181126_Bruce_Kirkham 26 Nov

Hi, I'm professor Bruce Kirkham, I am a rheumatologist at Guy's and St. Thomas' hospital in London and today I'd like to talk to you about ixekizumab and the ixekizumab clinical trial program in psoriatic arthritis. But first of all, let's talk about ixekizumab. Ixekizumab is a monoclonal antibody directed to IL-17A and you can see that the IL-17A is an important proinflammatory cytokine in psoriatic arthritis, spondyloarthropathy in general and also in psoriasis. Now ixekizumab is an IgG4 molecule, which is being engineered, so it doesn't bind complement to reduce unwanted side effects. It also has a very high affinity to IL-17A, so we can use a very effective dose in a small volume. Now the half-life of ixekizumab is 13 days, so the injection can be given once every four weeks, when a patient is in a stable state. The dose for patients with psoriatic arthritis is two injections that come in 80mg injections; the starting dose is two injections, i.e. that is 160mg, and then one injection 80mg every four weeks following that. For patients with moderate to severe psoriasis, they need a higher dose and so they actually start with 160mg followed by a single 80mg injection every two weeks for up to 12 weeks and after 12 weeks they carry on with 80mg every four weeks. Turning to the clinical trial program, this trial program is the SPIRIT program. There are three studies, two studies have finished already, the SPIRIT-P1, which is in patients who failed or not had conventional DMARDs. Then there is the SPIRIT-P2 study in patients who have failed TNF-blocker drugs. The SPIRIT-H2H study is a study of head-to-head properly powered to see if there is a difference between ixekizumab and adalimumab in patients with psoriatic arthritis. Looking at the SPIRIT-P1 study, this study had one of its outcomes to see if ixekizumab inhibited x-ray progression, so the patients were enriched for patients who could have progressions, so they either had a high CIP or they had an aversion at inclusion in this study. Patients had failed a DMARD or not had a DMARD, and there was an adalimumab arm in that study as a comparator to see if there was efficacy, but the patients were not powered to see if there is a difference in outcome between the arms. The study drugs were either 80mg every two weeks or every four weeks in the SPIRIT-P1 and the SPIRIT-P2 study, but I'll only be talking about the dose, which is now being used in clinical practice, which is 80mg every four weeks. The SPIRIT-P2 study is a very large study of patients who had either incomplete response to previous TNFblocker drugs, now interestingly, like in real practice, some of the patients had failed either one or two, and so 30% of patients had actually failed two TNF-blocker drugs. Some patients, about 10%, had had intolerance. So, let's go on and talk about the studies that have been completed, the P1 and P2 studies. So, looking at the study, the primary outcome measure, this is P1, is the ACR 20, and here we have the ACR 20, 50 and 70 outcomes. You can see a significant better outcome in the study drug compared to placebo. This to remind you that we are talking about the 80mg every four-week dose, which is the licensed dose of ixekizumab. Now when we look at the P2 study, you can see a very similar outcome in ACR 20, 50 and 70 for the P2, which is patients who have failed a TNF blocker drug. Now you may remember that the SPIRIT-P1 had an adalimumab arm, and here we have the ACR response to adalimumab in the trial, and you see that the response to adalimumab is what you would expect with that drug. Also, we must remember that the study was not powered or designed to make comparisons between the different arms of the study, i.e. ixekizumab and adalimumab. Now when we look at the P2, the patients who have either had methotrexate or not had methotrexate, is there a difference in outcome? And with most other drugs and biologics in psoriatic arthritis, we see that either with or without methotrexate makes no meaningful difference in outcome. Now when we talk about the P2, the interesting there is that some of the patients had failed two TNF blocker drugs, so we are really looking at a high-need group, quite hard to treat. And you can see here patients who had either failed one or two TNF blocker drugs had good outcomes to ixekizumab. So, this is very important, because the patients who failed two TNF blocker drugs have a high need. There is a small number of patients who had intolerance and again they respond to ixe, although some patients say, she had a placebo response, but the numbers are very small here and it's hard to understand what that means. When we move on and look at the longer-term outcomes. So we have here the 24-week data. Now, 24-week data is the placebo controlled part of the study and then we have the gold standard, NRI or non-responder imputation. That is really the gold standard way of looking at long-term data. We can see data here up to week 52 and we can see that the very good response at week 24 is maintained. And here we are looking at the ACR 50 data, because we want to look at something that is clinically relevant. You can see that it is maintained up to 52 weeks. This is the SPIRIT-P1 study. In the SPIRIT-P2 very similar longterm outcomes achieved, very good response at week 24 is maintained over to week 52. Now, the P1 study finished earlier than the P2 study, so we actually have data now up to three-year data. So, this is week 156 and this is using a slightly modified non-responder imputation. And you can see that over time, the very good outcomes of either ACR 50 or ACR 70 are maintained up to three years. So, we have a very good short-term response followed by very good continuation of that response for up to 3 years. Now, just looking at the x-ray changes. As we said before, the SPIRIT-P1 study had patients who we thought would actually have a progression of x-ray change, and you can see here at the grey bars, that the patients on placebo had some x-ray change and a significant inhibition of x-ray change in patients who received ixekizumab. So, this is the 24-week data. Looking at the 12-month data, this is the individual outcomes for change in the