a ninth safety review of available data from the trial which did not show any safety concern with the treatment. Based on the safety review, the DSMB recommended continuation of the trial without any modification. In June, Reseverlogix reported that the trial has reached 250 projected major adverse events (MACE) successfully. Successful data from this trial would enable Resverlogix to proceed towards the regulatory approval and commercialization. In September 2019, the company released the primary endpoint results [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] . In March 2020, efficacy data was presented at 2020 Annual Scientific Session of the American College of Cardiology and World Congress of Cardiology (ACC-WCC-2020) [35] [36] .

In November 2015, Resverlogix presented data from three phase II studies, ASSERT, SUSTAIN and ASSURE, detailing the actions of apabetalone in cardiovascular disease and chronic kidney disease (see below) [37] . Resverlogix presented data from two phase IIb studies, SUSTAIN and ASSURE, at the Annual Congress of the European Society of Cardiology (ESC-Card - 2015), in August 2015 [38] . In September 2017, the company presented pooled analysis of SUSTAIN and ASSURE trials at the Annual Congress of the European Society of Cardiology (USC-Card-2017) [39] .

Resverlogix and the Cleveland Clinic in the US completed a phase II, randomised, placebo-controlled, dose-ranging trial of apabetalone for the treatment of atherosclerosis in 299 patients with stable coronary artery disease (ASSERT; NCT01058018) [40] . The primary endpoint was the change in ApoA-I levels after 3 months of dosing [41] . Results were first presented in November 2010 [42] . Additional information was presented later that highlighted the potential role of RVX 208 in lowering high sensitivity C-Reactive Protein (hsCRP) levels and modifying the RCT pathway [43] [44] . In September 2019, Resverlogix presented pharmacodynamics data from the trial at the 55th Annual Meeting of the European Association for the Study of Diabetes (EASD-2019) [45] .

In June 2013, Resverlogix completed the double-blind phase IIb ASSURE 1 trial in atherosclerosis patients with type 2 diabetes mellitus and low high-density lipoprotein and top-line results showed the primary endpoint was not met (RVX222-CS-007; NCT01067820; EudraCT2010-023801-36) [46] [47] . A total of 324 patients with atherosclerosis were randomised to receive apabetalone or placebo, and dosing was completed in April 2013 [48] . The trial design had been modified in September 2010. Primary changes included increasing the number of patients, requiring that all patients undergo an intravascular ultrasound (IVUS) assessment, the inclusion of patients with low high-density cholesterol levels and changing the primary endpoint to plaque regression [49] [50] . In June 2011, the trial was re-initiated following the completion of the company's chronic repeated-dose toxicology studies, which were required by the US FDA. IVUS technology was used to determine coronary arterial plaque regression at 26 weeks (the primary endpoint). Patients were recruited at sites in Belgium, Hungary, Netherlands, Poland, Spain, Russia, Argentina and Brazil [48] [51] [52] [53] . The ASSURE study complemented the ASSERT trial in patients with stable coronary artery disease [54] [55] . Despite not meeting the primary endpoint, follow-up analyses of data from ASSURE revealed that the subgroup of patients who were taking rosuvastatin in combination with RVX 208 had a significant improvement in plaque regression, while those taking atorvastatin did not [56] . Further analyses identified significant improvements in a patient subgroup with heightened inflammation [57] [58] . In January 2014, the company reported results from a pooled analysis of data from the ASSURE and SUSTAIN trials, performed independently. Apabetalone had a positive impact on major adverse cardiac events (MACE). In March 2015, Resverlogix presented further biomarker and blood glucose level data from these trials at the 64th Annual Scientific Session of the American College of Cardiology and additional results from the analysis of data from diabetic and chronic kidney disease subpopulations were released in June 2015. Updated efficacy results from the trial, indicating that apabetalone may have a potential beneficial effect on ultrasonic measures of vulnerable atherosclerotic plaque, which may relate to its favourable effects on circulating HDL particle concentrations, were presented at the Annual Congress of the European Society of Cardiology (ESC-2017) [59] [60] [61] [62] [63] . In September 2018, Resverlogix released data, showing that serum proteins linked to cognitive decline and neurodegenerative disease were favourably affected by apabetalone treatment [64] [65] .

The primary and secondary endpoints have been met in the phase IIb SUSTAIN trial in 176 patients with high-risk cardiovascular disease (CVD). The primary endpoint was a significant increase in HDL-cholesterol after treatment with apabetalone, compared with baseline. The trial, which was conducted in South Africa (RVX222-CS-008; NCT01423188), assessed the change in baseline lipid parameters with apabetalone after 12 and 24 weeks' treatment when given in addition to optimised statin background therapy (including atorvastatin or rosuvastatin) in 176 patients with low baseline HDL-cholesterol (with or without documented coronary artery disease) [66] [53] [67] [68] [69] .

In August 2009, Resverlogix completed a double-blind, placebo-controlled, US-based, phase Ib/IIa trial investigating the safety, pharmacokinetics and pharmacodynamics of three dosages of apabetalone in 72 subjects with normal and low HDL levels (RVX222-CS-003; NCT00768274). Positive results reported from this 28-day trial showed apabetalone increased plasma levels of Apo-Al by 13.25% compared with placebo in patients with baseline HDL/Apo-Al [70] [71] [72] [73] [74] [75] [76] .

Based on pharmacokinetic data confirmed in the phase I [see below], Resverlogix plans to initiate a phase II trial of apabetalone in patients with renal impairment in early 2017 [77] .

Resverlogix has completed two arms of a phase I trial investigating the bioequivalence of apabetalone capsules and the original powder formulation. The final arm was expected to be completed by the end of the third quarter of 2009 [72] .

A phase Ia safety, tolerability and pharmacokinetics study has successfully met its objectives, being well tolerated and showing good oral absorption. The three-armed study comprised a single escalating dose portion, a food versus fasted effect on pharmacokinetics portion, and three cohorts with 7-day multiple dosing arms. The trial took place at a US contract research organisation and enrolled 80 healthy volunteers. Results concerning the effect of apabetalone on levels of HDL-cholesterol have been reported [78] [79] [80] [81] [82] .

In November 2016, Resverlogix completed a phase I trial that evaluated the pharmacokinetics, safety and tolerability of a single dose of apabetalone 100mg capsule in subjects with renal impairment and age-, weight- and gender- matched healthy volunteers (U1111-1182-3664; RVX222-CS-016; 370605; ACTRN1261600064248; ACTRN12616000642482p). The non-randomised, open-label, parallel trial was initiated in June 2016 and enrolled 16 volunteers in New Zealand. Results from the trial were released by Resverlogix in January 2017 [83] [77] [84] [85] .

Data from the 80th and 81st Scientific Sessions of the American Heart Association demonstrated that oral administration of apabetalone increased the production of serum ApoA-I levels and improved HDL-mediated cholesterol efflux in African Green Monkeys [80] [86] [87] .

In in vitro studies, apabetalone lowered the risk of major adverse cardiovascular events (MACE) in diabetes patients with CVD by affecting monocyte adhesion to endothelial cells [88] .

As of April 2008, apabetalone had undergone 126 preclinical trials comprising safety, toxicity, pharmacokinetics and pharmacology studies [81] .

Apabetalone has shown efficacy in raising apolipoprotein A-I (ApoA-I) production and HDL levels in human trials and also reduced plaque numbers in a mouse model of atherosclerosis [89] .

The US FDA approved an IND for a phase I trial of RVX 208 for the treatment of cardiovascular disorders in December 2007 [90] .

Prediabetes

A phase IIb trial investigating the effects of apabetalone on plasma glucose at 4 weeks did not meet the primary end point (409-12; RVX222CS010; NCT01728467). The trial, conducted in collaboration with the Baker IDI Heart & Diabetes Institute, was completed in March 2014 and enrolled 23 patients with pre-diabetes mellitus in Australia [91] [92] [93] . Interim efficacy data from the trial was released by Resverlogix and was consistent with pooled analysis data from the ASSURE and SUSTAIN trials. Further analysis of data from this trial will include HDL abundance, lipidomics, platelet aggregation, monocyte activation and neutrophil adhesion [63] . Additional pharmacodynamic data were presented at the 75th Annual Scientific Sessions of the American Diabetes Association (ADA - 2015) [94] .

Alzheimer's disease (AD)

Resverlogix plans to initiate a phase IIa trial to investigate the efficacy of apabetalone in patients with mild cognitive impairment for the treatment of Alzheimer's disease [8] [95] .

Resverlogix has conducted an exploratory phase Ia trial to evaluate apabetalone (2, 3 and 8 mg/kg) for the treatment of AD. This double-blind, dose-escalation, placebo-controlled trial enrolled 24 subjects in three separate dosing cohorts for a period of seven days. Plasma levels of amyloid-beta40 (Aβ40) were measured on days 1 and 7. Post hoc analysis revealed a 12-14% increase in plasma Aβ40 levels at the highest dose of apabetalone (8 mg/kg) after seven days of dosing. Based on the study hypothesis, these results trended towards significance versus placebo, despite the minimal number of study subjects [96] [97] .

Apabetalone has demonstrated positive effects on plasma Aβ40 levels in 299 patients with stable coronary artery disease in the phase II ASSERT trial population. After 12 weeks of treatment with apabetalone, 150mg twice daily, a highly significant change from baseline and 13.4% change compared with placebo was observed in the quartile of patients with the lowest plasma Aβ40 levels at baseline, which is known to increase the risk for developing AD. Resverlogix announced that the data further supports the phase I trial in AD and the hypothesis that RVX 208 can augment Aβ40 transport from the brain [98] .

Dyslipidaemias

Resverlogix planned a phase II clinical trial to assess the pharmacokinetics of multi-dose apabetalone in combination with either atorvastin or rosuvastatin in patients with dyslipidaemia, with or without coronary artery disease (NCT01863225). The open-label trial was intended to enrol 64 patients in Australia; however, the study was withdrawn prior to enrolment [99] .

Fabry's disease

Health Canada, Therapeutic Products Directorate, in May 2017, granted approval to Resverlogix to conduct a clinical study with apabetalone in patients with Fabry's disease. The 16-week, open-label, phase I/II exploratory study will evaluate the safety of treatment as the primary endpoint. Secondary endpoints will be the evaluation of treatment effects, determined by change in biomarkers such as alkaline phosphatase, high-sensitivity C-reactive protein and other markers of chronic kidney disease. The study will be conducted in approximately 16 patients with Fabry's disease, including those who are receiving enzyme replacement therapy (Cohort 1) as well as those who are not (Cohort 2) [100] [101] .

