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   .
In preclinical studies, apabetalone suppressed bromodomain and extra terminal domain (BET) the specialised protein that interacts with the SARS-CoV-2 viral protein  .
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                      . 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)   .
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)  . 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  . 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)  .
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)  . The primary endpoint was the change in ApoA-I levels after 3 months of dosing  . Results were first presented in November 2010  . 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   . 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)  .
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)   . A total of 324 patients with atherosclerosis were randomised to receive apabetalone or placebo, and dosing was completed in April 2013  . 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   . 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     . The ASSURE study complemented the ASSERT trial in patients with stable coronary artery disease   . 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  . Further analyses identified significant improvements in a patient subgroup with heightened inflammation   . 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)      . In September 2018, Resverlogix released data, showing that serum proteins linked to cognitive decline and neurodegenerative disease were favourably affected by apabetalone treatment   .
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)      .
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        .
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  .
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  .
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      .
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     .
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    .
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  .
As of April 2008, apabetalone had undergone 126 preclinical trials comprising safety, toxicity, pharmacokinetics and pharmacology studies  .
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  .
The US FDA approved an IND for a phase I trial of RVX 208 for the treatment of cardiovascular disorders in December 2007  .
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    . 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  . Additional pharmacodynamic data were presented at the 75th Annual Scientific Sessions of the American Diabetes Association (ADA - 2015)  .
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   .
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   .
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  .
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  .
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)   .
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  .
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   .
(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)    .
Preclinical studies of apabetalone for the treatment of chronic kidney disease is underway in Canada  .
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)  .
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)  .
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  .
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  .
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  .
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  .
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  .
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  .
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  .
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   .
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  .
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  . 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  .