Are your patients with moderate to severe RA getting the appropriate dose? Sponsored by Genentech, Inc Save

Welcome to the latest podcast where experts in rheumatology discuss dose response differences in treating patients with moderate to severe RA. And now here is our host, Doctor. Alvin Wells.

First of all, it's an honor and a privilege to be here for the discussions with not only some of my colleagues, but also what I consider some of my true friends, doctor Orin Traum, doctor Grace Wright, doctor Aaron Broadwell. We indeed have some of the experts from around The US. As you think about treating patients with moderate to severely active rheumatoid arthritis, we have a lot of treatment options. And what our goal of the podcast is give you some evidence based medicine to come up with appropriate treatment for your patients who have rheumatoid arthritis. Today, we're gonna discuss treatment options with Actemra, tocilizumab, as many of you know, and we'll talk about the data that providers might be less aware of as they were in regards to the different treatment option.

We have IV. We have subcutaneous. Why And don't we talk about what that does in regards to our treatment, the efficacy, safety, and adherence for our patient population? Before we begin the discussion, I want to remind the audience of a disclaimer, the indication and box warning information. This video and podcast are presented on behalf of Genentech, and the information presented is consistent with FDA guidelines.

We have been compensated by Genentech to serve as speakers for this program. This video is intended to provide education on Actemra and is not medical advice for any particular patient. All materials are the property of Genentech and may not be recorded, photographed, copied, reproduced. Actemra is indicated for the treatment of adult patients with moderate to severely active rheumatoid arthritis who have had an inadequate response to one or more disease modifying antirheumatic drugs. Important safety information: Risk of serious infections.

Patients treated with Actemra are at increased risk of developing serious infections that may lead to hospitalization or death, including tuberculosis, bacterial, invasive fungal, viral or other opportunistic infections. If a serious infection develops, interrupt Actemra until the infection is controlled. Reported infections include active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before Actemra use and during therapy. Treatment for latent infection should be initiated prior to Actemra use.

Invasive fungal infections including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated rather than localized disease. Bacterial, viral, and other infections due to operatives and pathogens. The risks and benefits of treatment with Actimra should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Actemra, including the possible development of tuberculosis in patients who have tested negative for latent tuberculosis infection prior to initiating therapy.

Actemra is contraindicated in patients with known hypersensitivity to Actemra. Other warnings and precautions include serious infections, gastrointestinal perforation, hepatotoxicity, laboratory monitoring, hypersensitivity reactions, and live vaccines. We will be discussing the safety information throughout this video, but please note that the full warnings and precautions and all other important safety information, including box warnings, can be found in the Actemra prescribing information. So let's get started. You know, as we talked about before, patients with rheumatoid arthritis have a lot of treatment options.

And if you look at the ACR guidelines and the URI guidelines, they they're they're patient centric. They say, let's put the patient up front. So, doctor Wright, when you think about that, talk about the goals. How do you talk address that with your patients, and particularly when you think about treating them with Actemra?

Well, it's so great to be here, Alvin. And as you, you know, mentioned this, my goal for my patients is to get them to remission. Patients in general wanna feel better, and I want them to feel well. I want to get their disease as low as possible and have that fully controlled. And so low disease activity is one such target, but remission for me is a much more stringent target that gets me the benefits of what I want for my patients.

And I know when we look at our clinical trials, we'll see ACR responder indices. We'll see a variety of measures. And and what I really point patients to are all of the benefits of controlling the totality of their disease by striving for remission.

I I like that point, and that's what I talk about my patients as well. I'm trying to get them as best as they can be. Right? I like how you talk about wellness. We talk about that for a physician, but sometimes we forget that with our patients.

One of the things I tell my patients is your time is joints. And the the more you have tender or swollen joints, the longer that it persists, I'm gonna, you know, think about, hey. What damage am I doing? Remembering in RADIATE trial, the primary endpoint was the proportion of patients who achieved an ACR twenty response at week twenty four. That's looking at, remember, the ACR components, the tender joints, the swollen joints, the patient paying, the patient global, and also assess an inflammatory parameter as well.

