A randomized double-blind, placebo-controlled, multicenter trial assessing the impact of lipoprotein (a) lowering with pelacarsen (TQJ230) on major cardiovascular events in patients with established cardiovascular disease (CVD).

Lipoprotein(a) [Lp(a)] is a lipoprotein in which the apolipoprotein B (apoB) component of lowdensity lipoprotein (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 are recognized as an independent risk factor for cardiovascular disease (CVD) (Kamstrup et al 2009, Nordestgaard et al 2010). Elevated baseline and on-statin Lp(a) were found 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 and medical societies, there is no specific drug treatment approved to reduce cardiovascular (CV) risk through lowering Lp(a) (Anderson et al 2016 Catapano et al 2016). Considering the magnitude of the CV risk born by patients with elevated Lp(a) it is imperative to develop new treatments which can address this unmet medical need. Such treatments should provide robust Lp(a) lowering as the clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration (Burgess et al 2018). Antisense oligonucleotides (ASOs) are emerging as therapeutic agents to treat disorders where overexpression of proteins is associated with a disease process. Apolipoprotein (a) is synthesized primarily in the liver, a target organ for ASOs, where it is subsequently covalently linked to the apoB-100 component of LDL to form the Lp(a) lipoprotein. The goal of treatment with pelacarsen (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 hypothesized that a pharmacologic reduction in Lp(a) could slow down or reverse cardiovascular disease by reducing 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 that TQJ230 is able to achieve dose-dependent reductions in Lp(a) level up to 75,1 mg/dL from a mean 99,3 mg/dL with the highest dose, 20 mg QW s.c. Treatment with pelacarsen (TQJ230) was also associated with dose-dependent statistically significant reductions in apoB, oxidized phospholipids (OxPL)-apo(a) and OxPL-apoB in all (aside from the lowest dose 20 mg Q4W) pelacarsen (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 endpoint analysis compared to pooled placebo for apoB, OxPL-apo(a), and OxPL-apoB, respectively. In conclusion, the efficacy data generated to date indicate that the drug is potent enough to improve CV outcomes in patients with elevated Lp(a). The most noteworthy safety finding with administration 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-related changes in platelet counts in humans at doses ranging from 20 mg Q4W to 20 mg QW (total dose ranging from 260 to 1040 mg) relative to placebo. The intensive monitoring of platelet counts in the Phase 2b study did not show a dose-response for a decrease in platelets and no patient had confirmed decrease in platelet count below 100,000/mm3. There was no imbalance in the incidence of any two occurrences of platelet counts < 140,000/mm3 between any of the individual pelacarsen (TQJ230) treatment groups or pooled pelacarsen (TQJ230) groups, and pooled placebo. There was no imbalance in the overall incidence of bleeding episodes. There were no clinically significant differences 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, pelacarsen (TQJ230) has shown an acceptable safety and tolerability profile to support further development in a phase 3 study. Additional details on the efficacy and safety of pelacarsen (TQJ230) are available in the Investigator Brochure (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 pelacarsen (TQJ230) 80 mg QM vs placebo reduces major adverse cardiovascular events (MACE) and characterize further the safety profile of the drug. See protocol 1 (p.21-22)

This study has been transitioned to CTIS with ID 2023-508292-37-00 check the CTIS register for the current data.

The study has two primary objectives addressing the same scientific hypothesis:
one in the full study population who is at a high risk of a CV event, and the
other one in a subpopulation expected to be at higher risk, i.e patients with
Lp(a) value >= 90 mg/dL. Successful achievement of the primary objectives
requires meeting one of the two, or both primary objectives. An independent
Clinical Endpoint Committee (CEC) will adjudicate all primary and secondary
endpoints. Definitions of all endpoints will be included in the CEC Charter and
Endpoints Manual, which will be provided to CEC and investigators, respectively.

See protocol 2 (p.22)

CTQJ230A12301 is a randomized, double- blind, parallel group,
placebo-controlled, multicenter study comparing pelacarsen (TQJ230) 80 mg s.c.
QM to placebo in subjects with established CVD as evidenced by history of
myocardial infarction, history of ischemic stroke or symptomatic peripheral
artery disease (PAD) and elevated levels of Lp(a). Recruitment will target
approximately 30% of randomized subjects to have had index myocardial
infarction (Section 5.1) between >= 3 month and approximately 12 months prior to
Randomization.
The study consists of a screening period of approximately 30 days, followed by
a period of CV risk factor therapy optimization of approximately 30-90 days, if
required, and a double-blind treatment period. The minimum follow-up in
double-blind period is required to be 2.5 years,
the overall trial duration is expected to be approximately 4.25 years during
which 993 primary endpoint events are expected to accumulate (Figure 3-1). The
study will end when either 993 CEC confirmed primary CV events have accumulated
or all subjects have had at least 2.5 years of follow-up time - whatever comes
later.