van der Heide sharp score over the 52-week period. You can see that hardly any patients had any change in the x-ray score. And that can either be from the data where all the individual points are here or alternatively we look at the other data, we are looking at the either patients with no change or when there is the smallest detectable difference, which probably is the most useful way of looking at it, you can see that very few patients had change in x-ray progression over the 52-week period. So, we have a drug that is useful in a clinical setting but also inhibits x-ray progression. So, this is what you really want from a biologic. Now turning to other outcome measures, obviously, psoriatic arthritis is not just a disease of joints, but enthesitis is a very important part of disease activity. This is the Leeds enthesitis index, which was the outcome measure in this study. And here we have the SPIRIT-P1 and -P2 data, showing significant improvements at week 24 in P1. In the P2 study the changes were not significant, we have to understand that, because actually by week 52 there were quite a significant number of patients. And this looking at the patients who had complete no enthesitis at these time points. So, this is an important outcome, and we can see that the P1 study shows a definite change. Looking at dactylitis, again dactylitis is another feature of psoriatic arthritis and we see significant improvements in dactylitis in both studies over a 24 and 52-week period. So, we are really starting to actually have an effect on the psoriatic arthritis component, but as we know in the study about two thirds of patients have significant psoriasis and we see significant psoriasis in our clinic. We are looking here at the PASI 90. Now, we may have got used to the PASI 75, but the actual gold standard now is moving to PASI 90, because PASI 90 is where patients have a significant improvement in quality of life. And this is because the IL-17 drugs are actually so good. So, we have the PASI 90 changes in the patients in the ixekizumab studies. You can see here that in the SPIRIT-P1 and the SPIRIT-P2 study PASI 90 responses are very good and they are maintained up to week 52. Now, let's get back to rheumatology. What about some patient-reported outcome measures? As we know, pain is a very important outcome for our patients. You can see here in the SPIRIT-P1 study, there is a significant reduction in pain very rapidly up to week 4 they get significant changes and that's maintained up to week 24. And the SPIRIT-P2 study shows very similar changes as well. So, it means that we are really starting to have an impact on the things that are very important to our patients. The other patient function is the HAQ-DI. So what we are looking at here is the percentage of patients who achieved a significant change in HAQ-DI, meaning the smallest meaningful clinical difference. And we see here that a significant number of patients in the SPIRIT-P1 and the SPIRIT-P2 study achieved this meaningful change in improvement of the function, the HAQ-DI. So, we have better patients, we have better function and better skin. Now looking at safety, obviously good drugs sometimes come at a price. We are looking here at the SPIRIT studies and we see here that there is some minor, some small number of infections, very few numbers of serious infections, but I think we see here that some patients had injection site reactions, so in the Q-4 weekly about 17% of patients had injection site reactions. So let's just look at them in more detail. And when we see that we see that almost all of them had mild injection site reactions. There were one or two patients who had more severe injection site reactions and they were the patients who dropped out. But actually you can see here that it's a very small number, so 0.4% of patients actually stopped the study because of an injection site reaction. That is something that we obviously need to share. Looking at the other side effects, the very important side effects which are really troublesome are rare, so we are going to look at the larger database. You can see here there is a lot of patients who received ixekizumab, over 5000 in the psoriasis studies and about 1200 or 1100 in the psoriatic arthritis studies. And this is where we can start to get some meaningful input on the serious, but rare things such as the serious infections. This is the rate per patient per 100 years, so we have serious infections can occur, but the rates are low; they are very similar in patients who had psoriasis or psoriatic arthritis, so some of the patients on psoriatic arthritis have some steroids, so we don't see an additive effect in psoriatic arthritis. There are some candida infections. This drug inhibits IL-17, so this is not unexpected, but they are transient, they are not severe infections. We see MACE, which is the cardiovascular endpoint. Again, there is no signal for MACE and also happily there is no signal for an increased risk of malignancies. So, this is very encouraging. Now, IL-17 inhibition is associated with very small number of patients who get worsening of inflammatory bowel disease or new onset. We can see here the rate in the psoriasis population and in the psoriatic arthritis population is present but very low. So, in summary we have seen that the SPIRIT clinical trial program shows that ixekizumab is highly effective in the treatment of psoriatic arthritis. It's effective for the improvement of the signs and symptoms of psoriatic arthritis, but also significantly inhibits radiographic progression. It can be used in patients who have either failed conventional DMARDs or be highly effective in patients who have failed a TNF blocker drug. And the interesting thing here is that it's the same doses used in both the SPIRIT-P1 and the SPIRIT-P2 study, so the same dose is recommended for patients who have failed a DMARD, i.e. first biologic or failed a TNF blocker drug. The side effect profile is very acceptable; it's what you would expect with an IL-17A drug. So, in general I think we have another drug, which hopefully will be able to help our patients with psoriatic arthritis. I'd like to say thank you very much for listening and watching this program.