The RheumNow Week In Review FDA Showdown For Baricitinib %284.27.18%29 Save

It's the 04/27/2018. This is the RheumNow we can review. I'm Doctor. Jack Cush, Executive Editor of roomnow.com. Good news for Plaquenil, bad news for hydroxychloroquine, and a split decision or showdown for Baricitinib at the FDA this past week.

This and more. At the top of the news is a study from UCSF and their lupus prospective cohort. Eight zero seven patients followed prospectively. An analysis done by Ed Yellen showed that poverty in lupus patients was associated with a higher rate of mortality. In their initial, run through on the numbers, showed out to be two point one as a hazard ratio that was significant when they made adjustments for age and disease activity, damage, etc.

It was no longer significant and went down to one point six eight. But nonetheless, they showed a few interesting things that it was numerically higher. It seemed that most of the poverty related deaths was related to damage and that the poor people that were in that study that actually did die, they actually live thirteen point nine or almost fourteen years less than those they were compared to, suggesting that poverty is a factor. There was a lot of interesting discussion online about what are we doing about this? How can we manage this?

How can we study this? I think it's a challenge and I think it's up to you and those of you who do lupus research to look into this and find out more about it, report on it. A large cardiovascular prevention trial looked at the incidence of gout amongst patients who had chronic kidney disease. Amongst almost twelve thousand plus patients that were followed prospectively, and these were mostly, in middle age between 35 and 57 years of age. CKD when it was present was found, and to be associated with higher risk of gout.

So in this cohort, they found seven twenty two new cases of gout and having chronic kidney disease increased the hazard ratio up to one point six one or a total of sixty one percent increased risk of developing gout with CKD and that was significant. What was interesting was that uric acid itself was not a risk factor for, developing gout in this cohort, and that the other factors that were was proteinuria and hematuria. So interesting data and I think that's something that we all deal with. Amongst almost two thousand patients, like two thousand six hundred patients with rheumatoid arthritis, that were followed and that were on hydroxychloroquine, it was shown that the use of hydroxychloroquine actually was associated with lower risk of CKD, that if you were on hydroxychloroquine, the risk was ten per one thousand, if you are not, it was thirteen point eight per one thousand patient years. So overall, the hydroxychloroquine treated patients had a lower risk of CKD, and that was dose dependent.

This follows the many wonders of hydroxychloroquine. While it may not be the greatest efficacy drug and inflammatory arthritis, it's tagged along potential in RA and lupus and other disorders is great. You should actually look at the article on RheumNow written by Doctor. Marty Bergman called The Nine Lives of Hydroxychloroquine to learn more about the extensive benefits of Plaquenil's therapy. An interesting study looked at the giant cell arteritis patients undergoing temporal artery biopsy and tried to find out the predictive value of other biomarkers specifically that gleaned from the complete blood count, the CBC.

So five thirty seven patients undergoing temporary biopsy. What they showed was that not surprisingly, CRP and ESR increased the odds of having giant cell arteritis and those that are undergoing biopsy increased at threefold. But equally as effective were things like the, neutrophil to lymphocyte ratio, that's the NLR, that had almost a twofold increased risk or the PLR, the platelet to lymphocyte ratio, which also had a three point two five odds ratio of predicting a positive biopsy and the diagnosis of GCA. So I've always used the the platelet count and the anemia of chronic disease as markers of inflammation when especially when patients may not have an elevated sedated CRP. These are other pro inflammatory biomarkers that again, they're within the CBC that you can look at, and we actually wrote about that on roomnow.com.

It's an article about the CBC and what you can glean from it. So the big news this week was the FDA hearing. On April 23, the FDA, Arthritis Advisory Committee met and considered the, application of baricitinib by Lilly for use in rheumatoid arthritis. As you know, the drug has been developed, has had many large studies done, all with very impressive results, but the whole process was derailed towards the end of last year when they received a complete response letter from the FDA suggesting that they couldn't proceed on the application, at least in a favorable manner with the concerns they had about safety where they had an imbalance of safety signals, venous thromboembolic events, VTE. They also had some concerns about the differences in dosing efficacy, which weren't that significant according to the FDA, that being the four milligram versus two milligram once a day.

The company, came back with a resubmission and then this hearing occurred where the FDA, was empowering the arthritis advisory group to, review the data and report back to them on several key questions. After a day of deliberation and presentations by the FDA and by the sponsor Lilly, the FDA panel went in and voted on five specific questions. Two questions were around efficacy. Does the four milligram and two milligram data merit, approval? And that was unanimous.

15 to zero and fourteen to one were in favor of, approving the drug based on efficacy at the four milligram and two milligram dose. Meaning that four milligram was significantly better than placebo, two milligram was significantly better than placebo as well. When they looked at the safety of the four milligram and two milligram doses, the there was a little less, clear. The panel said that there was a nine to six vote in favor of the two milligram dose as far as safety and, it was a total flip to an 11 to four against the four milligram dose for safety for reasons I'll mention in a few minutes. And then lastly, they voted overall on the last decision, which was which dose should be approved.