In March 2019, Resverlogix reported that a preclinical, ex vivo study, exploring the effect of apabetalone on primary blood cells taken directly from Fabry Disease patient, was underway [102] .

Paroxysmal nocturnal haemoglobinuria (PNH)

In October 2015, Resverlogix reported that the company plans to initiate a proof-of-concept, pilot phase II trial to investigate the effect of apabetalone in patients with PNH. Data demonstrating that apabetalone modulates and complements the coagulation pathway involved in cardiovascular disease, supports this trial [103] [104] .

Renal-failure

(chronic kidney disease): In May 2017, Resverlogix received IND approval from the US FDA Cardiovascular and Renal Division to proceed a phase i/IIa clinical trial. Previously, in February 2017, Resverlogix reported the minutes of an in-person Type-B meeting with the cardiovascular and renal products division of the US FDA, for a planned phase I/IIa trial which will be conducted in two parts. Part A will involve a open-label, single-dose pharmacokinetic study in eight patients who will receive haemodialysis. The pharmacokinetic results from Part A will lead to the dose selection for Part B. Part B will be a double-blind, randomised, placebo-controlled, sequential cross-over study to evaluate biomarker changes and safety parameters with apabetalone in up to 30 patients with end-stage renal disease treated with haemodialysis (NCT03160430) [105] [106] [107] .

Preclinical studies of apabetalone for the treatment of chronic kidney disease is underway in Canada [108] .

Pulmonary arterial hypertension (PHA)

As of November 2018, apabetalone is in preclinical studies for treatment of PHA. Also in November 2018, Resverlogix presented preclinical data for PHA at the 91st Annual Scientific Sessions of the American Heart Association (AHA-2018) [109] .

HIV-1 infections

In June 2018, Resverlogix released preclinical data of apabetalone which demonstrated the drug ability to expose and reactivate latent HIV-1 reservoirs, induce HIV-1 latent cell death, and reduce the side effects of standard of care (cART combination antiretroviral therapy) [1] .

Financing information

In June 2019, Resverlogix announced that it has closed a offering worth $US15.2 million. The company intends to utilise the offering to support clinical trial activities related to the phase III BETonMACE trial [110] .

In April 2019, Resverlogix announced that it has closed a private placement of approximately $US4.5 million equity units to Shenzhen Hepalink Pharmaceutical and $US0.6 million equity units to other subscribers at a price of $US3.00 per unit for gross proceeds of approximately $15.1 million (US$11.3 million). The company intends to utilise the net proceeds of placement to fund research and development activities, including but not limited to, clinical trial activities related to the phase III BETonMACE trial, general and administrative expenses, repayment of debt, working capital needs and other general corporate purposes [111] .
In March 2019, Resverlogix reported that it is advancing a $2.9 million project, primarily funded by the Canadian Institutes of Health Research (CIHR), through an operating grant. The CIHR funding is matched by Resverlogix, by both in-kind and direct investment. The project involves the conduction of a prospective phase II trial of apabetalone, by Resverlogix and Quebec Heart and Lung Institute, Laval University, in the treatment of pulmonary arterial hypertension [102] .

In January 2019, Resverlogix announced that it has closed a private placement $US6.6 million. The company intends to utilise the net proceeds of placement to fund research and development activities, including but not limited to, clinical trial activities related to the phase III BETonMACE trial, general and administrative expenses, repayment of debt, working capital needs and other general corporate purposes [112] .

In November 2018, Resverlogix announced that it has closed a private placement of approximately $US10.3 million. The company intends to utilise it to support clinical trial activities related to the phase III BETonMACE trial, and other general and administrative expenses [113] .

In August 2018, Resverlogix announced that it has closed a private placement of approximately $US26 million. The company will utilise the proceeds from the private placement to fund research and development activities, including but not limited to, clinical trial activities related to the company’s phase III BETonMACE trial and other general, corporate and administrative expenses [114] .

In May 2018, Resverlogix closed the previously announced $US30 million loan with Third Eye Capital. The net proceeds from the loan will be used to fund research and clinical development activities related to the phase III BETonMACE trial, and other general corporate purpose [115] .

In December 2017, Resverlogix completed a private placement with Shenzhen Hepalink Pharmaceutical, and earned $CAD87 million. The net proceeds will be used to repay the company's $CAD68.8 million secured loan, and to fund research and clinical development activities related to the phase III BETonMACE trial, and other general corporate purposes [116] [117] .

In June 2017, Resverlogix closed an equity offering of $US10 million, which it intends to utilise for activities related to clinical trials, including the BETonMACE trial, a phase IIa trial in patients with end-stage renal disease treated with haemodialysis and a trial in patients with Fabry's disease, and other general corporate purposes [118] .

In July 2014, Resverlogix secured an additional loan of $US30 million, raising its total loan amount to $US68.8 million, which the company intends to utilise in additional clinical trials of apabetalone, including a planned phase IIb trial, based on the epigenetic data from the ASSURE and SUSTAIN trials [119] . In September 2017, Resverlogix reported that the maturity date of loan of $US 68.8 million has been extended to December 26, 2017, and the company also intends to use the net proceeds for research and developmental activities related to clinical trials, including the BETonMACE trial [120] .

Patent Information

Resverlogix, in March 2017, received a Notice of Allowance from the United States Patent and Trademark Office (USPTO) for the use apabetalone in combination with rosuvastatin in the United States. The allowed patent entitled "Compositions and Therapeutic Methods for Accelerated Plaque Regression" covers claims for both a single composition as well as separate compositions of the two drugs [121] .

Resverlogix was granted two Chinese patents for apabetalone in April 2015. The patent no. 200 780 052 349.8, entitled "Compounds for the Prevention and Treatment of Cardiovascular Disease" covers composition of matter, and is valid till February 2027. The second patent 200 980 106 586.7, entitled "Methods of Preparing Quinazolinone Derivatives" is a manufacturing patent, and will expire in June 2029 [122] .

In March 2014, Resverlogix reported that it had been granted the European patent, no. 2 118 074, entitled "Compounds for the prevention and treatment of cardiovascular diseases". The patent covers apabetalone and will extend through February 2027 [123] .

Resverlogix was issued US Patent No. 8 053 440 covering apabetalone in November 2011. The patent contains composition of matter claims to RVX 208 and structurally related compounds, and provides coverage until 2030 [124] .

In November 2010, Resverlogix filed a patent application covering dosing combinations of apabetalone and leading statin therapeutics. The patent includes data from the ASSERT trial showing that apabetalone at certain doses in combination with statins markedly improved not only ApoA-I production, HDL and large HDL particles, but also important properties of LDL and ApoB particles. The synergistic effect of apabetalone was more pronounced with Pfizer's Lipitor® and AstraZeneca's Crestor® [125] .

Resverlogix, on behalf of RVX Therapeutics, announced the filing of a patent application covering NexVas™, its cardiovascular technology.

Drug Properties & Chemical Synopsis

  • Route of administration PO
  • Formulation Capsule, unspecified
  • Class Anti-inflammatories, Antidementias, Antihyperlipidaemics, Antihypertensives, Antiretrovirals, Cardiovascular therapies, Nootropics, Quinazolines, Small molecules, Urologics
  • Target Bromodomain and extraterminal domain protein
  • Mechanism of Action Bromodomain and extraterminal domain protein inhibitors
  • WHO ATC code

    A10B (Blood Glucose Lowering Drugs, Excl. Insulins)

    A16A (Other Alimentary Tract and Metabolism Products)

    C10A (Lipid Modifying Agents, Plain)

    G04 (Urologicals)

    J05 (Antivirals for Systemic Use)

    J05A (Direct acting antivirals)

    N06D (Anti-Dementia Drugs)

    R07A-X (Other respiratory system products)

  • EPhMRA code

    A10X9 (Other drugs used in diabetes)

    A16 (Other Alimentary Tract and Metabolism Products)

    C10A (Cholesterol and Triglyceride Regulating Preparations)

    G4 (Urologicals)

    J5 (Antivirals for Systemic Use)

    J5C (HIV antivirals)

    N7D (Anti-Alzheimer Products)

    R7X (All Other Respiratory System Products)

  • Chemical name 2-[4-(2-Hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxyquinazolin-4(3H)-one
  • Molecular formula C20 H22 N2 O5
  • Chemical Structure
  • CAS Registry Number 1044870-39-4