See protocol 3 (p.24-25)

Subjects will be randomized 1:1 to administer subcutaneous injections of
pelacarsen (TQJ230) 80 mg or placebo QM. Injections will be self-injected or
administered by a caregiver with the injection device TQJ230 Needle Safety
Device (NSD), or by the study site personnel. For details on how
injections should be performed, please refer to Section 6.7.2. Instructions for
prescribing and taking the study treatment.

See protocol 6 (p.33)

The risk of developing thrombocytopenia was identified during administration of pelacarsen (TQJ230) or similar ASOs in nonclinical studies. However, exposure to pelacarsen) (TQJ230) for up to 12 months in the phase 2b study and intensive monitoring of platelet count did not show any confirmed decrease in platelets below 100,000/mm3, nor was there an imbalance in the incidence of any two occurrences of platelet counts < 140,000/mm3 between pelacarsen (TQJ230) treatment groups, including the highest dose pelacarsen (TQJ230) 20 mg QW, and pooled placebo. While 80 mg QM was not directly evaluated in the phase 2b study (20mg QW was evaluated), it is re-assuring that safety margins for the exposure to pelacarsen (TQJ230) 80 mg QM are well below the NOAEL in chronic monkey studies (Section 4.2). To ensure that regular follow-up is performed during the initial period after initiation of treatment with the study drug, platelet count will be monitored on monthly intervals during the first 6 months. This will be followed by monitoring every 3 months up to the end of year 2, and every 6 months thereafter up to the end of the study. If thrombocytopenia occurs, and depending on its severity and/or occurence of bleeding events, respective rules for individual dose interruptions or permanent drug discontinuation are defined (Table 6-3), and possible treatment of severe events is recommended in Section 6.6.2. An independent Data Monitoring Committee (DMC) will review the safety data periodically, including changes in platelet counts and bleeding episodes, and can suggest changes in the frequency of platelet monitoring. Local injection site reactions, local erythema and bruising, were reported in the phase 2b study; however only one patient discontinued treatment due to this. To minimize the impact of frequent injections, patients in study CTQJ230A12301 will inject study drug every month. In case such events occur, possible treatment is recommended in Section 6.6.2. Specific dose-limiting toxicity definitions concerning the potential risks of liver events, and flu-like reactions, with guidance for required follow-up and discontinuation of study drug, are included in this protocol (Table 6-3). Immunogenicity responses were observed in the phase 2b study, in which among 239 subjects treated with pelacarsen, 100 (41.8%) subjects tested positive for ADA, 137 (57.3%) subjects tested negative, and 2 (0.8%) subjects were unknown. The incidence of ADA was observed to be dose-dependent. The median time of onset was 1 to 3 months, with no clear relationship to dose. The phase 2b data does not suggest a potential issue with ADA as the presence of ADA had minimal impact on steady-state PK parameters and was not associated with loss of efficacy or increases of safety findings. For detailed information on immunogenicity, please consult the most recent version of the Investigator*s Brochure. The long-term effect of ADA will be evaluated in this protocol in the ADA sub-study (Section 8.5.2). Hypersensitivity, including anaphylaxis to the study drug, has been reported during this ongoing study (CTQJ230A12301) and is established as an important identified risk. In case a hypersensitivity reaction occurs, guidance for its handling and management are provided in Section 6.5.2, Table 6-3, Section 6.6.2, Section 6.7.2.2 and subject*s updated informed consent form (ICF). Guidance for prophylaxis and management of specific adverse events (AEs) are provided in Section 6.6.2. For detailed information about potential and identified safety risk please consult the most recent version of the Investigator*s Brochure. Women of child-bearing potential must be informed that taking the study treatment may involve unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order to participate in the study they must adhere to the contraception requirements outlined in the exclusion criteria. If there is any question that the subject will not reliably comply, they should not be entered or continue in the study. The benefit a patient might have by participating in the study is the close monitoring of their condition and optimization of treatment of known risk factors during the full duration of the study. In general, the risk to subjects in this trial may be minimized by compliance with the eligibility criteria and study procedures, close clinical monitoring, as well as periodic review of all safety data by an independent DMC. While patients with underlying CV disease have an increased risk for unfavorable outcomes (e.g. respiratory failure, death) after contracting COVID-19, the risk of being exposed to SARSCoV-2 can be mitigated, if the measures recommended or enforced by national and/or local authorities are followed. It is considered, that if the study level and the population- level requirements are followed, the pandemics-related risk of a patient participating in the study should not exceed the risk of a patient with a similar condition not participating in the study.