PCSK9 Inhibition for HIV-Related Cardiovascular Risk

(EPIC-HIV Trial)

Overseen By Priscilla Hsue, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of California, San Francisco

Must be taking: Statins

Must not be taking: Insulin

Disqualifiers: Cancer, Heart failure, Alcoholism, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

140 Participants Needed

Trial Summary

What is the purpose of this trial?

Atherosclerosis in the setting of HIV infection is distinct and includes increased vascular inflammation, worsened endothelial function, and a predominance of non-calcified plaque. These outcomes can be assessed using specialized noninvasive imaging which strongly predict future CV events in the general population. PCSK9 has emerged as an important pharmacologic target for cholesterol lowering in the general population and recent studies among individuals without HIV have shown that PCSK9 inhibitor therapy is safely tolerated and significantly reduces major CV events in the general population. The investigators will perform a clinical trial of PCSK9 inhibition in the setting of HIV infection. This will be a randomized, placebo-controlled study to evaluate the effects of PCSK9 inhibition on vascular inflammation, endothelial function, and non-calcified plaque using a PCSK9 inhibitor called alirocumab. This study will recruit 140 treated individuals with HIV who are aged 40 and older, with known CVD or risk factors for CVD and who have evidence of vascular inflammation at baseline. The primary and secondary objective of this study is to determine whether PCSK9 inhibition can improve arterial inflammation as assessed by FDG-PET/CT and endothelial function as assessed by flow mediated vasodilation. The investigators will correlate changes in arterial inflammation and endothelial function with lipids and markers of inflammation and immune activation. The tertiary objective is to perform a pilot evaluation of the impact of PCSK9 inhibition on non-calcified plaque as measured by coronary CT angiography. Non-calcified plaque measurements will be correlated with changes in lipid parameters and markers of inflammation and immune activation.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you should not change your lipid-lowering or blood pressure medications within 90 days before starting the study or during the study. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drug Alirocumab for reducing cardiovascular risk in patients with HIV?

Alirocumab, a drug that lowers bad cholesterol (LDL-C), has been shown to reduce major heart-related events and death in people with high cholesterol, as seen in the ODYSSEY OUTCOMES trial. This suggests it could help reduce heart risks in people with HIV, who often have higher cholesterol levels. ^{1 2 3 4 5}

Is Alirocumab (Praluent) safe for humans?

Alirocumab, also known as Praluent, has been shown to have a safety profile generally comparable to a placebo in clinical trials, meaning it is generally safe for humans. It has been evaluated in multiple studies, including 16 Phase III trials, and is used to lower cholesterol levels. ^{2 3 4 6 7}

How is the drug Alirocumab unique for HIV-related cardiovascular risk?

Alirocumab is unique because it is a monoclonal antibody that targets PCSK9, a protein involved in cholesterol metabolism, and is administered via injection. This drug is particularly novel for HIV-related cardiovascular risk as it addresses elevated cholesterol levels, which are often higher in people living with HIV, potentially reducing cardiovascular events. ^{4 6 7 8 9}

Research Team

Priscilla Hsue, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for men and women over 40 with HIV, on stable antiretroviral therapy (ART) for at least 12 weeks, who have cardiovascular disease (CVD) or are at risk. They should not have had recent changes in heart or cholesterol medications, severe heart failure, uncontrolled blood pressure, certain medical conditions including recent cancer, or be pregnant. Participants must also have controlled HIV viral loads and meet specific criteria for cholesterol levels.

Inclusion Criteria

You have a certain number of CD4 T cells in your blood.

Your cholesterol and other fat levels will be checked before you can join the study.

Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study

Exclusion Criteria

I plan to change my HIV treatment within the next year.

Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Regeneron employees

I cannot receive injections, either by myself or from someone else.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive alirocumab or placebo every two weeks, with dose adjustments based on LDL-C levels

52 weeks

Bi-weekly visits for administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Alirocumab

Trial Overview The EPIC-HIV Study tests whether a drug called alirocumab can reduce vascular inflammation and improve endothelial function in people with treated HIV infection compared to a placebo. The study will use advanced imaging techniques to assess the effects of PCSK9 inhibition on arterial inflammation and non-calcified plaque in participants' arteries.