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

acute coronary syndromes

not specified

Alkaline phosphatase

1

acute coronary syndromes

Inclusion

A1C

1

acute coronary syndromes

Outcome Measure

Fibrinogen

CRP

Apo A-1

A1C

1

1

1

1

atherosclerosis

not specified

Alkaline phosphatase

1

atherosclerosis

Inclusion

A1C

1

atherosclerosis

Outcome Measure

Fibrinogen

CRP

Apo B

Apo A-1

A1C

1

1

1

3

1

cardiovascular disorders

not specified

Alkaline phosphatase

1

cardiovascular disorders

Inclusion

A1C

1

cardiovascular disorders

Outcome Measure

Fibrinogen

CRP

Apo A-1

A1C

1

1

1

1

coronary artery disease

Outcome Measure

CRP

Apo B

Apo A-1

1

1

2

Fabry's disease

Outcome Measure

RANKL

OPG

globotriaosyl lysosphingolipid

CRP

1

1

1

1

low HDL cholesterol

Outcome Measure

CRP

Apo A-1

1

2

myocardial infarction

not specified

Alkaline phosphatase

1

myocardial infarction

Inclusion

A1C

1

myocardial infarction

Outcome Measure

Fibrinogen

CRP

Apo A-1

A1C

1

1

1

1

renal failure

Exclusion

PTH

1

renal failure

Outcome Measure

RANKL

PTH

OPG

MCP1

IL8

IL6

IL13

CRP

Apo B

Apo A-1

1

1

1

1

1

1

1

1

1

1

stroke

not specified

Alkaline phosphatase

1

stroke

Inclusion

A1C

1

stroke

Outcome Measure

Fibrinogen

CRP

Apo A-1

A1C

1

1

1

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Apabetalone - Resverlogix A1C Inclusion, Outcome Measure
Alkaline phosphatase not specified
Apo A-1 Outcome Measure
Apo B Outcome Measure
CRP Outcome Measure
Fibrinogen Outcome Measure
globotriaosyl lysosphingolipid Outcome Measure
IL13 Outcome Measure
IL6 Outcome Measure
IL8 Outcome Measure
MCP1 Outcome Measure
OPG Outcome Measure
PTH Exclusion, Outcome Measure
RANKL Outcome Measure
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Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Acute coronary syndromes - - Phase III Belgium, Bulgaria, Croatia, Germany, Hungary, Israel, Russia, Slovakia, Taiwan PO / Capsule Resverlogix Corporation 28 Jun 2017
Acute coronary syndromes - - Phase II Argentina, Brazil, Netherlands, Poland, Spain, USA PO / Capsule Resverlogix Corporation 26 Sep 2011
Acute coronary syndromes in subjects with renal impairment and healthy volunteers - No development reported (I) New Zealand PO / Capsule Resverlogix Corporation 28 Jul 2019
Alzheimer's disease - - No development reported (I) USA PO / Capsule Resverlogix Corporation 04 Nov 2017
Atherosclerosis - - Phase III Belgium, Hungary PO / Capsule Resverlogix Corporation 01 Oct 2015
Atherosclerosis - - Phase II Argentina, Brazil, Netherlands, Poland, Russia, Spain, USA PO / Capsule Resverlogix Corporation 26 Sep 2011
COVID 2019 infections - - Research Canada PO / unspecified Resverlogix Corporation 24 Mar 2020
Fabry's disease - - Preclinical Canada PO / unspecified Resverlogix Corporation 18 Mar 2019
HIV infections - - Preclinical Canada unspecified / unspecified Resverlogix Corporation 07 Jun 2018
Low HDL cholesterol - - Phase III Belgium, Hungary, Israel, Russia, Taiwan PO / Capsule Resverlogix Corporation 28 Jun 2017
Low HDL cholesterol in patients at high cardiovascular disease risk - Phase II South Africa PO / Capsule Resverlogix Corporation 27 Sep 2011
Prediabetic state - - Phase II Australia PO / Capsule Resverlogix Corporation 16 Oct 2012
Pulmonary arterial hypertension - - Preclinical Canada, Netherlands PO / unspecified Resverlogix Corporation 05 Nov 2018
Renal failure with chronic kidney disease - Preclinical Canada PO / Capsule Resverlogix Corporation 24 May 2016

Commercial Information

Involved Organisations

Organisation Involvement Countries
Resverlogix Corporation Originator Canada
Resverlogix Corporation Owner Canada
Medison Pharma Market Licensee Israel
Shenzhen Hepalink Pharmaceutical Licensee China, Hong Kong, Macau, Taiwan
Canadian Institutes of Health Research Funder Canada
VU University Medical Center Collaborator Netherlands
Leiden University Collaborator Netherlands
University of Groningen Collaborator Netherlands
Cedars-Sinai Health System Collaborator USA
Emerald Logic Collaborator USA

Licensing Availability

Licensing Organisation Available Indication Available Phase Region Date
Resverlogix Corporation HIV infections Unspecified - 07 Jun 2018

Scientific Summary

Pharmacokinetics

Oral administration of apabetalone resulted in dose dependent pharmacokinetic parameters; the drug was given at either low (2 mg/kg), dose-escalating (3-6 mg/kg) or high (6 mg/kg) doses for a 28 days [71] .

Adverse Events

Apabetalone was demonstrated to be safe and well-tolerated in phase Ib/IIa study. Participants received apabetalone at low (2 mg/kg), weekly dose-escalation (3-6 mg/kg) or high (6 mg/kg) doses daily for 28 days [70] [127] [71] .

The results from phase III BETonMACE study showed that apabetalone was safe and well tolerated [14] .

Pharmacodynamics

Summary

Apabetalone demonstrated positive effects on plasma amyloid-beta40 (Aβ40) levels in 299 patients with stable coronary artery disease (the phase II ASSERT trial population). After 12 weeks of treatment with twice-daily apabetalone 150mg, a highly significant 34.8 pg/mL change from baseline and 13.4% change compared with placebo was observed in the quartile of patients with the lowest plasma Aβ40 levels at baseline, which is known to increase the risk for developing AD [98] .

The serum proteins linked to cognitive decline and neurodegenerative disease, including but not limited to ATP5O, HSPD1, APP, HSP90AB1, HSP90AA1, HSPA8, ANXA1, EEF1B2, RTN4R, ATP5B and APCS, were favourably affected by apabetalone treatment, during the phase II ASSURE trial (p < 0.05) [64] [65] .

A reduction in glucose absorption and suppression of endogenous glucose production was observed in patients with prediabetes who participated in a phase II study following daily treatment with 200mg apabetalone for 29 - 33 days. Additionally, treatment with apabetalone altered the lipid profile within the high-density lipoprotein of these patients towards the composition observed in healthy volunteers [94] .

Results from the in vitro studies in cultured THP 1 monocytes, HUVEC endothelial cells and primary human hepatocytes (PHH) exposed to HG or varying levels TMAO demonstrated enhanced adhesion of THP 1 to HUVEC by 2.4 fold . In presence of HG or TMAO, RVX 208 blocked the adhesion process by 30-70% at 20uM. HG induced very late antigen 4 (VLA-4) mRNA by 1.3-fold. RVX 208 suppressed VLA-4 antigen by >50% as it blocked the TMAO induction in THP-1. In HUVECs RVX 208 nullified HG induction of E-selectin and MYD88 mRNA by 2 and 1.3 fold and lowered TMAO induction of the mRNAs by >50%. In primary human hepatocytes (PHH) exposed for 24 hrs to RVX 208, FMO3 mRNA was lowered by 40% which also suppressed FMO3 gene transcription, farnesoid X receptor (FXR). BETi suppressed both FXR mRNA and protein within 6 hrs by >80%. ChiP data demonstrated that BRD4 dissociated rapidly from FXR DNA upon exposure to RVX 208 [88] .

Preclinical data demonstrated that apabetalone treated human liver cells significantly down-regulated the expression of complement components at gene expression and protein level and when the cells were stimulated with factors known to cause inflammation and immune response activation. Moreover, in apabetalone treated mouse model who were replaced with human liver cells, reductions in expression of components C4 (36%), C9 (46%) and MBL2 mRNA (61%) of the complement cascade were observed. This effect of apabetalone treatment on complement component expression and cascade activity had an impact on the pathologic activation of this cascade in chronic kidney disease [108] .

Phase I:

Results from a phase I trial for apabetalone demonstrated a reduction in inflamed protein biomarkers in patients with severe kidney disease. It was also observed that a highly differential protein signature was at baseline between chronic kidney disease (CKD) patients and controls, which changed within 12 hours of single dose administration, demonstrating a fast onset of drug action. Moreover, 33% of proteins had statistically significant changes (p < 0.05) compared to only 10% in the control. Data was reported from a double-blind, non-randomised trial conducted in 16 volunteers in New Zealand [83] [85] .

Clinical studies

Phase II

Results from the phase II ASSERT trial showed dose dependent increases in ApoA-I by 5.6%, statistically significant increases in HDL cholesterol including alpha1 particles or functional HDL by 8.3%, and large HDL particles by 21.1%. ApoA-I and other HDL particles continued to increase at the end of the 12-week study. Also in in vitro studies conducted on T cells and PBMCs from patients with type 2 diabetes and cardiovascular disease (CVD), apabetalone demonstrate the downregulation of T cells through preventing the upregulation of the transcription factor, T-bet and inhibiting the production of Th1 cytokines. Upon stimulation with CD3 and CD28 antibodies, apabetalone treated PBMCs collected from patients with T2D showed decreased expression of IL-2, IL-17 and TNF α by approximately 65% compared with controls. Apabetalone also attenuated production of IFN-γ by 40% and upregulation of T-bet by 50% in PBMCs from patients T2D. In diabetic CVD patients, treated with 200mg apabetalone for 24 weeks, plasma IL-2 and IFN-γ were reduced by 11% and 21% versus baseline, respectively. In placebo group, plasma IL2 was increased by 22% and IFN-γ was reduced by 2% [45] [42] [40] .

Phase I

Results from a phase Ib/IIa study conducted in 72 patients with normal or low high density lipoprotein cholesterol levels demonstrated apabetalone to be associated with a significant increase in ApoA-I levels. The primary endpoint, plasma ApoA-I increase compared to placebo, achieved a range of 5.1%-10.4% in all patients at all doses at days 8 and 28, respectively. At the lowest dose of 1 mg/kg twice-daily in patients with low levels of HDL-c, significantly increased plasma ApoA-levels by 5.7% and 7.8% were observed at day 8 and 28, respectively (p < 0.05). A critical reverse cholesterol transport (RCT) functionality marker, alpha-1 HDL particles, also demonstrated significance with an increase of 46.7% (p < 0.004) in all patients and 57.2% (p < 0.02) in the low dose arm over placebo at day 28. Apabetalone was shown to be compatible with simvastatin (40mg) [70] [127] [71] [72] .

An interim analysis of 24 healthy volunteers who participated in a 7-day phase I trial of apabetalone showed statistically significant improvements over placebo in three of the four key variables assessed. Significant improvements included increases in pre-beta HDL of 42%, cholesterol efflux of 11% and serum apolipoprotein A-I (ApoA-I) of 11%. A fourth variable, high density lipoprotein-cholesterol (HDL-C) level, increased by 10% but the change was not significant. A rapid onset of action was observed, with the serum ApoA-I increases surpassing the previous 8% 5-week average benchmark totals displayed by the apolipoprotein A-1 milano agent developed by Pfizer [78] [128] . Apabetalone was dosed at 2, 3 or 8 mg/kg/day. Further analysis of the data revealed that after 7 days, apabetalone increased the change for ApoA-I by 11% versus placebo (p = 0.03). The corresponding pre-beta HDL change was 42% (p = 0.007) versus placebo. This change correlated with ABCA1-dependent cholesterol efflux change, which increased by 10% (p = 0.03) [80] [79] .

Preclinical studies

highly significant increases in average serum ApoA-I and HDL-C levels (57% and 92%, respectively) occurred in African Green monkeys that received apabetalone (7.5, 15 and 30 mg/kg twice daily and 60 mg/kg once daily). The distribution of HDL particle size was also modified after drug administration; there was a significant increase in pre-beta and alpha HDL particles. In a cell culture model, apabetalone significantly increased the ability of serum to promote cholesterol efflux via ABCA1, ABCG1 or SR-BI-dependent pathways [80] [79] .

