VICTORION-INCEPTION is a phase IIIb, randomized, parallel-group, open-label, multicenter, US-based trial currently enrolling patients at high risk for a recurrent cardiovascular event in the first year following acute coronary syndrome to receive either usual care or inclisiran to reduce LDL-C levels plus usual care. The rationale and design of this study was presented at the 2022 American Heart Association Scientific Sessions by Dr. Jeffrey Anderson.1

Many patients fail to achieve guideline recommended LDL-C less than 70 mg/dL within 12 months of an acute coronary syndrome (ACS) event. Early LDL-C evaluation and intensification of lipid-lowering treatment after recent ACS may reduce recurrent cardiovascular (CV) event risk. In prior phase III trials, inclisiran plus maximally tolerated statin therapy effectively reduced LDL-C in patients with established atherosclerotic cardiovascular disease.2-5 Because patients with an ACS within 3 months of screening were excluded from these trials, the efficacy of inclisiran in these patients is unknown.

Physician’s Weekly spoke with Dr. Anderson to learn more.

PW: Could you please place the data in the context of the unmet need?

Dr. Anderson: The gap in optimal therapy after a myocardial infarction (MI) is aggressively treating lipid levels. We know that lipid level, LDL-C particularly, is probably the most potent risk factor for myocardial infarction (MI), along with hypertension, diabetes, and smoking, of course, all of which are major modifiable risk factors. We have excellent therapies now for lowering LDL-C, but we found that—perhaps because of attention to other priorities after an MI—optimal therapy is often not provided by the time of discharge or early in the post-op/post-admission timeframe.

The rationale behind VICTORION-INCEPTION is to see whether we could augment early therapy to bring levels of LDL-C down to at least guideline-recommended levels within the first few weeks after an MI by potentially adding-on inclisiran to usual care. Inclisiran is a simple injection, which can dramatically augment lipid lowering by 50% to 60%, beyond what is accomplished by statins alone. The LDL-C threshold for trial entry is 70 mg/dL, meaning that patients who already have lower levels of LDL-C would not be given inclisiran on top of their usual care. In fact, the new cholesterol consensus pathway guidelines for treating cholesterol from the American College of Cardiology suggest that after an acute MI, the newly recommended threshold is even 55 mg/dL.6

For this study, however, we are using the more traditional cut-off level of 70 mg/dL. That gives us ample room to improve the achieved LDL levels with additional therapy. If a consenting patient has, at a screening visit, an LDL level above 70 mg/dL, they can then be randomized to either inclisiran or usual care alone at that time. For example, a patient I had today was randomized to aggressive therapy with inclisiran. So, I gave him an injection of inclisiran to try to bring his level down from greater than 100 mg/dL to certainly less than 70 mg/dL, but even less than 55 mg/dL. He will come back at 3 months to get a booster injection and then again 6 months later. Thereafter, participants get additional injections every 6 months on treatment.

The primary endpoint in the VICTORION-INCEPTION study is the percentage of patients who achieve an LDL-C less than 70 mg/dL at 1 year. Of course, we will also be looking at the overall response. In other words, the change from the baseline level on treatment in either arm will be our primary outcome measure. This trial is not as tightly controlled as in other studies; we have created maximum flexibility in the design for the treating cardiologist to do whatever needed to optimize LDL-C levels. In many respects, the control arm here is real-world evidence. In the investigational arm, those patients get inclisiran upfront in addition to anything else that is added on. We like to have the participants continue on their statin, of course. We think the combination of statin and inclisiran is a really wonderfully complementary regimen to reduce risk and optimize outcomes.

That’s the study in brief. The number of patients in the study is not very large; just a few hundred. However, we hope to be fully enrolled sometime in early 2023 and then follow-up for another year with the results. We hope the topline data will be available in the first half of 2024, and so we look forward to that as a way to potentially optimize treatment after MI, which is a very high-risk period of time for a recurrent event.

PW: What are the secondary outcomes?