When you look at the data on Actemra, that eight milligram per kilogram dose, the four milligram per kilogram dose compared to placebo, those ACR responses were fifty percent, thirty percent, and ten percent, respectively. There were also some secondary endpoints we talk about, the ACR fifties, ACR 70, and the dash 28 scores. We're gonna come back to those and talk about how we use those in our clinic and put those in perspective. The difference in the dash 28 scores of the three arms were 30.1%, 7.6%, and 1.6 respectively. Actemra four milligrams per kilogram plus methotrexate results for ACR fifty, ACR seventy, and DAS twenty eight are descriptive only, and no formal conclusions can be drawn.

Doctor Trom, I know you lose use these measures in the in the clinic. So talk a little bit not only about the ACR score, but how do you approach your patients if you put them on Actimra? I know we got IV. We got SubQ. What do you, how do you help your patients decide?

Alvin, I also, am thrilled to be here with you and our colleagues. But to answer your question specifically, I wanna get patients into remission, as doctor Wright said, as quickly as possible. I start with if I'm using intravenous four milligrams per kilogram, I look for my patient's clinical response soon after starting therapy. If I don't see that or a substantial reduction in disease activity on four milligrams per kilogram IV or with the every other week sub q dosing, then I would increase the IV dose to eight milligrams per kilogram for the next dose or modify the their sub q dosing to weekly to be the fact that the quicker you can get people into remission or at least slow disease activity, the better they will do in the long run. Damage happens early.

You don't want people to kind of smolder and have ongoing inflammation.

I always like to talk about and say, what would I do if I was on the other side of the exam table? So, doctor Trom, if you were that patient, how do you decide? Hey. Do I go IV or sub q? Does it depend on the patient's lifestyle?

Are they traveling all over the world like you and doctor Wright do all the time? So how would you put that in perspective?

Let's just make this, clear, doctor Wells. I think you're amongst you, doctor Rognall, all of us. It really is a patient preference. And then, of course, it's, it's what is paid for by their insurance that may sometimes have a a lot to do with it. But, I bring this up because, you know, we're all talking about how patients and physicians or providers should really have a shared decision making process, and that's what it comes down to.

I thank you, Eileen. Keep the hold that thought because we're gonna come back to reimbursement and what we talk to our patients about and what are some of the programs that we put in place with Genentech. Doctor Broadwell, let me get you into the mix here. You look at the data here from the RADIATE trial. We see so look at the that onset of action within two weeks.

We look at the ACR 50 response and some of the other secondary endpoints. Are these data points compelling to you, and how do you translate that to your patients?

Absolutely. And, again, thanks for for having me on. And I I look at this study, at the RADIATE study, remember this is a TNFIR study. Many, but clearly not all, of our patients on AgTemra IV are TNFIR, and so I find that it's very applicable. While you can see those ACR scores and you can see those differences that were noted earlier, as we then shift from that kind of primary response criteria just into true low dose activity or really remission is what we're looking at here in the DAS twenty eight, that's where we start to see some of that peeling away, and and that's where we see that eight milligram per kilogram.

So similar similarly to doctor Trom, we're we're gonna start at four milligrams per kilogram. I think that's a very reasonable thing to do. We're gonna reassess very frequently with many of our patients, assuming their disease control needs it moving up to eight milligrams per kilogram. And, again, I think that's coming back to we want that titer control. We like that remission, and and that's where the data comes from from the RADIATE trial.

Doctor Wells, like, you know, how do you then translate that into the sub q? I mean, do do you see similar things there?

Yes. And one of the things we do, for example, I like what doctor Wright said. I sit down with the patient and say, hey. This is what your goal is gonna be. It's gonna be getting you as close as you can to do the activities and do the things you want to do when we start off.

