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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called alirocumab (a PCSK9 inhibitor) to determine if it can reduce heart risks in people living with HIV. Researchers aim to discover if this drug can improve blood vessel health and reduce inflammation, common issues for people with HIV. Participants will receive either alirocumab or a placebo to compare effects. People with HIV who have heart disease or risk factors like high cholesterol or hypertension (high blood pressure) and signs of artery inflammation might be suitable candidates. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that alirocumab, a type of medication, is generally safe for people. In past studies, most participants experienced only mild side effects, such as minor skin irritations at the injection site.

Current research indicates no major safety concerns with alirocumab. Studies on individuals without HIV have shown that it significantly lowers cholesterol and reduces heart-related risks. While alirocumab is approved for lowering cholesterol, this study specifically examines its potential benefits for heart health in people with HIV.

Overall, the treatment has been well-tolerated by the general population, which is encouraging for its use in this study focused on HIV. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for managing HIV-related cardiovascular risk, which typically focus on antiretroviral therapy and lifestyle changes, alirocumab offers a novel approach by directly targeting PCSK9, a protein that affects cholesterol levels. This mechanism allows alirocumab to effectively reduce LDL cholesterol, offering a potential advantage for HIV patients who often face higher cardiovascular risks. Researchers are excited about alirocumab because it provides a tailored solution to lowering cholesterol in a population with unique health challenges, potentially leading to better heart health outcomes.

What evidence suggests that PCSK9 inhibition might be an effective treatment for HIV-related cardiovascular risk?

Studies have shown that PCSK9 inhibitors, such as alirocumab, can significantly lower LDL cholesterol, often referred to as "bad" cholesterol. In individuals with a high genetic risk for heart disease, alirocumab reduced major heart-related problems by 6%. For those with HIV, who face higher risks of heart disease, PCSK9 inhibitors have effectively lowered these risks. In this trial, participants will be randomized to receive either alirocumab or a placebo. When combined with statins, alirocumab reduces LDL cholesterol levels more effectively than increasing the statin dose alone. These findings suggest that alirocumab could help manage heart disease risks in people with HIV. ^{1 2 4 6 7}

Who Is on the Research Team?

Priscilla Hsue, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03207945

Effect of PCSK9 Inhibition on Cardiovascular Risk in ... Individuals with HIV have higher rates of coronary events compared to controls even in the setting of treated and suppressed disease and a growing body of ...

2. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT03207945

Effect of PCSK9 Inhibition on Cardiovascular Risk in Treated ... Recently, addition of evolocumab was found to result in a greater decrease in percent atheroma volume using intravascular ultrasound. All of ...

3. withpower.com withpower.com/trial/phase-3-hiv-infections-3-2018-75767

PCSK9 Inhibition for HIV-Related Cardiovascular Risk 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 ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9562883/

PCSK9 Inhibition: From Current Advances to Evolving Future In addition, alirocumab in combination with statins showed a significant reduction in LDL-C compared with patients who were given double the dose of statins ...

5. academic.oup.com academic.oup.com/eurheartj/article/45/Supplement_1/ehae666.2841/7837170

PCSK9 inhibitors in HIV patients with dyslipidemia The outcomes were mortality, myocardial infarction, heart failure and stroke. Results. A total of 485 patients were included in the study. PCSK9 ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0753332222013464

Review Safety of PCSK9 inhibitors Alirocumab was associated with a 27% increased risk of injection site reaction compared with evolocumab. However, there were no significant differences in terms ...

7. jacc.org jacc.org/doi/10.1016/j.jacc.2020.03.062

Safety of Evolocumab in People Living With HIV Infection No major safety concerns were identified, and LDL-C was reduced by 57%, which was consistent with previous PCSK9 inhibitor trials in patients ...