Dr. Anderson: There are many secondary outcomes, looking at different levels, and we obviously always look for clinical events, but this study is not large enough to have the power to determine the impact on events that is being tested. Another study that we’re involved with—called ORION-4, which is targeting 15,000 patients worldwide, and for which I think we’re beyond 10,000 at this point in terms of enrollment—will have the power to look at the ability to reduce heart attacks, strokes, and cardiovascular deaths. We’ll certainly look at that, and we’ll look at safety endpoints as well. But that question is being tested in the ORION-4 study, which will not be reporting until 2026-2027.

PW: What are the inclusion criteria besides LDL levels greater than 70 mg/dL? 

Dr. Anderson: Patients were all hospitalized for an acute MI or ACS, either after emergency room evaluation or in-hospital inpatient admission, but in some rare cases, outpatient management was allowed. The participant will have to be hospitalized or at least evaluated as an emergency situation and receive a definite diagnosis of ACS. Beyond that, there could be either a STEMI, or a non-STEMI, or it could be a documented unstable angina. Those simple requirements qualify you to be screened for the study. Beyond that, there are not too many additional criteria except that after initial treatment and hospital discharge, we draw labs and the LDL-C has to be above 70 mg/dL. The labs will also have to show a minimal renal function threshold; an eGFR of greater than 20.

PW: What are some of the possible impacts you see this particular study bringing with it as opposed to the ORION-4? 

Dr. Anderson: VICTORION-INCEPTION will provide shorter-term data while we’re waiting for the ORION-4 to roll out, but the studies also ask somewhat different questions. With VICTORION-INCEPTION, we want to see, of those screened, how many are actually achieving LDL-C levels of less than 70 mg/dL. In other words, what is the gap in terms of optimal management of MI patients? That will be very important to determine. Assuming the data make us recognize that these patients are sub-optimally treated, that data will inform the treating cardiologist for the other aspects of the patient’s care.

Another distinction from the other ORION trials is the population; patients in all the other trials generally could not be enrolled until at least 3 months after a coronary event. We are very curious how many of those cardiologists will respond and augment therapy quickly to get the LDL-C levels down, as compared with the study-directed treatment arm. And then of course, we really want to understand how effective is inclisiran in this particular immediate post-infarction event scenario.

Critically, we have not yet built the experience for those early months post-infarction when the risk is very high for a recurrent event and the potential to further reduce that risk is present. Is the drug just as well tolerated in this setting? Is it just as effective at lowering LDL levels in those first few months as it was in the more chronic studies?

PW: Do you have any safety concerns?

Dr. Anderson:No. I’ve been working in the ORION study program for over 4 years; my experience is consistent with that of the study as a whole. Namely, the number of side effects were really just identical to that in the placebo group. There wasn’t any signal except somewhat more injection site reactions in the active therapy group than the placebo group. So far, the effects of inclisiran are very encouraging in terms of its impact on liver function, impact on muscle function, renal function, and so forth. Inclisiran has a highly encouraging safety profile.

Regarding adherence, once we give the shot, adherence is at 100% for the next 3-6 months, depending on when the next injection is due. We can keep track of adherence completely, whereas with a a pill, we just don’t know if they’re taking it for example, or how frequently. I had just had a patient today who claimed to be on a statin and we drew the levels and her LDL had gone quite up since last time we had seen her. Adherence has been an issue we all struggle with in the cardiologist clinic.

PW: Any final comments?

Dr. Anderson: We know that LDL-C is now a causal factor for cardiovascular events; there are a lot of data. If an agent lowers LDL-C with a very clean safety record, I think there is very strong evidence to suggest that it should also lower events. Obviously, we want to see the results of the outcomes trial; that’s necessary. However, in the shorter term, the data from VICTORION-INCEPTION will provide a strong impetus for early intervention with aggressive lipid-lowering treatments immediately post-infarction. We will see if inclisiran is well tolerated, safely lowers LDL-C, and achieves the target range more frequently than with standard care alone. I think that will be really an important observation.