Phase II

Biomarker analysis from the SUSTAIN and ASSURE trials demonstrated that in patients treated with apabetalone, compared with placebo, the serum alkaline phosphatase decreased by 6 U/L (p < 0.0001), HDL-c increased by 3 mg/dL (p < 0.001), ApoA-I increased by 7.5 mg/dL (p < 0.01), large HDL increased by 0.7 umol/L (p < 0.05), HDL size increased by 0.1 (p < 0.05) and total HDL particles increased by 1.8 umol/L (p < 0.1). Patients with diabetes mellitus (DM) or chronic kidney disease appeared to experience the highest benefit from the treatment. In 192 patients with DM administered apabetalone, glucose levels were unchanged, whereas the glucose levels of patients given placebo showed a non-significant (p < 0.1) increase by 0.7 mmol/L. In 119 patients with DM and low HDL (<40 mg/dL), apabetalone reduced glucose significantly (p < 0.01) by 0.3 mmol/L, whereas in the placebo group, the glucose increased by 0.9 mmol/L. Additional data demonstrated that apabetalone significantly reduced serum levels of alkaline phosphatase in all treated patients with increased effects in patients with diabetes and chronic kidney disease. A reduction of -10.98% was observed in apabetalone-treated patients (n = 331), compared with -3.23% in the placebo group (n = 168) (p < 0.0001), at the combined time points of 24 and 26 weeks. In patients with a history of diabetes, a significant reduction in ALP of -13.9% was observed in the apabetalone treated group (n=127) compared to -4.49% in the placebo treated group (n=65) (p<0.0001). In patients with chronic kidney disease (estimated glomerular filtration < 60 mL/min/1.73 m2), patients treated with apabetalone (n=35) had reduced ALP levels of -13.9% versus -6.28% in placebo (n=13) (p=0.008). Additionally, after six months of treatment, an increase in eGFR of +3.4% (p=0.04 vs. baseline) was observed in the apabetalone-treated group while a decrease of -5.9% was observed in the placebo group [126] [60] . In order to understand the potential biologic processes underlying the benefit of RVX 208 in the study patients, primary human hepatocytes were evaluated after exposing to RVX 208 and then changes in gene expression were noted. RVX 208 treatment reduced the expression of many genes involved in fatty acid synthesis, cholesterol synthesis, glucose processing, innate immunity, coagulation cascade and complement pathway. RVX 208 decreased expression. Significant decrease of 7-12% compared with the baseline in complement (i.e. complement factor 3) and coagulation components was reported. In a separate ex-vivo study, donor whole blood was exposed to RVX 208 followed by micro-array analysis, RVX 208 lowered atherogenesis by downregulating (8 of 11) pro-atherogenic genes but in contrast, upregulated (5 of 7) anti-atherogenic genes that control monocyte recruitment, migration and activation, macrophage function, inflammatory signaling and plaque stability. Overall, data from both the primary human hepatocytes and whole blood studies suggest an anti-atherosclerotic benefit of RVX 208 that extends beyond its ApoA-I/HDL enhancing effects [38] [65] [69] .

Pooled biomarker analysis of phase II SUSTAIN and ASSURE trials demonstrated 8% reduction in neutrophil to lymphocyte ratio (NLR) in apabetalone as compared with 1% reduction in placebo (p < 0.001). This reduction sustained at six months period with 7.5% for apabetalone and 3.5% for placebo (p < 0.001). Similar reductions of in the NLR were also observed with apabetalone treatment in diabetes patients involved in the trial with compared with placebo (7% reduction; n = 127 for apabetalone and n = 65 for placebo) (p < 0.10) [39] [65] [69] .

Preclinical studies:

Pulmonary arterial hypertension

In in vitro studies treatment with dose-dependent apabetalone in human PAH endothelial and smooth muscle cells decreased the expression of FoxM1 and PLK1, apoptosis-resistance, inflammation and fibrosis. Apabetalone also repressed genotoxicity by normalizing the pro-inflammatory phenotype (NFAT/NFκB/TGFβ activity and expression of IL6 and 8) and by promoting BMPR2/ID1 expression. Oral treatment of apabetalone in rat models (MCT/shunt and Su5416/hypoxia) improved vascular remodeling and pulmonary hemodynamics compared with vehicle (n = 6-12/group, p < 0.01). Apabetalone also improved right ventricle contractility in rats [109] .

Immunogenicity

Treatment with apabetalone demonstrated that the activation of proinflammatory monocyte is hypersensitive to the BET inhibitor apabetalone indicating that it is driven by epigenetic mechanisms. Reduction in IL-1 and IL-8 mRNA (p<0.001) was observed. Diabetes mellitus (DM) + cardiovascular disease (CVD) monocytes were observed to be hyper responsive to IFNγ, with enhanced expression of TNFα, MYD88 and RELA in comparison to the healthy controls (+30%, p<0.05). IFNγ induced secretion of IL-1β and TNFα was observed to be selectively reduced in DM+CVD monocytes by apabetalone. In total, 22 IFNγ targets involved in monocyte chemoattraction (CCL2, CCL7, CCL8, CXCL9, CXCL10, CCR1), pattern recognition receptor signaling (TLR1, TLR8, LY96, FPR2, TICAM2, RELA, MYD88), uptake of modified LDL (MSR1), and reactive oxygen species (CYBB) were observed to be downregulated by more than 40% (p<0.05) in DM+CVD cells following apabetalone treatment [35] [17]

Therapeutic Trials

Apabetalone met the primary and secondary endpoints in the phase IIb SUSTAIN trial in patients (n = 176) with established atherosclerotic cardiovascular disease (CVD) and low high-density cholesterol (HDL-C). After 24 weeks of treatment, apabetalone was associated with a significant increase in HDL-C compared with baseline (p = 0.01; primary endpoint), as well as significant increases in Apo-Al (p = 0.002; secondary endpoint) and large HDL particles (p = 0.02; secondary endpoint) [66] .

Data from three phase II studies, ASSERT, SUSTAIN and ASSURE, showed that patients, with baseline estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2, treated with apabetalone for 12-26 weeks, had an improvement in eGFR and a significant reduction in alkaline phosphate (ALP) (p<0.01). A post-hoc analysis of SUSTAIN and ASSURE trials showed that, compared to baseline, the ALP levels were higher by 3 IU/L, in all the apabetalone-treated patients (n = 331), who suffered from major adverse cardiac events (MACE), while in event free patients (n = 313), ALP decreased by 8 IU/L (p = 0.02) [37] .

Apabetalone significantly reduced the incidence of major adverse cardiac events (MACE) in high-risk patients with atherosclerosis by > 65%, compared with placebo, according to a pooled analysis of data from both the phase IIb ASSURE and SUSTAIN trials (n = 499). Fewer cumulative MACE events were seen in patients treated with apabetalone (n = 331) than in the placebo group (n = 168) (6.74% vs 15.09%; p = 0.02). In patients with elevated CRP > 2 mg/dL (n = 283), the cumulative MACE rate was 6.42% vs 20.53% for RVX 208 (n = 179) and placebo (n = 104), respectively (p = 0.007). Administration of apabetalone reduced blood glucose levels, compared with placebo after 12 weeks of treatment and a subset of patients with low HDL had a lower blood glucose after treatment [62] [63] . Apabetalone was also associated with a 55% relative risk reduction (RRR) in MACE (p=0.02). This effect was notable in patients with diabetes mellitus, who had a RRR in MACE lowered by 77% (p=0.01) [61] [65] [69] .

In phase III BETonMACE trial, apabetalone reduced first hospitalisation for congestive heart failure (CHF) [ABP 2.4% compared with placebo 4.0%; HR 0.59; 95% Cl 0.38-0.94; p = 0.03]. Apabetalone reduced total (first or recurrent) hospitalisation for CHF [HR 0.47; 95% CI 0.27-0.83; p=0.01] and the composite of cardiovascular death or hospitalisation for CHF. The trial enrolled 2 425 patients with acute coronary syndromes [36] [17]

In the phase IIb ASSURE 1 trial of apabetalone, showed that attenuated plaque (AP) was observed in 31 (11%) patients. The apabetalone group displayed reductions in AP length by 1mm (p=0.03), AP arc by 37.0o (p=0.004) and the AP index (API) by 34.6mmo (p=0.02). API change correlated with the on-treatment HDL particle concentration (r=-0.50, p=0.007), but not HDL-C (r=-0.20, p=0.36) or apoA-1 (r=-0.20, P=0.25). Multivariable analysis demonstrated that on-treatment concentrations of HDL (p=0.03) and VLDL (p=0.01) particle concentrations were independent of changes in API. Earlier results showed that the trial did not meet its primary endpoint of a -0.6% change in percent atheroma volume, as determined by intravascular ultrasound, in 324 patients with atherosclerosis and acute coronary syndromes. Patients treated with apabetalone had a -0.4% plaque regression (p = 0.08) in the 26-week, multi-centre, randomised, placebo-controlled trial. In patients who received apabetalone, the secondary endpoints of regression of total coronary atheroma volume and increases in apolipoprotein A-I and HDL cholesterol were met. Unexpectedly, strong placebo results were observed [46] . Subgroup analyses from the ASSURE 1 trial revealed a significant Percent Atheroma Volume (PAV) plaque regression in patients who were taking rosuvastatin in combination with apabetalone (−1.43%; p < 0.002), while there was no significant change in PAV plaque progression in those taking atorvastatin (+0.19%; p > 0.05) [56] . Further analyses demonstrated significant improvements in a patient subgroup with high sensitivity C-Reactive Protein (hsCRP) serum levels of >2.0 mg/dL (n = 184). Of patients treated with apabetalone in this subgroup (n = 130), the incidence of Major Adverse Cardiac Events (MACE) was lowered by > 65% (p = 0.023) when compared with the placebo group (n = 54). In updated results, 6.9% of patients who were treated with apabetalone experienced a MACE, compared with 19.9% for the placebo treated group (n = unknown). Furthermore, patients with hsCRP >2.0 mg/dL treated with RVX 208 demonstrated a 60% reduction in hsCRP compared with baseline (p < 0.0001) and compared with placebo (p = 0.054). Patients treated with apabetalone in this subgroup displayed atheroma regression, as measured by reductions of −0.75% in PAV (p < 0.03), −6.3mm3 in total atheroma volume (TAV; p < 0.001) and −2.63mm3 in the worst 10mm TAV segment (p < 0.001), compared with baseline. The use of a new catheter (Volcano Revolution 45mghz) for virtual histology intravascular ultrasound (VH-IVUS) in 87 of a total 323 patients provided evidence for a reduced vulnerability of atherosclerotic plaque to rupture in patients treated with apabetalone. In treated patients analysed with VH-IVUS (n = 61), the necrotic core to dense calcium (NC/DC) ratio was reduced by −7.5% (p < 0.03) compared with baseline, while patients given placebo (n = 24) had a non-significant reduction of −3.8% (p = 0.47) [59] [57] [58] [65] .

