Principal Investigator: Peter Tekiela
Keywords: Stroke , lipoprotein (a) , TQJ230 , pelacarsen , cardiovascular disease Department: Neurology
IRB Number: 00137034 Co Investigator: Adam  DeHavenon
Specialty: Cardiology, Neurology
Sub Specialties: Heart Failure, Stroke
Recruitment Status: Recruiting

Contact Information

Theodore Rock
theodore.rock@hsc.utah.edu
801-585-0541

Simple Summary

Study TQJ230A12301 is a pivotal phase 3 study designed to test the hypothesis that treatmentwith pelacarsen (TQJ230) 80 mg s.c QM will significantly reduce the risk of MACE, i.e. CVdeaths, non-fatal myocardial infarction (MI), non-fatal stroke and urgent coronary revascularizationin patients with established CVD and elevated levels of Lp(a) who are treatedfor CV risk factors other than Lp(a) according to local practice/guidelines for the reduction ofcardiovascular risk in patients with established CVD and elevated Lp(a).

Detailed Description

1 Introduction1.1 BackgroundLipoprotein(a) [Lp(a)] is a lipoprotein in which the apolipoprotein B (apoB) component of lowdensitylipoprotein (LDL) is linked by a disulfide bond to apolipoprotein(a) (apo[a])(Willeit et al 2018). Its level in humans is genetically determined and elevated levels arerecognized as an independent risk factor for cardiovascular disease (CVD)(Kamstrup et al 2009, Nordestgaard et al 2010). Elevated baseline and on-statin Lp(a) werefound to be independently and approximately linearly related with CVD risk, with 31% to 43%,respectively, increased risk for patients with Lp(a) 50 mg/dL or higher (Willeit et al 2018).Although screening for elevated Lp(a) is currently recommended by several scientific andmedical societies, there is no specific drug treatment approved to reduce cardiovascular (CV)risk through lowering Lp(a) (Anderson et al 2016; Mach et al, 2020). Considering themagnitude of the CV risk born by patients with elevated Lp(a) it is imperative to develop newtreatments which can address this unmet medical need. Such treatments should provide robustLp(a) lowering as the clinical benefit of lowering Lp(a) is likely to be proportional to theabsolute reduction in Lp(a) concentration (Burgess et al 2018).Antisense oligonucleotides (ASOs) are emerging as therapeutic agents to treat disorders whereoverexpression of proteins is associated with a disease process. Apolipoprotein (a) issynthesized primarily in the liver, a target organ for ASOs, where it is subsequently covalentlylinked to the apoB-100 component of LDL to form the Lp(a) lipoprotein. The goal of treatmentwith TQJ230 is to reduce the production of apo(a) in the liver and thus, the level of Lp(a)lipoprotein, by using an ASO directed against the mRNA of apo(a). It has been hypothesizedthat a pharmacologic reduction in Lp(a) could slow down or reverse cardiovascular disease byreducing the thrombotic, atherogenic, or inflammatory effects of elevated Lp(a) levels(Nordestgaard et al 2010). The results from the Phase 2 dose-response study indicate thatTQJ230 is able to achieve dose-dependent reductions in Lp(a) level up to 75.1 mg/dL from amean 99.3 mg/dL with the highest dose, 20 mg QW s.c. Treatment with TQJ230 was alsoassociated with dose-dependent statistically significant reductions in apoB, oxidizedphospholipids (OxPL)-apo(a) and OxPL-apoB in all (aside from the lowest dose 20 mg Q4W)TQJ230-treated cohorts, compared to pooled placebo group. The most efficacious cohort,20 mg QW, achieved 24%, 62%, and 89% decrease from baseline at the primary endpointanalysis compared to pooled placebo for apoB, OxPL-apo(a), and OxPL-apoB, respectively. Inconclusion, the efficacy data generated to date indicate that the drug is potent enough to improveCV outcomes in patients with elevated Lp(a). The most noteworthy safety finding withadministration of TQJ230 or similar ASOs in nonclinical studies was thrombocytopenia(Henry et al 2017). In the Phase 2 program, there were no clinically meaningful TQJ230-relatedchanges in platelet counts in humans at doses ranging from 20 mg Q4W to 20 mg QW (totaldose ranging from 260 to 1040 mg) relative to placebo. The intensive monitoring of plateletcounts in the Phase 2b study did not show a dose-response for a decrease in platelets and nopatient had confirmed decrease in platelet count below 100,000/mm3. There was no imbalancein the incidence of any two occurrences of platelet counts < 140,000/mm3 between any of theindividual TQJ230 treatment groups or pooled TQJ230 groups, and pooled placebo. There wasno imbalance in the overall incidence of bleeding episodes. There were no clinically significantdifferences in the incidence of liver function tests (LFTs) increases, mean serum creatinine or eGFR over time between treatment groups in the Phase 2b study. Overall, TQJ230 has shownan acceptable safety and tolerability profile to support further development in a phase 3 study.Additional details on the efficacy and safety of TQJ230 are available in the InvestigatorBrochure (IB). Rationale for the selected dose, 80 mg s.c. QM is provided in Section 4.2.Study TQJ230A12301 is planned to investigate if treatment with TQJ230 80 mg QM vs placeboreduces major adverse cardiovascular events (MACE) and characterize further the safety profileof the drug.1.2 PurposeStudy TQJ230A12301 is a pivotal phase 3 study designed to test the hypothesis that treatmentwith TQJ230 80 mg s.c QM will significantly reduce the risk of MACE, i.e. CV deaths, nonfatalmyocardial infarction (MI), non-fatal stroke and urgent coronary re-vascularization inpatients with established CVD and elevated levels of Lp(a) who are treated for CV risk factorsother than Lp(a) according to local guidelines for the reduction of cardiovascular risk in patientswith established CVD and elevated Lp(a).

