Dr R Scott Wright (Mayo Clinic, Rochester, MN, US) summarises a pooled analyses of phase 3 studies showing how Inclisiran potently and durably reduces Ldl-c.
Questions:
1. What prompted the study?
2. How does Inclisiran work?
3. What is the study design?
4. Who were the patients?
5. What were the efficacy results?
6. What were the safety findings?
7. What are the implications of this study?
Filmed remotely from Rochester.
Interviewer: Victoria Perroud
Transcript Below:
[Wright] I'm Dr. R Scott Wright, a professor of medicine and cardiology at Mayo Clinic in the Unites States. I was principal investigator of the ORION-10 trial and a member of the ORION Executive Steering Committee. Today, on behalf of Professor Kausik Ray, and Professor Frederick Raal, I'm able and delighted to talk about the pooled analysis of all of the phase three trials of Inclisiran across the entirety of the ORION worldwide programme.
Question : What prompted the study ?
[Wright] The ORION programme is testing whether a new treatment for elevated cholesterol is effective and safe. The current study was done as a planned analysis of the entirety of the phase three programme of Inclisiran. We presented and published three large phase three treatment studies last year. All were randomised placebo-controlled studies, comparing Inclisiran against placebo in patients who were on maximally tolerated oral lipid-lowering therapies. 92% were on statins. Of those on statins, three out of four were taking high dose, high intensity statins. And about 13% of patients were taking ezetimibe and a small percent, three or four, were not on any oral therapy because they had muscle symptoms or other signs of intolerance. The three groups that we examined as part of individual trials were patients with familial hypercholesterolemia in the ORION-9 trial. Patients with cardio atherosclerotic cardiovascular disease in the ORION-10 study, and patients with atherosclerotic cardiovascular disease or risk equivalence in the ORION-11 study. ORION-9 was led by a principal investigator from South Africa, and the study was conducted in South Africa, the Middle East and Europe. ORION-10 was led by myself and conducted in the United States exclusively. And ORION-11 was led by Professor Ray from London and conducted in Great Britain and in a few European countries. But we knew that the individual studies would have much more power if we pre-specified a planned pooled analysis. So, the combined analysis is the latest data that I presented at the American College of Cardiology meeting last week in Chicago.
Question : How does Inclisiran work ?
[Wright] Inclisiran is a double stranded RNA that's sort of a new and novel treatment for treating elevated cholesterol. It's taken up by the body and is taken directly to the liver cell, because it has an attached GalNAc complex, a sugar moiety called GalNAc, that that allows it to be delivered to the hepatocyte. And once it's taken into the hepatocyte, it uses the body's natural process of silencing the translation of messenger RNA through the RISC complex. And it inhibits the translation of messenger RNA for PCSK9, resulting in substantial reductions in the synthesis of the PCSK9 protein, so that circulating levels of PCSK9 fall precipitously, and the levels of LDL also fall. So, it works that way. It's given, on average, twice a year, as opposed to the more recently developed monoclonal antibodies which are typically given 26 times a year. And we've tested Inclisiran largely, not exclusively, but largely in patients already on daily oral lipid-lowering therapies. But it's also been tested in patients who have not taken any lipid therapy and shown to be equally effective as in those taking a statin or a statin with another oral agent like ezetimibe.
Question : What is the study design ?
[Wright] The study design is randomising patients on day one to either receive an injection of placebo or Inclisiran. They then receive the subcutaneous injections of 1.5 CCs on days one and 90, and then every six months thereafter. They've had to be on a stable dose of oral, maximally tolerated, oral lipid therapies, and have an entry LDL of greater than 70 and those with ASCVD greater than 100, and those with risk equivalence or FH. And then we follow them and do periodic blood measures over a total of 18 months. The co-primary endpoints of the trial looked at the efficacy of LDL lowering at day 510, Inclisiran compared to placebo. And also, the time average reduction or change in LDL of Inclisiran versus placebo. Because one could imagine that if you're giving a drug infrequently, you want to make sure it's working across time and not just at pre specified time points where you measure. So, we looked at time average reductions. In addition, after the design of the trial and the initiation, elegant work from Brian Ference in Cambridge was published showing that really time averaged reductions of LDL over decades is probably the best predictor of secondary prevention benefits. So, we feel very delighted that our co-primary endpoint has been, you know, corroborated as an important endpoint by the work of Professor Ference.
Questions : Who were the patients ?
[Wright] Yeah, the patients were either those with heterozygous FH and ORION-9, atherosclerotic cardiovascular disease, which was ischemic heart disease, you know, coronary heart disease, peripheral arterial disease or cerebral vascular disease, in ORION 10 and 11, or those who had risk equivalence equivalent to ASCVD, were about 20% of the patients at ORION-11. So, those were the patients. There were, you know, mainly men in the study, as I recall. We had 68% were men, so two out of three were men. A little over a third were type two diabetics, 35%. And the baseline LDL, at the time of randomization, was 111 in the placebo group, and 112 in the treatment group. So, despite, you know, a maximally tolerated oral therapy, they still had fairly high LDLs. Median age was 65 in both groups and about 44% were from the United States and the remainder were from rest of the world. So, that was the patient population as an aggregate.