Future Events

Expected Date Event Type Description Updated
30 Jun 2019 Trial Update Resverlogix and Laval University plan an early phase I pilot study (BRD4i) in Pulmonary arterial hypertension (In adults, In the elderly, Second-line therapy or greater) in Canada in the first half of 2019 [102] 22 Mar 2019
30 Sep 2018 Trial Update Resverlogix plans a phase I/II trial in Fabry's disease in Canada in September 2018 (NCT03228940) (700285326) 11 Jun 2018
31 Jul 2018 Trial Update Resverlogix plans a phase I/IIa trial for Renal failure in July 2018(NCT03160430) (700279169) 11 Jun 2018
28 Feb 2017 Regulatory Status Resverlogix intends to files an IND application with the FDA in USA for Renal failure (9211952) 23 May 2017

Development History

Event Date Update Type Comment
28 Mar 2020 Scientific Update Immunogenicity data from phase III BETonMACE trial in Acute coronary syndromes presented at 2020 Annual Scientific Session of the American College of Cardiology and World Congress of Cardiology (ACC-WCC-2020) [35] Updated 31 May 2020
28 Mar 2020 Scientific Update Efficacy data from phase III BETonMACE trial in Acute coronary syndromes presented at 2020 Annual Scientific Session of the American College of Cardiology and World Congress of Cardiology (ACC-WCC-2020) [36] Updated 28 May 2020
24 Mar 2020 Phase Change Early research in COVID-2019 infections in Canada (PO) [13] Updated 01 Apr 2020
24 Mar 2020 Trial Update Resverlogix plans preclinical and clinical development of apabetalone for COVID-19 infections [13] Updated 01 Apr 2020
16 Sep 2019 Scientific Update Pharmacodynamics data from the phase II ASSERT trial in Atherosclerosis presented at the 55th Annual Meeting of the European Association for the Study of Diabetes (EASD-2019) [45] Updated 09 Jan 2020
28 Jul 2019 Phase Change - No development reported No recent reports of development identified for phase-I development in Acute coronary syndromes in New Zealand (PO, Capsule) Updated 28 Jul 2019
18 Mar 2019 Phase Change - Preclinical Preclinical trials in Fabry's disease in Canada (PO) [102] Updated 22 Mar 2019
18 Mar 2019 Trial Update Resverlogix and Laval University plan an early phase I pilot study (BRD4i) in Pulmonary arterial hypertension (In adults, In the elderly, Second-line therapy or greater) in Canada in the first half of 2019 [102] Updated 22 Mar 2019
18 Mar 2019 Trial Update Resverlogix and Quebec Heart and Lung Institute, Laval University plan a phase II trial for Pulmonary arterial hypertension in Canada [102] Updated 22 Mar 2019
05 Nov 2018 Phase Change - Preclinical Preclinical trials in Pulmonary arterial hypertension in Canada, Netherlands (PO) [109] Updated 11 Dec 2018
05 Nov 2018 Scientific Update Pharmacodynamics data from preclinical trial in Pulmonary arterial hypertension presented at the 91st Annual Scientific Sessions of the American Heart Association (AHA-2018) [109] Updated 11 Dec 2018
01 Oct 2018 Scientific Update Pharmacokinetic data from in vitro studies in Diabetes presented at 54th Annual Meeting of the European Association for the Study of Diabetes (EASD-2018) [88] Updated 18 Oct 2018
05 Sep 2018 Scientific Update Pharmacodynamics data from the phase II ASSURE trial released by Resverlogix Corporation [64] Updated 06 Sep 2018
04 Sep 2018 Regulatory Status NCT03655704 - added planned trial although trial is not company-sponsored, since drug is not launched (also indication is new); also added planned phase II trial from NCT record Updated 04 Sep 2018
31 Aug 2018 Trial Update Laval University plans a phase II trial in Pulmonary arterial hypertension (NCT03655704) Updated 04 Sep 2018
07 Aug 2018 Regulatory Status Data and Safety Monitoring Board recommends to continue the phase III BETonMACE trial in Low HDL cholesterol (PO) [19] Updated 08 Aug 2018
24 Jun 2018 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
07 Jun 2018 Licensing Status Apabetalone - Resverlogix is available for licensing as of 07 Jun 2018. www.resverlogix.com Updated 11 Jun 2018
07 Jun 2018 Phase Change - Preclinical Preclinical trials in HIV infections in Canada before June 2018 (for HIV-1 eradication) Updated 11 Jun 2018
19 Mar 2018 Trial Update Resverlogix Corporation completes enrolment in the phase III BETonMACE trial in Low HDL cholesterol (PO) [20] Updated 21 Mar 2018
15 Feb 2018 Trial Update Resverlogix plans a phase I/II trial in Fabry's disease in Canada in September 2018 (NCT03228940) Updated 11 Jun 2018
08 Jan 2018 Licensing Status Apabetalone market licensed to Medison Pharma in Israel [2] Updated 11 Jan 2018
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for phase-I development in Alzheimer's-disease in USA (PO, Capsule) Updated 04 Nov 2017
24 Oct 2017 Licensing Status Hepalink USA enters into a Right of First Refusal Agreement with Resverlogix Corporation to develop, manufacture and commercialise pharmaceutical products containing apabetalone in USA [5] Updated 27 Oct 2017
26 Aug 2017 Scientific Update Updated efficacy data from the phase II trial in Atherosclerosis presented at the Annual Congress of the European Society of Cardiology (Aug-2017) [59] Updated 04 Oct 2017
26 Aug 2017 Scientific Update Pooled pharmacodynamics data from phase II SUSTAIN and ASSURE trial in Atherosclerosis presented at the Annual Congress of the European Society of Cardiology (USC-Card-2017) [39] Updated 03 Oct 2017
28 Jun 2017 Phase Change - III Phase-III clinical trials in Acute coronary syndromes in Taiwan, Russia (PO) [25] Updated 06 Jul 2017
28 Jun 2017 Phase Change - III Phase-III clinical trials in Low HDL cholesterol in Taiwan, Russia (PO) [25] Updated 06 Jul 2017
28 Jun 2017 Regulatory Status Resverlogix receives fourth positive recommendation from Data Safety Monitoring Board for Apabetalone [25] Updated 06 Jul 2017
30 May 2017 Regulatory Status Health Canada grants approval to conduct a clinical trial in Fabry's disease [100] Updated 31 May 2017
30 May 2017 Trial Update Resverlogix Corporation plans a clinical trial in Fabry's disease in Canada [100] Updated 31 May 2017
15 May 2017 Regulatory Status The US FDA approves IND application for apabetalone in Renal failure [105] Updated 23 May 2017
15 Mar 2017 Patent Information Reseverlogix receives notice of allowance from USPTO for patent claims covering apabetalone in combination with rosuvastatin in the US [121] Updated 21 Mar 2017
27 Feb 2017 Regulatory Status Resverlogix intends to files an IND application with the FDA in USA for Renal failure [106] Updated 23 May 2017
23 Feb 2017 Trial Update Resverlogix plans a phase I/IIa trial for Renal failure in July 2018(NCT03160430) Updated 11 Jun 2018
23 Jan 2017 Scientific Update Pharmacodynamics data from a phase I pharmacokinetics trial released by Resverlogix [83] Updated 01 Feb 2017
17 Nov 2016 Trial Update Resverlogix completes a phase I trial in Acute coronary syndromes (In subjects with renal impairment and healthy volunteers) in New Zealand [77] Updated 24 Nov 2016
17 Nov 2016 Trial Update Resverlogix Corporation plans a phase II trial for Renal Impairment in early 2017 [77] Updated 24 Nov 2016
20 Jul 2016 Phase Change - III Phase-III clinical trials in Acute coronary syndromes in Israel (PO) (NCT02586155) Updated 06 Jul 2017
20 Jul 2016 Phase Change - III Phase-III clinical trials in Low HDL cholesterol in Israel (PO) (NCT02586155) Updated 06 Jul 2017
01 Jun 2016 Phase Change - I Phase-I clinical trials in Acute coronary syndromes (In subjects with renal impairment and healthy volunteers) in New Zealand (PO) (ACTRN12616000642482) Updated 27 Jun 2016
24 May 2016 Trial Update Resverlogix plans a phase I pharmacokinetics trial in New Zealand (PO) (ACTRN12616000642482) Updated 14 Jun 2016
24 May 2016 Phase Change - Preclinical Preclinical trials in Renal failure in Canada (PO) before May 2016 [108] Updated 31 May 2016
24 May 2016 Scientific Update Pharmacodynamics data from a preclinical study in Renal failure released by Resverlogix [108] Updated 31 May 2016
17 Dec 2015 Licensing Status Apabetalone is available for licensing in territories, excluding China, Hong Kong, Macau, Taiwan - http://www.resverlogix.com/partnering/opportunities.html Updated 17 Dec 2015
09 Nov 2015 Scientific Update Efficacy data from ASSERT, SUSTAIN and ASSURE trials in Cardiovascular disease and Chronic kidney disease released by Resverlogix [37] Updated 16 Nov 2015
01 Oct 2015 Phase Change - III Phase-III clinical trials in Acute coronary syndromes in Bulgaria ,Croatia, Slovakia, Germany (PO) (EudraCT2015-002040-14) (NCT02586155) Updated 11 Dec 2018
01 Oct 2015 Phase Change - III Phase-III clinical trials in Acute coronary syndromes in Belgium, Hungary (PO) Updated 09 Nov 2015
01 Oct 2015 Phase Change - III Phase-III clinical trials in Atherosclerosis in Belgium, Hungary (PO) Updated 09 Nov 2015
01 Oct 2015 Phase Change - III Phase-III clinical trials in Low HDL cholesterol in Belgium, Hungary (PO) Updated 09 Nov 2015
24 Sep 2015 Trial Update Resverlogix plans a phase II trial for Paroxysmal Nocturnal Haemoglobinuria [103] Updated 15 Oct 2015
31 Aug 2015 Scientific Update Pharmacodynamics data from the SUSTAIN and ASSURE trials presented at the Annual Congress of the European Society of Cardiology (ESC-Card) [38] Updated 02 Dec 2015
