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Clinical Trials

Date: 2018-11-12

Type of information: Presentation of results at a congress

phase: 2b

Announcement: presentation of results at the American Heart Association Scientific Sessions

Company: Akcea Therapeutics (USA - MA), a subsidiary of Ionis Pharmaceuticals (USA - CA)

Product: AKCEA-APO(a)-LRx

Action mechanism:

  • antisense oligonucleotide. AAKCEA-APO(a)-LRx is an antisense drug that inhibits the production of apolipoprotein(a), or Apo(a) protein, thereby reducing lipoprotein(a), or Lp(a). Ionis discovered AKCEA-APO(a)-LRx using its proprietary ligand-conjugated antisense (LICA) technology and has co-developed the drug with Akcea.
  • LICA technology has the potential to produce new drugs that are highly potent and can be used at lower doses and with less frequent administration than non-LICA antisense drugs. Results from separate Phase 1 studies of eight LICA drugs in development, including three at Akcea, have shown that doses up to 30-fold lower than non-LICA drugs can result in consistent target reductions with a favorable safety and tolerability profile.
  • AKCEA-APO(a)-LRx is part of Akcea's strategic collaboration with Novartis to develop and commercialize drugs to treat patients who are at high cardiovascular risk due to inadequately treated lipid disorders.

Disease: patients with hyperlipoproteinemia(a) and established cardiovascular disease.

Therapeutic area: Cardiovascular diseases - Metabolic diseases

Country: Canada, Denmark, Germany, Netherlands, USA

Trial details:

  • This trial is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the safety, including tolerability, of AKCEA-APO(a)-LRx (ISIS 681257) and to assess the efficacy of different doses and dosing regimens of AKCEA-APO(a)-LRx (ISIS 681257) for reduction of plasma Lp(a) levels in patients with hyperlipoproteinemia(a) and established cardiovascular disease (CVD).
  • The study had a five to one randomization testing different doses and dose frequencies of AKCEA-APO(a)-LRx. Weekly, every other week and monthly doses were tested ranging from 20mg to 60mg. Patients were dosed for at least six months with some patients dosed up to one year. The primary efficacy endpoint was the percent change in Lp(a) from baseline at the primary analysis time point (6 months) compared to placebo.
  • (NCT03070782)

Latest news:

  • • On November 12, 2018, Akcea Therapeutics, an affiliate of Ionis Pharmaceuticals, and Ionis Pharmaceuticals announced that data from the Phase 2 clinical study of AKCEA-APO(a)-LRx in patients with established cardiovascular disease (CVD) and elevated levels of lipoprotein(a), or Lp(a), were presented in a late-breaking clinical trial presentation at the American Heart Association Scientific Sessions in Chicago November 10, 2018. Patients were treated with AKCEA-APO(a)-LRx or placebo for at least six months, with some patients treated up to one year. The study met all primary and secondary efficacy endpoints analyzed at 6 months. Results from the study show statistically significant and dose dependent reductions from baseline in Lp(a) levels:
    Lp(a) Pooled placebo (n=47) 20 mg every 4 weeks (n=48) 40 mg every 4 weeks (n=48) 20 mg every 2 weeks (n=48) 60 mg every 4 weeks (n=47) 20 mg weekly (n=48)
    LSMean % change in Lp(a) -6 -35 P=0.0032 -56 P<0.0001 -58 P<0.0001 -72 P<0.0001 -80 P<0.0001
    *LSMean: Least squares mean
    • Approximately 98% of patients in the 20mg weekly cohort and approximately 81% of patients in the 60mg every 4 week cohort achieved clinically significant reductions in Lp(a) levels bringing them below the recommended threshold of risk for CVD events (<50 mg/dL).
    • Treatment with AKCEA-APO(a)-LRx was associated with decreases in LDL-C, apoB, OxPL-apoB, OxPL-apo(a).
    • Most adverse events were mild.  The most frequent adverse events were injection site reactions (ISRs). ISRs occurred in 26% of patients and were mostly mild and one patient discontinued due to an ISR.
    • There were no safety concerns related to platelet counts, liver function or renal function.
    • No patient in the study experienced a confirmed platelet count below 100,000/mm3. The incidence of platelet levels below normal (140,000/mm3) was comparable between the active (10.5%) and placebo (14.9%) groups.
    • Approximately 90% of patients completed treatment and the rate of discontinuation was comparable between the active (12.1%) and placebo (14.9%) groups.
    Akcea and Novartis are now working to prepare for an end of Phase 2 meeting with FDA. We look forward to advancing this important development program into Phase 3.
  • • On September 24, 2018, Akcea Therapeutics announced positive topline results from a Phase 2 clinical study of AKCEA-APO(a)-LRx in patients with established cardiovascular disease (CVD) and elevated levels of lipoprotein(a), or Lp(a). Additional data from the Phase 2 study will be presented as a late-breaking clinical trial presentation at the American Heart Association Scientific Sessions in Chicago. The goal of the Phase 2 study was to characterize the safety and tolerability of AKCEA-APO(a)-LRx and to inform dose and dose frequency selection for the planned Phase 3 cardiovascular outcomes study. The randomized, double-blind, placebo-controlled, dose-ranging study included 286 patients with established CVD and high Lp(a) (baseline mean of approximately 100 mg/dL [250 nmol/L] – more than three times the upper limit of normal). All patients were treated for at least six months, with some patients treated up to one year. Results from the study show: Statistically significant dose-dependent reductions of Lp(a) compared to placebo at all dose levels, including low monthly doses of AKCEA-APO(a)-LRx. Most patients in the active group achieved Lp(a) reductions below the established threshold of risk for CVD events. Treatment emergent adverse events were balanced between the active and placebo groups. Most common adverse event was injection site reactions (ISRs). ISRs were mostly mild and occurred in a minority of patients. No patient in the study experienced a confirmed platelet level below 100,000/mm3. The incidence of platelet levels below normal (140,000/mm3) was comparable between the active (10.5%) and placebo (14.9%) groups. Approximately 90% of patients completed treatment and the rate of treatment discontinuation was comparable between the active and placebo groups.
  • • On February 7, 2018, Akcea Therapeutics announced it had completed enrollment of a Phase 2b clinical study of investigational drug AKCEA-APO(a)-LRx. Akcea is conducting the study in patients with high Lp(a) and established cardiovascular disease (CVD) to determine the dose level and frequency of administration for a future planned Phase 3 cardiovascular outcome study and to determine the safety and tolerability profile of AKCEA-APO(a)-LRx. The study enrolled over 270 patients with high Lp(a) and established cardiovascular disease
  • • On March 30, 2017, Akcea Therapeutics announced the initiation of a Phase 2b dose-ranging study of AKCEA-APO(a)-LRx in patients with hyperlipoproteinemia(a) and established cardiovascular disease. The goal of the study is to determine the dose level and frequency for use of AKCEA-APO(a)-LRx in a planned Phase 3 cardiovascular outcome study.
  • The randomized, double-blind, placebo-controlled, dose-ranging Phase 2b study will evaluate the safety and efficacy of different doses of AKCEA-APO(a)-LRx in approximately 270 patients with hyperlipoproteinemia(a) and established cardiovascular disease.
  • In a Phase 1/2 study with AKCEA-APO(a)-LRx in patients with elevated levels of Lp(a), significant and sustained reductions in Lp(a) of up to 97% were observed, with a mean reduction of 79% after only a single, small volume dose of AKCEA-APO(a)-LRx. With multiple doses of AKCEA-APO(a)-LRx, even greater reductions of Lp(a) of up to 99% were observed, with a mean reduction of 92%. AKCEA-APO(a)-LRx was generally safe and well tolerated in the study, which supported continued development. Out of 165 injections, there were no injection site reactions or flu-like symptoms reported.

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