Inclusion Criteria

Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female 18 to ≤ 80 years of age
3. Lp(a) ≥ 70 mg/dL at the screening visit, measured at the Central laboratory
4. LDL-cholesterol lowering treatment at Randomization as follows:
 subjects must be on an optimal LDL-C lowering treatment to meet the target LDL-C
level according to local practice/guidelines, or
 if subjects do not meet the target LDL-C level according to local practice/guidelines,
they should be treated with the highest tolerated doses of statins and/or with other
optimized LDL-lowering therapy (e.g. ezetimibe, cholesterol absorption inhibitor,
fibrate, PCSK9 inhibitor, bempedoic acid), or
 if subjects have a contraindication or do not tolerate statin treatment, they must be
treated with other optimized LDL-lowering therapy (e.g. ezetimibe, cholesterol
absorption inhibitor, fibrate, PCSK9 inhibitor, bempedoic acid) according to local
practice/guidelines
5. At the randomization visit subjects must be optimally treated for other CV risk factors
according to local practice/guidelines

Established CV disease defined as ANY of the following three conditions:
1. History of spontaneous myocardial infarction (not resulting from PCI or CABG)
having occurred in the period ≥ 3 months from screening and randomization visits to
≤ 10 years prior to the screening visit and documented as follows
(Thygesen et al 2019):
 Acute MI (hospitalization records): requires documentation of a rise and/or fall of
cardiac biomarkers (preferably cardiac troponin) with at least one value above the
99th percentile of the upper reference limit (URL) and at least one of the following :
 Symptoms of ischemia
 ECG changes indicative of acute myocardial ischemia (new ST-T changes or new
LBBB; please see Appendix 2 for ST and T-wave changes)
 Development of pathological Q waves (please see Appendix 2 for definitions of
pathological Q waves)
 Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality in a pattern consistent with an ischemic etiology
 Identification of a coronary thrombus by angiography including intracoronary
imaging
 Prior MI (no complete hospital records for acute event available): requires
documentation of any one of the following :
 Pathological Q waves (please see Appendix 2 for definitions of pathological Q
waves), with or without symptoms, in the absence of a non-ischemic cause
 Imaging evidence of a region of loss of viable myocardium or regional wall
motion abnormality in a pattern consistent with an ischemic etiology
2. History of ischemic stroke (an acute episode of focal cerebral, spinal, or visual
dysfunction caused by infarction of central nervous system tissue) having occurred in
the period ≥ 3 months from screening and randomization visits to ≤ 10 years prior to
the screening visit documented by CT scan, MRI or other visualization method.
Transient ischemic attack or embolic stroke (not of atherosclerotic origin) are not
qualifying events.
3. Clinically significant symptomatic peripheral artery disease, evidenced by intermittent
claudication with an ankle-brachial index ≤ 0.90 and/or limb amputation or revascularization
due to lower limb ischemia. Thromboangiitis obliterans is not a
qualifying event.