05 Aug 2015 Active Status Review Phase-II development completed for high-risk cardiovascular disease in patients with diabetes and low HDL worldwide Updated 05 Aug 2015
08 Jul 2015 Licensing Status RVX 208 licensed to Shenzhen Hepalink Pharmaceutical in China, Hong Kong, Taiwan and Macau [4] Updated 12 Jul 2015
08 Jun 2015 Scientific Update Pharmacodynamics data from a phase II trial in Prediabetic state presented at the 75th Annual Scientific Sessions of the American Diabetes Association (ADA-2015) [94] Updated 08 Jul 2015
01 Jun 2015 Scientific Update Additional pharmacodynamics data from the ASSURE and SUSTAIN trials released by Resverlogix [126] Updated 06 Jul 2015
27 Apr 2015 Licensing Status Shenzhen Hepalink Pharmaceutical enters into a framework agreement with Resverlogix for RVX 208 in China, Hong Kong, Taiwan and Macau [3] Updated 12 Jul 2015
07 Apr 2015 Patent Information Resverlogix has patent protection for apabetalone in China [122] Updated 09 Apr 2015
16 Mar 2015 Scientific Update Pharmacodynamics data from the ASSURE and SUSTAIN trials presented at the 64th Annual Scientific Session of the American College of Cardiology (ACC-2015) [60] Updated 14 Apr 2015
14 Jan 2015 Trial Update Resverlogix plans a phase III trial (BETONMACE) for Cardiovascular disorders in Argentina, Belgium, Bulgaria, Croatia, Germany, Hungary, Israel, Mexico, Poland, Serbia and Slovakia (NCT02586155) Updated 15 Apr 2015
02 Sep 2014 Scientific Update Pooled efficacy data from the phase IIb ASSURE and SUSTAIN trials in Atherosclerosis presented at the European Society of Cardiology Congress (ESC-2014) [61] Updated 13 Oct 2014
31 Mar 2014 Trial Update Resverlogix completes a phase II trial for Prediabetic state in Australia (9161204; NCT01728467) Updated 02 Apr 2014
15 Jan 2014 Scientific Update Pooled efficacy data from the phase IIb ASSURE and SUSTAIN trials in Atherosclerosis released by Resverlogix [62] Updated 07 Feb 2014
23 Dec 2013 Trial Update Resverlogix completes enrolment in its phase II trial for Prediabetic state in Australia [91] , NCT01728467) Updated 27 Dec 2013
04 Nov 2013 Scientific Update Further efficacy data from the phase IIb ASSURE-1 trial in Atherosclerosis/Acute coronary syndromes released by Resverlogix [58] Updated 23 Nov 2013
06 Sep 2013 Scientific Update Efficacy data from a sugroup analysis of the ASSURE-1 trial in Atherosclerosis/Acute coronary syndromes released by Resverlogix [56] Updated 06 Sep 2013
28 Jun 2013 Trial Update Resverlogix withdraws a phase II trial for Dyslipidaemias (combination therapy) prior to enrolment (NCT01863225) Updated 02 Jul 2013
27 Jun 2013 Scientific Update Efficacy data from the phase IIb ASSURE 1 trial in Atherosclerosis/Acute coronary syndromes released by Resverlogix [46] Updated 05 Jul 2013
01 Jun 2013 Trial Update Resverlogix completes a phase IIb ASSURE 1 trial for Atherosclerosis/Acute coronary syndromes in Belgium, Hungary, Netherlands, Poland, Spain, Russia, Argentina & Brazil (NCT01067820) Updated 27 Jun 2013
16 May 2013 Trial Update Resverlogix plans a phase II trial for Dyslipidaemias (combination therapy) in Australia (NCT01863225) Updated 02 Jul 2013
08 Apr 2013 Trial Update Resverlogix Corporation plans a phase II trial for Alzheimer's disease [8] Updated 07 May 2013
16 Oct 2012 Phase Change - II Phase-II clinical trials in Prediabetic state in Australia (PO) Updated 18 Oct 2012
26 Sep 2012 Trial Update Resverlogix completes enrolment in the phase IIb ASSURE 1 trial for Atherosclerosis/Acute coronary syndromes in Belgium, Hungary, Netherlands, Poland, Spain, Russia, Argentina & Brazil (NCT01067820) Updated 27 Sep 2012
29 Aug 2012 Scientific Update Topline efficacy data from the SUSTAIN trial for Low HDL cholesterol released by Resverlogix [66] Updated 29 Aug 2012
28 Aug 2012 Trial Update Resverlogix completes the phase II SUSTAIN trial for Low HDL cholesterol in South Africa (NCT01423188) Updated 30 Aug 2012
28 Nov 2011 Trial Update Resverlogix completes enrolment in the phase IIb SUSTAIN trial for Low HDL cholesterol in South Africa (NCT01423188) Updated 29 Nov 2011
27 Sep 2011 Phase Change - II Phase-II clinical trials in Low HDL cholesterol (in patients at high-risk of cardiovascular disease) in South Africa (PO) Updated 29 Sep 2011
26 Sep 2011 Phase Change - II Phase-II clinical trials in Acute coronary syndromes in Argentina (PO) Updated 28 Sep 2011
26 Sep 2011 Phase Change - II Phase-II clinical trials in Acute coronary syndromes in Brazil (PO) Updated 28 Sep 2011
26 Sep 2011 Phase Change - II Phase-II clinical trials in Acute coronary syndromes in Russia (PO) Updated 28 Sep 2011
26 Sep 2011 Phase Change - II Phase-II clinical trials in Acute coronary syndromes in Belgium, Hungary, Netherlands, Poland and Spain (PO) Updated 28 Sep 2011
26 Sep 2011 Phase Change - II Phase-II clinical trials in Atherosclerosis in Argentina (PO) Updated 28 Sep 2011
26 Sep 2011 Phase Change - II Phase-II clinical trials in Atherosclerosis in Belgium, Hungary, Netherlands, Poland and Spain (PO) Updated 28 Sep 2011
26 Sep 2011 Phase Change - II Phase-II clinical trials in Atherosclerosis in Brazil (PO) Updated 28 Sep 2011
26 Sep 2011 Phase Change - II Phase-II clinical trials in Atherosclerosis in Russia (PO) Updated 28 Sep 2011
13 Jun 2011 Trial Update Resverlogix re-initiates enrolment in the phase II ASSURE 1 trial for Acute coronary syndromes in USA [54] Updated 16 Jun 2011
25 Jan 2011 Scientific Update Pharmacodynamics data from a phase II trial in Atherosclerosis/Acute coronary syndromes that support ongoing development in Alzheimer's disease released by Resverlogix [98] Updated 28 Jan 2011
17 Nov 2010 Scientific Update Pharmacodynamics data from the phase II ASSERT trial in Atherosclerosis presented at the 83rd Annual Scientific Sessions of the American Heart Association (AHA-2010) [42] Updated 22 Nov 2010
07 Oct 2010 Trial Update Resverlogix completes the phase II ASSERT trial for Atherosclerosis in the USA (NCT01058018) Updated 16 Feb 2011
23 Jun 2010 Scientific Update Pharmacodynamics and adverse events data from a phase Ia/IIb trial in volunteers with normal or low high density lipoprotein cholesterol released by Resverlogix [70] , [127] Updated 24 Jun 2010
12 May 2010 Trial Update Resverlogix suspends enrolment in the phase II ASSURE 1 trial for Acute coronary syndromes in USA [49] Updated 14 May 2010
25 Feb 2010 Trial Update Resverlogix initiates enrolment in the phase II ASSURE 1 trial for Acute coronary syndromes in USA Updated 15 Mar 2010
09 Feb 2010 Trial Update Resverlogix completes enrolment in the ASSERT trial for Atherosclerosis in the USA (NCT01058018) Updated 10 Feb 2010
22 Dec 2009 Phase Change - II Phase-II clinical trials in Atherosclerosis in USA (PO) Updated 15 Mar 2010
22 Dec 2009 Phase Change - II Phase-II clinical trials in Acute coronary syndromes in USA (PO) Updated 15 Mar 2010
29 Sep 2009 Scientific Update Final pharmacodynamics, pharmacokinetic and adverse events data from a phase Ia/IIb trial in volunteers with normal or low density lipoprotein cholesterol relaesed by Resverlogix Corporation [71] Updated 02 Oct 2009
25 Aug 2009 Scientific Update Interim pharmacodynamics data from a phase Ib/IIa trial in volunteers with normal or low high density lipoprotein cholesterol released by Resverlogix [72] Updated 31 Aug 2009
25 Aug 2009 Trial Update Resverlogix completes a phase Ib/IIa trial in subjects with normal or low high density lipoprotein cholesterol levels in the US Updated 31 Aug 2009
31 Mar 2009 Scientific Update Interim pharmacodynamics data from a phase I trial in Cardiovascular disorders presented at the 58th Annual Scientific Session of the American College of Cardiology (ACC-2009) [78] Updated 01 Apr 2009
10 Nov 2008 Scientific Update Pharmacodynamics data from a phase Ia & a preclinical trial in Cardiovascular disorders presented at the 81st Annual Scientific Sessions of the American Heart Association (AHA-2008) [80] Updated 14 Nov 2008
10 Nov 2008 Phase Change - I Phase-I clinical trials in Alzheimer's disease in USA (PO) Updated 13 Nov 2008
21 Oct 2008 Trial Update Resverlogix advances apabetalone to the second arm of a phase Ib/IIa trial in the US [75] Updated 23 Oct 2008
30 Sep 2008 Phase Change - I/II Phase-I/II clinical trials in Cardiovascular disorders in USA (PO) Updated 23 Oct 2008
18 Jun 2008 Scientific Update Interim pharmacodynamics data from a phase I trial in Cardiovascular disorders released by Resverlogix [128] Updated 20 Jun 2008
22 Apr 2008 Trial Update Resverlogix completes dosing in its phase Ia trial for Cardiovascular disorders in USA Updated 30 Apr 2008
14 Jan 2008 Phase Change - I Phase-I clinical trials in Cardiovascular disorders in USA (PO) Updated 16 Jan 2008
10 Dec 2007 Regulatory Status The US FDA approves IND application to begin phase I trial of apabetalone in Cardiovascular disorders (PO) Updated 01 May 2008
29 Nov 2006 Phase Change - Preclinical Preclinical trials in Cardiovascular disorders in USA (PO) Updated 30 Apr 2008

References

  1. Resverlogix Highlights Potential to Develop Apabetalone as a Therapeutic for HIV-1 Eradication Utilizing the Shock and Kill Approach.

