apollo trial

1. APOLLO TRIAL
Single Ascending Dose Study of a Short Interfering RNA Targeting
Lipoprotein(a) Production in Individual with Elevated Plasma
Lipoprotein(a) Levels

3. INTRODUCTION:
• Patients with Lp(a) concentrations in the highest decile (approximately 350
nmol/L) have a lifetime risk of cardiovascular disease equivalent to those with
familial hypercholesterolemia.
• Elevated levels of Lp(a) also have been associated with aortic valve calcification,
development and more rapid progression of aortic stenosis, and a higher rate of
aortic valve replacement.
• Although some therapies have moderate Lp(a)-lowering effects, such as
administration of niacin or PCSK9 inhibitors, currently no drug treatments for
elevated Lp(a) concentrations have received regulatory approval.

4. • The LPA gene encodes for apolipoprotein(a) (apo[a]), a dominant and a rate-
limiting component in the hepatic synthesis of the Lp(a) particle.
• The current study examined a strategy to lowering Lp(a) using SLN360, a short
interfering RNA (siRNA) to target LPA messenger RNA. SLN360 is a 19-mer
siRNA covalently linked to a triantennary N-acetyl-galactosamine (GalNAc)
moiety.
• The tolerability of SLN360 following a single dose and measured Lp(a)
concentrations to a maximum of 150 days following administration are evaluated.

6. INCLUSION CRITERIA:
• Adults aged 18 years or older with no known atherosclerotic cardiovascular
disease, an Lp(a) concentration of 150 nmol/L or greater (approximately >60
mg/dL), and a body mass index of 18 to 45.
• Individuals of childbearing potential were required to have a negative serum
pregnancy test result at screening and a negative urine pregnancy test result 1
day prior to treatment.
• All participants (male and female) agreed to adhere to contraception
requirements from the beginning of the screening period until 3 months after the
last administration of study drug.
• Participants were required to have a hemoglobin A1c of less than 6.5% if not
diagnosed previously as having diabetes or less than 8.5% if known to have
diabetes.

7. EXCLUSION CRITERIA:
• Moderate or severe hepatic cirrhosis, a positive test result for HIV or hepatitis B
or C virus, or other liver disease that could increase the risk of drug-induced liver
injury or influence the pharmacology of SLN360.
• platelet count below the lower limit of normal or an alanine aminotransferase
(ALT) or aspartate aminotransferase (AST) more than 1.5 times the upper limit of
normal.
• Patients on Medications that could influence Lp(a) levels required doses to be
stable for at least 8 weeks prior to enrollment, including antiestrogen or estrogen
receptor modulators, PCSK9 inhibitors, prescription-dose niacin, fibrates, statins,
or ezetimibe.
• Participants who received any other investigational agent within 90 days (or 10
half-lives, whichever was longer) or other oligonucleotide therapy within
12months before.
• Clinically significant illness within 7 days before the first dose of study drug, a
positive nucleic acid test result for SARS-CoV-2.

9. • Participants had scheduled visits at days 7, 14, 30, 45, 60, 90, and 150 following drug
administration

10. PRIMARY OUTCOME:
• Because this is a first-in-human study, the safety and tolerability of SLN360 were
defined as a primary outcome of interest:
• changes in vital signs, physical examination,
• electrocardiography, and
• laboratory assessments of chemistry, hematology, urinalysis, and coagulation
parameters.
• adverse events of special interest, which included injection site adverse
events or any identified dose-limiting toxicity.

11. SECONDARY OUTCOME:
• Plasma Lp(a) concentrations from baseline to 150 days following dosing.
• assessment of changes in lipid parameters (lowdensity lipoprotein, high-density
lipoprotein, and total cholesterol and triglycerides).
• plasma pharmacokinetics of SLN360 following administration (maximum
concentration, time to maximum concentration, and area under the curve to last
measurable concentration).
• A post hoc analysis examined Lp(a) concentration changes at 150 days following
drug administration.

19. CONCLUSIONS:
• In this phase 1 study of 32 participants with elevated Lp(a) levels and no known
cardiovascular disease, the siRNA SLN360 was well tolerated.
• Subcutaneous injection of an siRNA (SLN360) targeting mRNA for the LPAgene lowered
lipoprotein(a) up to 98%.
• >70% and >80% reductions in Lp(a) persisted for 150 days after the 300 mg and 600 mg
doses.
• The highest doses reduced LDL-C and ApoB by 20-30%.
• There were no major safety issues, although low-grade, transient, dose-dependent
injection site reactions occurred.

20. LIMITATIONS:
• This was a small, first in man phase 1 trial involving only 32
participants.
• Safety cannot be comprehensively assessed in a trial of this size and
duration.
• A population without known cardiovascular risk was selected for the
study.
• Single dose administered- effects of multiple doses uncertain-
although a multidose is trial underway.