Like all of you, based on the RADIATE data, I started at four milligrams per kilogram, and then very rapid, if they're not close to where they and I have agreed they want to be, we're moving that dose up. Not only for the IV going from four milligrams to eight milligrams per kilogram, but also for sub q. You got the dose where you can do it twice a month or you can go go do it every week, and I think that's really, really telling as well. Doctor Wright, what about you? If you had think about this, what do you think about when you talk about the IV versus sub q?

What are some pearls and how you translate that for your patients?

Yeah. You know, again, a lot of this comes to either the payer preference or the patient preference. And for some patients, I've had them say, look. I don't trust myself to stay on target and do this all the time, and I like coming in and talking to other people, being in a space where there are others who are like me where I feel accepted.

You know, when we talk about the efficacy, of course, we have to balance that with safety. I'm gonna highlight some of that. When you look at the data on on on on ACTREM, we see the most common adverse reactions that were the instance of at least five percent were upper respiratory tract infection, nasopharyngitis, headache, hypertension, increased ALT, and injection site reactions. In the RADIATE trial, the difference in serious infections for the eight milligram per kilogram dose, the four milligram per kilogram dose in the placebo arms were four point six percent, one point eight percent, and three point one percent respectively. Even though they were numerically different, the three arms were similar to, or comparable in terms of safety results.

Can we spend a minute here talking about safety? Because I you know, it's always a balancing act. You know, I I love it when my patients say, hey. I hear some of these side effects, they sound worse than my disease. So, doctor Trump, what do you do?

How do you how do you kinda I won't say dummy it down, but how do you translate the safe into real world experience for your patients? And when you talk about the IV versus sub q, what what do you tell your patients, and what do you tell some of your colleagues as you ram the water cooler?

Doctor Wells, I I agree that it looks, like there's a difference here, but I think we all do clinical trials, that part of this panel. And we all know that, infections, in in particular upper respiratory tract infections, are the most common. The things I really look at are the serious adverse events, serious infections, things that get people hospitalized, need IV antibiotics, death. I mean, those are serious. And then the significant benefit of going from the four mgs per kg up to the eight or from the every two weeks, weekly, I think it it it's telling that you really wanna get patients to their disease being under great control.

Most of our patients come in and say, please don't talk about biologics. Do you know have you read about the side effects? Right. Yes. We've read about the side effects.

We have to discuss that when we talk about clinical trials. But the reality is, I mean, unless I have a particularly ill patient with many comorbidities where I might spend a little bit more time, I said, gee, I think the activity of the disease is actually contributing to some of your comorbidities. You have to take that into consideration, and it really is a balancing act. When they understand that best, then they are more prone to getting into the appropriate therapy, and we I try to encourage them to do that.

And I agree to doctor Truman. That's indeed what we're paying them for. They're paying for our best medical advice, but it is that balance of that. I like how you talked about that. We talked about setting goals for that patient.

We talked about some safety. At the end of the day, none of this matter if I can't get the drug for my patients. Right? So, doctor Broadwell, let's talk a little bit about access and reimbursements. Have you had any issues there?

What kind of pearls can we use to help our colleagues when they think about getting Actemra, eight milligrams per kilogram?

Yeah. So I I'm I'm heavily active in access throughout The US looking at multiple different drugs and with different organizations. And so I do pride myself on making sure that I am the best trained to make sure that whatever type of access I can try and get. What I found, especially with having both formulations, is that oftentimes you may have some access with one where you don't with another. We know pharmacy benefit managers oftentimes change what we wanna do, things like that.

And and and then further, I haven't had it locally as much pushback with more advanced dosing, either that being weekly, sub q, or with the eight milligrams per kilogram. Clearly, there are differences with different payers in different regions, so I wanna respect that.

That's such a good point. So, I mean, Grace, you're in New York, and and with the the patient that you're seeing, are there any major issues, or what kind of pearls could you share with some of our colleagues who might see this presentation?