Question : What were the efficacy results ?
[Wright] At day 510, Inclisiran compared to placebo reduced LDL by 55%. And a time average reduction from days 90 to 540 showed a 52% reduction in LDL. Both of these were highly statistically significant. So, once the drug is approved, presuming and hopefully that it is approved this year by the regulatory authorities, doctors are asking if we use Inclisiran, what percent of my patients will get to an LDL threshold? So, we took high risk patients, you know, heterozygous FH and patients with ASCVD or their risk equivalents, so many of them now have treatment based guideline thresholds of 70 or lower. So, we know from the study that 76% of patients on Inclisiran and only 14% on placebo achieved an LDL of less than 70 on treatment. And 58% achieved an LDL of less than 50 versus 2% on placebo. So, Inclisiranin was quite effective at achieving, not only potent reductions in LDL, but also achieving certain LDL thresholds. Some clinicians worried that taking LDL too low could be problematic. And we looked at what percent of patients achieved an LDL of less than 25 milligrammes per deciliter, and that was 16% in the Inclisiran group and 0.3% in the placebo arm. We've often been asked too, you know, what were the secondary endpoints. So, PCSK9 was reduced by 83%, Inclisiran versus placebo. Total cholesterol, 32%. Non HDL, the total atherogenic burden, 46%, ApoB, 42% and Lipoprotein A was reduced 20%. And all of the secondary endpoints were highly statistically significant, as were the co-primary endpoints. We did forest plot analyses as well, looking at effects of various factors and looking for heterogeneity. So, there were no differences between sex. So, men and women had equally efficacious LDL lowering. Age was not an issue. Those under 65, those over 65 had similar efficacy. The same was true for an age threshold of 75 or lower. Race was not an issue. The use of oral therapy or not, on a statin or not on a statin, did not affect the efficacy of results. And the presence of a metabolic issue, like diabetes or metabolic syndrome, showed no attenuation or enhancement of efficacy. It was comparable to what we saw for those who had no metabolic abnormalities. So, we feel fairly comfortable saying that the efficacy is robust and durable, as well as quite potent.
Question : What were the safety findings ?
[Wright} I think with a new drug and a new class, it's important to look at safety and we looked at treatment, emergent, adverse events, and they were comparable between the groups, there were no differences at all, except for injection site reactions. There were about 5% of patients on Inclisiran and 1% on placebo had some mild or moderate erythema or pruritus, itching or a rash, slight rash of a small diameter, that tended to go away after a few days and did not recur if they received further injections as they did. There were no differences in elevations of liver enzyme test or CK, or creatinines above two or platelet counts less than 75,000. These were pre-specified blood markers we looked at, so no differences between placebo and Inclisiran. The overall mortality was no different. It was one and a half percent in both arms, placebo and Inclisiran. The rates of cancer were the same. The the rates of new or worsening or recurrent malignancies were incomparable. And drug discontinuation was quite low. It was less than two and a half percent in both groups. We also did an exploratory endpoint, which looked at a MedDRA basket of major adverse cardiovascular events; cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction and haemorrhagic or ischaemic stroke. And we used the MedDRA terms that the European Medicines Authority, the British authorities and the U.S. FDA agreed were the proper terms, and we saw a pre-specified CV MACE rate of 9.4% in the placebo group and 7.1%, in the Inclisiran group. So, there was, you know, fewer events in the Inclisiran group. We're not drawing any firm conclusions about that, except to say that the trend was in the correct direction as far as we are concerned, it showed a benefit. But it can't be statistically derived, because it's associational. Because the study was not powered, you know, for a pure outcomes thing. And we are currently conducting a phase three outcomes trial through the group at Oxford, Professor Collins and colleagues, called ORION-4. And so, we're relying on that trial to give us the total adverse and outcomes events on that. So, those are the data and the results.
Question: What are the implications of this study ?
[Wright} I think there are several, one, that the drug is potent and durable. So, giving it infrequently, roughly every six months, shows very robust lowering of LDL, that's also durable, with 55% reductions at day 510, and a 52% time average reduction over days 90 to 540. Second, that it's safe compared to placebo. There were no signals of any safety concerns or issues. The design of the trial gives us a lot of experience now with using Inclisiran. Pooling the data gives us a lot of patient years to look at. All of the data that you heard me describe now and that you've seen at ACC are submitted to the regulatory authorities in the United Kingdom and in Europe and in the United States. So, they have the full picture. But we've been as transparent as we know to be, and can be with the data. We have not seen any signal. So, it's safe, it's durable, it's effective. We also think it's novel. And finally, we think it's a practical way to help patients further to lower LDL and stay on treatment that will keep their LDL low. So, giving something twice a year assures that if a patient misses a dose of a statin or misses a week of a statin, the Inclisiran is there to sort of help them and hold them down. It's not that we're recommending people skip medicines. But the reality of clinical practice is that most patients skip medicines. And unfortunately, data show that 50 to 60% of patients on statins are non-compliant after a year, even those who have had serious life threatening events like a myocardial infarction, or a stroke. So, we need medicines that are effective, durable, and that can help improve adherence. So, we believe that Inclisiran offers all of those and are optimistic that clinicians will find it that way once it's approved and available for use commercially.