Participant Groups

Group I: Alirocumab Experimental Treatment 1 Intervention

Patients randomized into the alirocumab arm will start off with 75 mg alirocumab administered every two weeks for two doses and will be upwardly titrated to 150 mg alirocumab if subjects demonstrate LDL ≥ 50 mg/dL at week 4. Subjects demonstrating LDL-C \<50mg/dl will remain on the same 75mg dose throughout the trial.

Group II: Placebo Placebo Group 1 Intervention

Patients randomized into the placebo arm will receive 75 mg or 150 mg or placebo administered once every two weeks throughout the trial

Alirocumab is already approved in European Union, United States for the following indications:

Approved in European Union as Praluent for:

• High cholesterol - Familial Homozygous
• Cardiovascular Risk Reduction
• High cholesterol - Familial Heterozygous
• High Cholesterol

Approved in United States as Praluent for:

• High cholesterol - Familial Homozygous
• Cardiovascular Risk Reduction
• High cholesterol - Familial Heterozygous
• Primary hyperlipidemia

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Massachusetts General Hospital

Collaborator

Trials

3,066

Recruited

13,430,000+

Findings from Research

The BEIJERINCK study is a randomized, double-blind, placebo-controlled trial involving 464 people living with HIV and hypercholesterolemia, assessing the safety and efficacy of evolocumab, a PCSK9 inhibitor, in lowering LDL cholesterol levels.

This study is significant as it targets a high-risk population for atherosclerotic cardiovascular disease, with many participants unable to tolerate high-intensity statins, thus exploring a new treatment option for managing cholesterol in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolocumab treatment in patients with HIV and hypercholesterolemia/mixed dyslipidemia: BEIJERINCK study design and baseline characteristics. Boccara, F., Kumar, P., Caramelli, B., et al.[2021]

Alirocumab (Praluent) is the first drug in a new class of medications known as PCSK9 inhibitors, which are designed to lower cholesterol levels in the blood.

This innovative treatment offers a new option for patients who need additional cholesterol management beyond traditional therapies, potentially improving cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alirocumab (Praluent): First in the New Class of PCSK9 Inhibitors. Manniello, M., Pisano, M.[2020]

In the ODYSSEY OUTCOMES trial involving 18,924 patients with acute coronary syndrome, a high polygenic risk score (PRS) for coronary artery disease (CAD) was linked to a significantly higher incidence of major adverse cardiovascular events (MACE), independent of baseline LDL cholesterol levels and other risk factors.

Patients with a high PRS for CAD experienced a greater benefit from alirocumab treatment, showing a 6.0% absolute reduction in MACE compared to 1.5% in those with a lower PRS, highlighting the potential of using PRS for personalized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial. Damask, A., Steg, PG., Schwartz, GG., et al.[2021]

Alirocumab, a PCSK9 inhibitor, has been approved by the US FDA and can lower LDL cholesterol levels by 45-62%, demonstrating significant efficacy in lipid management.

The safety profile of alirocumab is generally comparable to that of a placebo, indicating it is a safe option for patients needing cholesterol reduction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alirocumab for hyperlipidemia: ODYSSEY Phase III clinical trial results and US FDA approval indications. Roth, EM.[2019]

Evolocumab consistently reduced low-density lipoprotein cholesterol (LDL-C) levels by approximately 56% over a 5-year period, demonstrating its long-term efficacy in managing hypercholesterolemia in patients.