I really have not had pushback going from four mgs to eight mgs per kilogram or in the sub q dose. But, again, it's New York City. It's a particular payer distribution that we have here, and that's not the same, let's say, across the banks of the river the West Coast Of Manhattan. So, again, very variable.

And I think that's why it's important to hear the experience from around the country. Doctor Trung, what about you in California? With any of the payors, any major issues there?

You know, we were, at least at one time, one of the most highly penetrated managed carrier of the country. I still think we're at least high to the top. We also have incorporated them now with the Providence Health Care System, folks that, you know, help us with our, prior authorizations and just take it from our our clinic records as to why we think it's important. I have not had pushback, and I think it's, it's been made readily available to us. Us.

So it's either weekly sub q dosing, it's eight milligram per kg as opposed to four. If we're willing to to say at least something, which means it's reflected in our notes, then it can happen.

And I totally agree with all of you. And my practice is very similar. One of the things we've also done is partner with specialty pharmacies in our area. So they do the heavy lifting. They write the prioritizations.

They do all those forms, and they indeed help to get those things covered because my job is to help treat these patients and do like all of you do at the end of the day. So I think the take home message here for our audience is that that with Akyemra, you have a different dosage. You have the four milligrams per kilogram, you have the eight milligrams per kilogram, and you also have that sub q. One is not gonna fit for all patients, but you have that's a luxury of being a rheumatologist. We won't be replaced by AI because it's that art.

And so which one's gonna be good for the others? We're showing you the efficacy. We're seeing some safety. And then reimbursement in our hands is not that big of an issue. Thank you for listening to our expert discussion.

Please keep listening to this podcast to hear the RADIATE trial study design and full important safety information. RADIATE is a phase three randomized double blind placebo controlled twenty four week study in rheumatoid arthritis patients who failed at least one tumor necrosis factor antagonist. One hundred and seventy patients received eight mgkg IV Actemra, 161 patients received four mgkg IV Actemra, and one hundred and fifty eight patients received placebo every four weeks while continuing background methotrexate. No other disease modifying antirheumatic drugs were allowed.

Important safety information continued. Actemra is contraindicated in patients with known hypersensitivity to actemra. Warnings and precautions. Gastrointestinal perforations. Events of gastrointestinal GI perforation have been reported in clinical trials, primarily as complications of diverticulitis in RA patients.

Use Actemra with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with fever, new onset abdominal symptoms, and a change in bowel habits for early identification of GI perforation. Hepatotoxicity. Serious cases of hepatic injury have been observed in patients taking intravenous or subcutaneous Actemra. Some of these cases have resulted in liver transplant or death.

Time to onset for cases ranged from months to years after treatment initiation. Most cases presented with marked elevations of transaminases greater than five times ULN, and some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases. Treatment with Actemra was associated with a higher incidence of transaminase elevations. Increased frequency and magnitude of these elevations were observed when Actemra was used in combination with potentially hepatotoxic drugs, for example methotrexate. It is not recommended to initiate Actemra treatment in patients with elevated transaminases ALT or AST, greater than 1.5 times ULN.

In patients who develop elevated ALT or AST greater than five times ULN, discontinue Actemra. Measure liver tests promptly in patients who report symptoms that may indicate liver injury. If the patient is found to have abnormal liver tests, Actemra treatment should be interrupted. Actemra should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests. Laboratory parameters.

Laboratory monitoring is recommended due to potential consequences of treatment related laboratory abnormalities in neutrophils, platelets, lipids, and liver function tests. Dosage modifications may be required. Neutropenia Treatment with Actemra was associated with a higher incidence of neutropenia. It is not recommended to initiate Actemra treatment in patients with a low neutrophil count, for example, absolute neutrophil count ANC less than 2,000 per cubic millimeter in patients who develop an ANC, less than 500 per cubic millimeter treatment is not recommended. Thrombocytopenia.