This is the fifth and sixth votes considering the four milligram and two milligram dose. They voted in favor of approval, and this is in when you look at the totality of evidence and the risk benefit ratio behind a particular dose, they voted 10 to five in favor of approving the two milligram once a day dose of baricitinib, but voted against 10 to five against, the approval of the four milligram dose. There, the panel that voted against it cited concerns about venous thromboembolic events, and maybe some issues regarding platelets. So, you know, as you know, baricitinib is a JAK one, JAK two inhibitor. There are some concerning, effects of JAK two inhibition on hematologic parameters, and hence, these findings of VTE and thrombocytosis are of of concern.

So the FDA did review this data. They again, the real problems that were had within the panel was first the discussion of does four milligrams offer a significant better benefit over the two milligram dose. And it turns out that while something they're having and they had four, phase three trials that they reviewed, in, you know, DMARD and and TNF inhibitor naive patients, methotrexate incomplete responders, TNF incomplete responders, etc. And you can look at the website for more data on these specific studies which were called begin, beam, build and beacon. But the problem was, that some of the studies did, there were two studies that head to head looked at two milligrams versus four milligrams, all the studies looked at the four milligram dose, but only two studies looked at two milligram dose and hence there was only two studies where you can compare the two.

One, there seemed to be a stepwise dose related comparison where four was better, the other one, they were exactly the same. The company came back and showed data that suggested where they were the same, you could see a differential response if you looked at the cohorts based on how many DMARDs they failed, meaning for all patients, it didn't seem to make a difference. However, if the patients had failed only one DMARD, it didn't make any difference which dose you got. But if they had failed two or more DMARDs, then there was a differential stepwise response, not always significant, but sometimes significant. Again, that's a sub analysis.

The other evidence in favor of a four milligram versus two milligram difference were all those patients on four milligrams who rolled over into the JADY long term extension study. There a cohort, again, there was 900 plus patients and about half of them were then randomly and blindly tapered down to two milligrams a day and the other half were continued at four milligrams a day. When you follow those patients out for as long as forty eight weeks, there was a small difference, but the vast majority of patients could do well on two milligrams when they had previously responded to four milligrams. Again, a good news about continuing at a lower dose once you achieve the four milligram response, which is I think what the company was looking for as far as an indication. However, when you look the forty eight week, data, there was about a twelve percent difference between those who continued at a remission versus those who didn't.

This is remission and LDAS all combined, that there was a 12% difference suggesting that there is a difference between four and two milligram dose and that twelve percent of patients wouldn't do quite as well. So again, there was some small concerns and there was a lot of discussion about the efficacy, but it really was the safety and specifically the VTE events in the first sixteen weeks in a double blind randomized placebo controlled portion of the study. There were six cases of VTE that included DVT and PE events in those on four milligram, none on two milligrams and none on placebo. After sixteen weeks, a lot of patients rolled over and another study by twenty four weeks everybody rolled over, so you don't have a long term placebo comparison. Overall, there were forty two VTE events amongst the three thousand four hundred and sixty four, patients treated with baricitinib that had a total of seven thousand eight hundred and sixty patient years of exposure.

So in the first, sixteen weeks, the event rate was one point seven per 100 patient years. The weeks one through 52, it went down, it went down to the number that seeing here was roughly about zero point eight per 100 patient years, and then after week 52 fell to zero point five per 100 patient years. What does that mean? The RA background rate, a number often quoted by most people who have looked at RA patients not on this therapy or other therapies, is roughly around five, maybe five to six. So that overall number of five to eight, I'm sorry, zero point five to zero point eight per 100 patient years, is really in congruence with the zero point five per 100 patient years in the general RA population.

It was soon after exposure that the number seemed to be higher and the question is, was that random or not? Clearly the panel had concerns especially with the four milligram dose. Another concern was the issue of thrombocytosis or thrombophilia, that soon after getting baricitinib there is this spike of platelet counts that goes up on average 40 to 60,000 since most people started the study around 300 something thousand, it's not sort of an inconsequential bump in platelets and it goes down to normal after two weeks. No one can explain it, there was one postage by the FDA that I thought was weak and really the company had tried to study this and they really couldn't find a good reason for this. The number of patients that had high thrombocytosis, meaning greater than 450,000, cells, was only about ten percent.

And again, that's only at any time during the administration, and most of that was right after administration, right after the drug was started. So again, there was an overall view that the two milligram and four milligram dose was effective. There was a concern that it may have a safety signal. All the other safety parameters that we're seeing here are pretty much what you'd expect for JAK inhibitor and for many of the drugs that we see these days. Serious adverse events and serious infections, a few malignancies.

Again, nothing really out of the ordinary other than zoster which you would expect with a JAK inhibitor, and there the rate of zoster was three point seven per 100 patient years, about the same as that seen with tofacitinib which is I think four point three per 100 patient years. So this led to a split vote. We're all in favor as far as efficacy, but they were split on the overall approval and split on the safety favoring the two milligram dose. The problem is that they didn't have enough patients treated at the two milligram dose to be approved. The FDA likes to see a thousand patients treated at the proposed dose.

They had four zero three patients treated in the phase three, studies, they had a total of over 700 patients that were exposed to the two milligram dose overall, and I think they had over twelve seventy five patient years of total exposure on the two milligram dose. Is that enough for the FDA to approve? Again, the panel came back with relatively positive, data with some major negatives and how the FDA responds remains to be seen. But we should know that hopefully by June, at the latest. That's it for this week at RheumNow.

Make sure you tell all your friends to tune into the podcast and to watch RheumNow. Bye.