Exclusion Criteria

Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) ≥ 160 mmHg
and/ or diastolic blood pressure (DBP) ≥ 100 mmHg (mean of 3 measurements for each
SBP and DBP assessment) at the Screening visit.
2. Treatment with niacin ≥ 2000 mg (2 g) daily in the 3 months before the screening visit;
niacin in multi-vitamins is allowed
3. Treatment with stable dose of a PCSK9 inhibitor (evolocumab, alirocumab) for less than
12 weeks before Randomization

4. Current treatment with lipoprotein apheresis, or already planned to start lipoprotein
apheresis during the study
5. Within 3 months of screening and between Screening visit and Randomization visit (Day
1): myocardial infarction, stroke, coronary or lower limb re-vascularization, major cardiac
or non-cardiac surgery. The subjects can be re-screened 3 months after the relevant
event/procedure.
6. Planned or expected cardiac, cerebrovascular or peripheral artery surgery or coronary revascularization
after Randomization visit (Day 1)
7. Heart failure New York Heart Association (NYHA) class IV at Screening visit or
at Randomization visit (Day 1)
8. History of hemorrhagic stroke or other major bleeding, or if occurring between Screening
visit and Randomization visit
9. Severe concomitant non-CV disease that is expected to reduce life expectancy to less
than 5 years, at Screening visit or at Randomization visit (Day 1)
10. Known active severe infection or major hematologic, metabolic, gastrointestinal or
endocrine dysfunction (e.g. uncontrolled thyroid dysfunction or uncontrolled diabetes
mellitus) in the judgment of the investigator, at Screening visit or at Randomization
visit (Day 1)
11. History of malignancy of any organ system (other than localized basal cell carcinoma or
squamous cell carcinoma of the skin, or in situ cervical cancer), treated or untreated,
within the past 5 years, or if diagnosed between Screening visit and Randomization visit
(Day 1), regardless of whether there is evidence of local recurrence or metastases.
12. Platelet count <140,000 per mm3 from central laboratory test at Visit 1 or at a CV risk
factor optimization visit, confirmed by a second central laboratory test prior to the
Randomization visit (Day 1)
13. eGFR ≤ 30 mL/min/1.73m2 from central laboratory test at Visit 1 or at a CV risk factor
optimization visit, confirmed by a second central laboratory test prior to the
Randomization visit (Day 1); or patient on dialysis
14. Significant glomerular disease (including but not limited to IgA nephropathy, diabetic
nephropathy, systemic lupus erythematosus, etc.) with urinary protein-creatinine ratio
(PCR) > 500 mg/g (50 mg/mmol) at Visit 1 or at a CV risk factor optimization visit,
confirmed by a second central laboratory test prior to the Randomization visit (Day 1)
15. Active liver disease or hepatic dysfunction, defined as AST or ALT ≥ 2 times the
ULN from central laboratory test at Visit 1 or at a CV risk factor optimization
visit, confirmed by a second central laboratory test prior to the Randomization visit (Day
1)
16. Total bilirubin ≥ 1.5 times the ULN from central laboratory test at Visit 1 or at a CV risk
factor optimization visit, confirmed by a second central laboratory test prior to the
Randomization visit (Day 1)
17. Positive HIV, Hepatitis C screening or Hepatitis B Surface Antigen tests from central
laboratory test at Screening visit
18. Any other conditions, at Screening visit or between Screening visit and Randomization
visit (Day 1), which in the opinion of the Investigator would make the patient unsuitable
for inclusion, or could interfere with the patient participating in or completing the study 19. Treatment with an oligonucleotide or SiRNA within 9 months of screening visit.
Exceptions are GalNac oligonucleotide or GalNac siRNA which can be used if approved
by health authorities and if allowed for use in the study by the Sponsor.
20. History of hypersensitivity to the study drug or their excipients or to drugs of similar
chemical classes
21. Use of other investigational drugs within 5 half-lives of Screening visit, or within 30 days,
whichever is longer
22. Unwillingness or inability (e.g. physical or cognitive) to comply with study procedures
and medication administration (injections) and schedule
23. Pregnant or nursing (lactating) women
24. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and 16 weeks after the last dose of the investigational drug. Such methods
include:
 Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception
 Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before
taking study treatment. In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment
 Male sterilization (at least 6 months prior to screening). For female subjects on the
study, the vasectomized male partner should be the sole partner for that subject
 Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of
contraception or placement of an intrauterine device (IUD) or intrauterine system
(IUS), or other forms of hormonal contraception that have comparable efficacy
(failure rate <1%), for example hormone vaginal ring or transdermal hormone
contraception
In case of use of oral contraception women should have been stable on the same pill for a
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age,
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with
or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago.
In the case of oophorectomy alone, only when the reproductive status of the woman has been
confirmed by follow up hormone level assessment is she considered not of child-bearing
potential.
If local regulations deviate from the contraception methods listed above to prevent pregnancy,
local regulations apply and will be described in the Informed consent form (ICF).

Participant Reimbursement

If all 20 study in-person visits are completed, the maximum total received is $1000, $50 per visit.