The safety profile of evolocumab was comparable to standard care, with yearly serious adverse event rates similar to those in the control group, and no neutralizing antibodies were detected, indicating a favorable tolerance over the extended treatment duration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Efficacy and Safety of Evolocumab in Patients With Hypercholesterolemia. Koren, MJ., Sabatine, MS., Giugliano, RP., et al.[2020]

In a pooled analysis of 10 ODYSSEY phase III trials involving participants with hypercholesterolaemia, alirocumab significantly reduced LDL cholesterol levels by 44.0-61.8% in those with prediabetes and 45.8-59.5% in those with normoglycaemia over a follow-up period of 24-104 weeks.

Alirocumab did not affect blood sugar levels (HbA1c or fasting plasma glucose) in either group, indicating it is safe for use in individuals with prediabetes, and its safety profile was comparable to that of control treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of alirocumab in people with prediabetes vs those with normoglycaemia at baseline: a pooled analysis of 10 phase III ODYSSEY clinical trials. Leiter, LA., Müller-Wieland, D., Baccara-Dinet, MT., et al.[2022]

A single subcutaneous injection of alirocumab 75 mg was well tolerated and showed similar pharmacokinetics and pharmacodynamics regardless of whether it was injected into the abdomen, upper arm, or thigh, based on a study involving 60 healthy subjects.

All injection sites effectively reduced LDL-C levels, with mean percentage reductions of 48.4% (abdomen), 39.5% (upper arm), and 45.6% (thigh) by Day 15, indicating that the injection site does not significantly impact the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized study of the relative pharmacokinetics, pharmacodynamics, and safety of alirocumab, a fully human monoclonal antibody to PCSK9, after single subcutaneous administration at three different injection sites in healthy subjects. Lunven, C., Paehler, T., Poitiers, F., et al.[2021]

Alirocumab, administered in single doses of 75, 150, and 300 mg, was found to be safe and well-tolerated in a study of 35 healthy Chinese subjects, with only mild adverse events reported, such as nasal congestion and injection-site reactions.

The treatment led to significant reductions in LDL cholesterol levels, with maximum reductions of 55.3%, 63.7%, and 73.7% observed at different doses, demonstrating its efficacy in lowering cholesterol similar to results seen in other populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alirocumab in Healthy Chinese Subjects: A Randomized, Double-Blind, Placebo-Controlled, Ascending Single-Dose Study. Li, H., Wei, Y., Yang, Z., et al.[2021]

In a study involving 80 HIV-positive individuals and 40 uninfected controls, baseline levels of PCSK9 were significantly higher in people living with HIV, correlating with HIV-1 RNA levels and CD4 T-cell counts.

Initiating antiretroviral therapy (ART) led to significant reductions in PCSK9 and inflammation markers, but PCSK9 levels remained elevated compared to uninfected controls, indicating ongoing dysregulation in cholesterol metabolism despite treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of antiretroviral therapy on proprotein convertase subtilisin/kexin 9: focus on lipids, inflammation and immunovirological parameters. Bianconi, V., Schiaroli, E., Pirro, M., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Evolocumab treatment in patients with HIV and hypercholesterolemia/mixed dyslipidemia: BEIJERINCK study design and baseline characteristics. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Alirocumab (Praluent): First in the New Class of PCSK9 Inhibitors. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Alirocumab for hyperlipidemia: ODYSSEY Phase III clinical trial results and US FDA approval indications. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Long-Term Efficacy and Safety of Evolocumab in Patients With Hypercholesterolemia. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of alirocumab in people with prediabetes vs those with normoglycaemia at baseline: a pooled analysis of 10 phase III ODYSSEY clinical trials. [2022]

7. England pubmed.ncbi.nlm.nih.gov

A randomized study of the relative pharmacokinetics, pharmacodynamics, and safety of alirocumab, a fully human monoclonal antibody to PCSK9, after single subcutaneous administration at three different injection sites in healthy subjects. [2021]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alirocumab in Healthy Chinese Subjects: A Randomized, Double-Blind, Placebo-Controlled, Ascending Single-Dose Study. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Effects of antiretroviral therapy on proprotein convertase subtilisin/kexin 9: focus on lipids, inflammation and immunovirological parameters. [2021]