    Media Release
  2. Resverlogix and Medison Pharma Ltd. Announce Strategic Licensing Agreement.

    Media Release
  3. Resverlogix and China-based Shenzhen Hepalink Pharmaceutical Co., Ltd. Announce a Combination Licensing and Equity Arrangement.

    Media Release
  4. Resverlogix Closes License Agreement and Enters Into Definitive Stock Purchase Agreement With Hepalink.

    Media Release
  5. Resverlogix Announces Right of First Refusal Agreement with Hepalink USA Inc.

    Media Release
  6. Resverlogix Collaborates with Emerald Logic to Identify Factors Driving Drug Response and Efficacy in Phase 2 Program.

    Media Release
  7. Resverlogix Corp. Establishes Subsidiary: RVX Therapeutics Inc.

    Media Release
  8. Resverlogix to Spin-out RVX Therapeutics Inc. to Shareholders.

    Media Release
  9. Resverlogix Corp. Announces International Research Collaboration Program With Cedars-Sinai Medical Center and Atherosclerosis Researcher Dr. Prediman K. Shah.

    Media Release
  10. Breakthrough in Apo AI Research: Resverlogix Expands NEXVAS Program Into Acute Coronary Market.

    Media Release
  11. Resverlogix Announces FDA Confirmation Regarding Filing Pathway for Apabetalone.

    Media Release
  12. Resverlogix Receives Approval Pathway from the FDA as to the Inclusion of USA Patients in the Phase 3 BETonMACE Trial.

    Media Release
  13. Resverlogix clinical candidate Apabetalone identified as potential COVID-19 treatment in recent issue.

    Media Release
  14. Resverlogix Announces Topline Results in BETonMACE Phase 3 Epigenetics Trial.

    Media Release
  15. RESVERLOGIX' BETONMACE PHASE 3 TRIAL SUCCESSFULLY REACHES ITS TARGETED 250 MACE EVENTS.

    Media Release
  16. Resverlogix Announces Ninth Positive Data Safety Monitoring Board Recommendation for Phase 3 Study of Apabetalone.

    Media Release
  17. A Phase III Multi-Center, Double-Blind, Randomized, Parallel Group, Placebo-Controlled Clinical Trial in High-Risk Type 2 Diabetes Mellitus (T2DM) Subjects with Coronary Artery Disease (CAD) to Determine Whether Bromodomain Extraterminal Domain (BET) Inhibition Treatment with RVX000222 Increases the Time to Major Adverse Cardiovascular Events (MACE)

    ctiprofile
  18. Resverlogix Announces Eighth Positive Data Safety Monitoring Board Recommendation For Phase 3 Study of Apabetalone.

    Media Release
  19. Resverlogix Announces Seventh Positive Recommendation From The Data Safety Monitoring Board For Phase 3 Study of Apabetalone.

    Media Release
  20. Resverlogix Exceeds Full Enrollment for the Pivotal Phase 3 BETonMACE Clinical Trial.

    Media Release
  21. Resverlogix Announces Sixth Positive Recommendation From Data Safety Monitoring Board For Phase 3 Study of Apabetalone.

    Media Release
  22. Resverlogix Receives FDA Protocol Acceptance for the Ongoing Phase 3 BETonMACE Trial.

    Media Release
  23. Resverlogix Announces Fifth Positive Recommendation From Data Safety Monitoring Board For Phase 3 Study of Apabetalone.

    Media Release
  24. Resverlogix Randomizes First Patient in Taiwan/China Portion of the Phase 3 BETonMACE Clinical Trial.

    Media Release
  25. Resverlogix Announces Fourth Positive Recommendation From Data Safety Monitoring Board For Phase 3 Study of Apabetalone.

    Media Release
  26. Resverlogix Announces Third Positive Recommendation From Data Safety Monitoring Board For Phase 3 Study of Apabetalone and Provides an Update on Corporate Activities.

    Media Release
  27. Resverlogix Announces Second Positive Recommendation From Data Safety Monitoring Board For Phase 3 Study of Apabetalone (RVX-208).

    Media Release
  28. Resverlogix Commences Dosing in Phase 3 Clinical Trial BETonMACE.

    Media Release
  29. Resverlogix Commences Phase 3 Clinical Trial BETonMACE With Apabetalone.

    Media Release
  30. International Clinical Steering Committee Announced for Resverlogix's Phase 3 BETonMACE Clinical Trial with RVX-208 apabetalone.

    Media Release
  31. Resverlogix Officially Attains Phase 3 Status with a European Regulatory Authority.

    Media Release
  32. Resverlogix Presents at Biotech Showcase During JP Morgan Week.

    Media Release
  33. Resverlogix Names Michael Sweeney, M.D., as Senior Vice President of Clinical Development.

    Media Release
  34. Resverlogix Announces Positive Recommendation From Data Safety Monitoring Board For Phase 3 Study of Apabetalone (RVX-208).

    Media Release
  35. Wasiak S, Dzobo KE, Bahjat M, Rakai BD, Kaiser Y, Versloot M, et al. Epigenetic Reader Inhibitor Apabetalone (Rvx-208) Counters Proinflammatory Hyperactivation of Cd14+ Monocytes from Patients with Type 2 Diabetes and Cardiovascular Disease. ACC-WCC-2020 2020; abstr. 1080-05.

    Available from: URL: https://www.sciencedirect.com/science/article/pii/S0735109720328448
  36. Sweeney M, Nicholls SJ, Ray KK, Buhr K, Ginsberg H, Johansson J, et al. The Bet Protein Inhibitor Apabetalone Reduces Congestive Heart Failure Incidence in Patients with Acute Coronary Syndrome and Diabetes: Results from the Betonmace Trial. ACC-WCC-2020 2020; abstr. 1315-168.

    Available from: URL: https://www.sciencedirect.com/science/article/pii/S0735109720307956
  37. Resverlogix Presents Important New Data at the Annual American Society of Nephrology Kidney Week Conference.

    Media Release
  38. Resverlogix Presents New Data at the European Society of Cardiology Congress 2015 on RVX-208 'apabetalone' a Selective BET Inhibitor.

    Media Release
  39. Nicholls S, Kulikowski E, Halliday C, Lebioda K, Johansson J, Sweeney M, et al. Lowering the neutrophil to lymphocyte ratio by the BET inhibitor, apabetalone: potential implications for cardiovascular events in high risk patients. ESC-Card-2017 2017; abstr. P1769.

    Available from: URL: http://congress365.escardio.org/vgn-ext-templating/PresentationViewer/Abstract/C365PRESENTATION159384
  40. Phase II Multi-center, Double-blind, Randomized, Parallel Group, Placebo-controlled Clinical Trial for Dose-finding and Safety Study of RVX000222 in Subjects With Stable Coronary Artery Disease

    ctiprofile
  41. Resverlogix Commences Phase 2 Atherosclerosis Clinical Trial.

    Media Release
  42. Resverlogix Presents ASSERT Human Clinical Trial Data at the American Heart Association Late Breaker Session.

    Media Release
  43. Resverlogix Presents Two Abstracts on Analysis of the Phase 2 ASSERT Clinical Trial at The ESC Congress 2011.

    Media Release
  44. Resverlogix Presents New Findings on RVX-208 at European Atherosclerosis Society.

    Media Release
  45. Wong NCW, Fu L, Tsujikawa LM, Rakai BD, Wasiak S, Sweeney M, et al. Apabetalone modulates Th1 responses in diabetes and CVD through intrinsic and extrinsic mechanisms: in vitro and in human studies. EASD-2019 2019; abstr. 661.

    Available from: URL: http://www.easd.org/
  46. Resverlogix Reports Top-Line Results from ASSURE Clinical Trial.

    Media Release
  47. Resverlogix Completes Enrollment In ASSURE Trial

    Media Release
  48. Resverlogix Completes Dosing in ASSURE Clinical Trial.

    Media Release
  49. Resverlogix Completes Dosing for ASSERT Trial.

    Media Release
  50. Resverlogix's Phase 2 ASSURE Trial Amended.

    Media Release
  51. Resverlogix Activates Study Sites in ASSURE Phase 2b IVUS Trial for Atherosclerotic Plaque Regression.

    Media Release
  52. Resverlogix Commences Dosing in ASSURE a Phase 2b IVUS Clinical Trial Targeting High-Risk Cardiovascular Disease Patients.

    Media Release
  53. Resverlogix Completes Dosing of RVX-208 in SUSTAIN, a Phase 2b Clinical Trial Targeting High-Risk Cardiovascular Disease Patients.

    Media Release
  54. Resverlogix Launches Phase IIb ASSURE Trial for RVX-208 Cholesterol Transport Drug, Safety Data Completed and Filed.

    Media Release
  55. Resverlogix Activates First Site for ASSURE 1 Clinical Trial.

    Media Release
  56. Further Analysis of the ASSURE Data Finds a Responder Group for RVX-208 with Statistically Significant Regression of Coronary Atherosclerosis.

    Media Release
  57. Cleveland Clinic Presents RVX-208 Data at American College of Cardiology (ACC) Conference in Washington DC March 31, 2014.

    Media Release
  58. Resverlogix Announces Two New Findings from the ASSURE Trial Relating to Inflammation and Plaque Vulnerability.

    Media Release
  59. Shishikura DS, Kataoka YK, Honda SH, Takata KT, Kim SK, Andrews JA, et al. The effect of apabetalone on attenuated coronary atherosclerotic plaque: insights from the ASSURE trial. ESC-Card-2017 2017; abstr. P1104.

    Available from: URL: http://congress365.escardio.org/vgn-ext-templating/PresentationViewer/Abstract/C365PRESENTATION157305
  60. Resverlogix Presents at the Prestigious American College of Cardiology 64th Annual Scientific Session & Expo (ACC.15).

    Media Release
  61. RVX-208 Leads to a 77% Relative Risk Reduction of Major Adverse Cardiovascular Events (MACE) in Patients with Diabetes Mellitus.

    Media Release
  62. Resverlogix Announces Combined RVX-208 findings from SUSTAIN & ASSURE Phase 2b Trials.

    Media Release
  63. RVX-208 Reduces Major Adverse Cardiovascular Events (MACE) Significantly in Patients with Diabetes Mellitus.

    Media Release
  64. Resverlogix Presents at Clinical Trials in Alzheimers Disease (CTAD) Asia 2018.

    Media Release
  65. Phase IIb Multi-center, Double-blind, Randomized, Parallel Group, Placebo-controlled Clinical Trial for the Assessment of Coronary Plaque Changes With RVX000222 as Determined by Intravascular Ultrasound

    ctiprofile
  66. Resverlogix's BET Protein Inhibitor RVX-208 Meets Primary Endpoint in SUSTAIN Clinical Trial in Patients With High Risk Cardiovascular Disease

    Media Release
  67. Resverlogix Announces Full Enrollment of SUSTAIN, a Phase 2b Clinical Trial Targeting High-Risk Cardiovascular Disease Patients.

    Media Release
  68. Resverlogix Expands Phase 2b Program with the Commencement of Dosing in SUSTAIN.

    Media Release
  69. Phase IIb Multi-center, Double-blind, Randomized, Parallel Group, Placebo Controlled Clinical Trial for the Assessment of Lipid Trends and Safety of RVX000222 in Statin Treated Subjects With Low Baseline HDL-C Concentrations.

    ctiprofile
  70. Resverlogix Scientific Data Presented at EAS Congress.

    Media Release
  71. Resverlogix RVX-208 Second Clinical Trial Demonstrates Success on Key Reverse Cholesterol Transport Markers.

    Media Release
  72. Resverlogix Phase 1b/2a Study Meets Primary Endpoint.

    Media Release
  73. Resverlogix Provides Quarterly Update.

    Media Release
  74. Resverlogix Board of Directors Update - 26 November 2008.

    Media Release
  75. Resverlogix Advances to Second Arm of Phase 1b/2a Clinical Trial.

    Media Release
  76. A Safety, Pharmacokinetic, and Pharmacodynamic Assessment of 28-Day Oral Dosing of RVX000222 in Healthy Subjects and Subjects With Low High Density Lipoprotein (HDL)

    ctiprofile
  77. Resverlogix Announces Successful Phase 1 Renal Trial Results: Clears Path for Future Phase 2 Studies.

    Media Release
  78. Gordon A, Jahagirdar R, Johansson J, Wagner G, Bailey D, Hansen H, et al. RVX-208 a small molecule that induces apolipoprotein A-I production progresses to phase Ib/IIa clinical trials. 58th-ACC-2009 2009;205 abstr. 1021-74.

    Available from: URL: http://www.sciencedirect.com
  79. Krimbou L, Jahagirdar R, Bailey D, Hafiane A, Ruel I, Wong N, et al. Compound RVX-208 modulates HDL-C levels and function in non-human primates and in early (phase I) human trials. 81st-AHA-2008 2008;371 abstr. 1696.

    Available from: URL: http://scientificsessions.americanheart.org
  80. RVX-208 Data Demonstrates Increase in Functional HDL Particles.

    Media Release
  81. Dosing for RVX-208 Phase 1a Clinical Study Completed.

    Media Release
  82. Progress Report from RVX-208 Phase 1 Clinical Study.

    Media Release
  83. Resverlogix Provides Groundbreaking Results in Patients with Severe Kidney Impairments.

    Media Release
  84. Resverlogix Announces Dosing of First Two Patients in Expanded Renal and Orphan Programs.

    Media Release
  85. A Phase I, Open-Label, Parallel Group Study to Evaluate the Safety and Pharmacokinetics of a Single Oral Dose of RVX000222 in Subjects with Severe Renal Impairment.

    ctiprofile
  86. Reverse Cholesterol Transport by RVX-208 a Small Molecule for ApoA-I Production Increase Presented at American Heart Association Scientific Meeting.

    Media Release
  87. Krimbou L, Jahagirdar R, Ruel I, Johansson J, Genest J. Oral administration of compound RVX-208 increases serum levels of ApoA-I and improves high-density lipoprotein-mediated cholesterol efflux in African green monkeys. Circulation 2007;116(16):126.

  88. Wong NCW, Tsujikawa L, Kulikowski E, Calosing C, Wasiak S, Gilham D, et al. Apabetalone (RVX-208) an epigenetic modifier lowers risk of MACE in diabetes patients with CVD by affecting monocyte adhesion to endothelial cells. EASD-2018 2018; abstr. 128.

    Available from: URL: http://www.abstractsonline.com/pp8/#!/4612/presentation/4197
  89. Resverlogix Scientific Data Presented at ATVB Conference.

    Media Release
  90. FDA Grants Resverlogix Approval to Commence a Phase 1 Clinical Trial for RVX-208.

    Media Release
  91. Resverlogix Completes Enrollment of Phase 2 Clinical Trial of RVX-208 in Patients with Pre-Diabetes Mellitus.

    Media Release
  92. Resverlogix Initiates Phase 2 Clinical Trial of RVX-208 in Patients with Pre-Diabetes Mellitus.

    Media Release
  93. Phase 2 Randomised, Double-blind, Placebo-controlled, Cross-over Study for the Assessment of Glucose Metabolism Changes With RVX000222 in Individuals With Pre-diabetes

    ctiprofile
  94. Resverlogix Reports on the Beneficial Effects of RVX-208 on Glucose Metabolism in Prediabetes Mellitus at the American Diabetes Association's (ADA) Scientific Sessions in Boston, MA.

    Media Release
  95. Phase II trial of RVX-208 in patients with mild cognitive impairment

    ctiprofile
  96. RVX-208 Exploratory Study Illustrates Early Potential for Alzheimer's Disease.

    Media Release
  97. Phase Ia trial of RVX 208 in volunteers.

    ctiprofile
  98. Resverlogix ASSERT Trial Data Illustrates Potential for RVX-208 in Alzheimer′s Disease.

    Media Release
  99. A Phase 2 Multiple-Dose Study to Characterize the Pharmacokinetics of RVX000222 Capsule Formulation in Combination With Either Atorvastatin or Rosuvastatin in Patients With Dyslipidemia

    ctiprofile
  100. Resverlogix Receives Approval From Health Canada To Proceed With Fabry Disease Clinical Trial With Lead Compound Apabetalone.

    Media Release
  101. An Open-Label Study to Assess the Safety and Effect on Key Biomarkers of Oral RVX000222 in Subjects With Fabry Disease

    ctiprofile
  102. Resverlogix Proudly Announces Funding for Phase 2 Trial Evaluating Apabetalone in Pulmonary Arterial Hypertension Led by Quebec Heart and Lung Institute Laval University Researcher.

    Media Release
  103. Resverlogix Announces the commencement of an Orphan Disease Program specific for Complement Mediated Diseases.

    Media Release
  104. A pilot phase 2 study of apabetalone in patients with Paroxysmal Nocturnal Hemoglobinuria

    ctiprofile
  105. Resverlogix Receives Approval From The FDA Cardiovascular and Renal Division To Proceed With A Requested Apabetalone Clinical Trial.

    Media Release
  106. Resverlogix Reports Positive FDA Type B Meeting on Design Issues Relating to a Proposed Phase 2a Kidney Dialysis Trial.

    Media Release
  107. A Two-Part Phase 2a Study in Patients With End-Stage Renal Disease Treated With Hemodialysis; Part A is an Open-Label Study Arm to Evaluate the Effect of Hemodialysis on the Pharmacokinetics of 100 mg RVX000222; and Part B is a Double-Blind, Randomized, Placebo-Controlled, Sequential Cross-Over Study Arm to Evaluate the Efficacy, Safety, and Pharmacokinetics of RVX000222

    ctiprofile
  108. Resverlogix Presents New Complement Data and Establishes Renal Clinical Advisory Board at the 53rd Annual European Renal Association - European Dialysis & Transplant Association Congress (ERA-EDTA).

    Media Release
  109. van der Feen DE, Kurakula K, Boucherat O, Bossers GP, Tremblay E, Jahagirdar R, et al. BRD4 Antagonist RVX208 Reverses Vascular Remodeling and Supports the Right Ventricle in Pulmonary Arterial Hypertension via PLK1 and FoxM1. AHA-2018 2018; abstr. 16556.

    Available from: URL: https://www.ahajournals.org/doi/10.1161/circ.138.suppl_1.16556
  110. Resverlogix Announces Closing of $15 Million Offering.

    Media Release
  111. Resverlogix Announces $15.1 Million of Private Placements.

    Media Release
  112. Resverlogix Closes $6.6 Million Private Placement with Shenzhen Hepalink.

    Media Release
  113. Resverlogix Closes $13.5 Million Private Placement.

    Media Release
  114. Resverlogix Announces $26 Million Private Placement.

    Media Release
  115. Resverlogix Closes US$30 Million Loan.

    Media Release
  116. Resverlogix Closes Previously Announced $87 Million Private Placement with Shenzhen Hepalink.

    Media Release
  117. Resverlogix Announces $87 Million Private Placement with Shenzhen Hepalink.

    Media Release
  118. Resverlogix Closes $10 Million of Equity Subscriptions.

    Media Release
  119. Resverlogix Secures an Additional $30 million from Citibank Loan.

    Media Release
  120. Resverlogix Closes Extension of Maturity Date of Loan and Announces Private Placement.

    Media Release
  121. Resverlogix Announces Receipt of Notice of Allowance from the United States Patent and Trademark Office.

    Media Release
  122. Resverlogix Receives Two Patents for RVX-208 in China.

    Media Release
  123. Resverlogix Update.

    Media Release
  124. Resverlogix Announces the Issuing of Patent Covering RVX-208.

    Media Release
  125. Successful ASSERT Trial Results in Resverlogix Filing New RVX-208 Patent.

    Media Release
  126. Resverlogix Presents New Data at 52nd Annual European Renal Association - European Dialysis & Transplant Association Congress (ERA-EDTA).

    Media Release
  127. Wong NC, Gordon A, Johansson J, Wagner G, Chiacchia FS, McLure K, et al. RVX-208 given orally to humans raises plasma ApoA-I and HDL in a phase 1b/2a clinical trial. 59th-ACC-2010 2010; abstr. 1164-333.

    Available from: URL: http://www.abstractsonline.com
  128. Key Primary Resverlogix Objective Obtained.

    Media Release
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