Treatment with Actemra was associated with a reduction in platelet counts. It is not recommended to initiate actemra in patients with a platelet count below 100,000 per cubic millimeter. In patients who develop a platelet count less than 50,000 per cubic millimeter, treatment is not recommended. Elevated liver enzymes. It is not recommended to initiate Actemra treatment in patients with elevated transaminases ALT or AST greater than 1.5 times ULN.

In patients who develop elevated ALT or AST greater than five times ULN, treatment is not recommended. Lipid abnormalities. Treatment with Actemra was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterols, and or HDL cholesterol. Immunosuppression. The impact of treatment with Actemra on the development of malignancies is not known, but malignancies were observed in clinical studies with Actemra.

Actemra is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies. Hypersensitivity reactions. Hypersensitivity reactions, including anaphylaxis, have been reported in association with actemra, and anaphylactic events with a fatal outcome have been reported with intravenous infusion of actemra. In addition, serious cutaneous reactions, including drug reaction with eosinophilia and systemic symptoms D R E S S, have been reported in patients with autoinflammatory conditions treated with actemra. Actemra, for intravenous use, should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis.

For Actemra subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If a hypersensitivity reaction occurs, immediately discontinue Actemra, treat promptly and monitor until signs and symptoms resolve. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in zero point one percent (three out of two thousand six hundred and forty four) of patients in the six month controlled trials of intravenous Actemra (0.2 percent, eight out of four thousand and nine of patients) of patients in the intravenous all exposure RA population, zero point seven percent (eight out of ten sixty eight) in the subcutaneous six month controlled RA trials, and in zero point seven percent (ten out of fourteen sixty five) of patients in the subcutaneous all exposure population. Demyelinating disorders. The impact of treatment with Actemra on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in clinical studies.

Monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of Actemra in patients with preexisting or recent onset demyelinating disorders: active hepatic disease and hepatic impairment. Treatment with Actemra is not recommended in patients with active hepatic disease or hepatic impairment. Vaccinations. Avoid use of live vaccines concurrently with Actemra.

No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving Actemra or on the effectiveness of vaccination in patients receiving Actemra. Patients should be brought up to date on all recommended vaccinations prior to initiation of Actemra therapy: adverse reactions, rheumatoid arthritis The most common serious adverse reactions were serious infections. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, and bacterial arthritis. In the Actemra IV monotherapy clinical study, the rate of serious infections was three point six per one hundred patient years in the Actemra group and one point five per one hundred patient years in the methotrexate group. The rate of serious infections in the four mgkg and eight mgkg Actemra plus DMARDI groups was four point four and five point three events per 100 patient years, respectively, compared to three point nine events per 100 patient years in the placebo plus Bemayardi group.

In the five phase three clinical trials, the most common adverse reactions greater than or equal to five percent of patients treated with Actemra IV through six months were URTI, nasopharyngitis, headache, hypertension, and increased ALT. The safety observed for Actemra administered subcutaneously was consistent with a known safety profile of intravenous Actemra, with the exception of injection site reactions, which were more common with Actemra subcutaneous compared with placebo subcutaneous injection's IV arm. In the six month control period in SCI, the frequency of injection site reactions was ten point one percent, sixty four out of six thirty one, and two point four percent, fifteen out of six thirty one, for the weekly Actemra SC and placebo SC IV arm group, respectively. In SC2, the frequency of injection site reactions was seven point one percent, thirty one out of four thirty seven, and four point one percent, nine out of two eighteen for the every other week Actemri SC and placebo SC groups, respectively. These injection site reactions were mild to moderate in severity.

The majority resolved without any treatment, and none necessitated drug discontinuation. Drug interactions. Cytochrome P450s in the liver are downregulated by infection and inflammation stimuli, including cytokines such as IL-six. Inhibition of IL-six, signaling in RA patients treated with Actemra, may restore CYP-four 50 activities to higher levels than those in the absence of Actemra, leading to increased metabolism of drugs that are CYP-four 50 substrates. Exercise caution when co administering Actemra with CYP-3A-four substrate drugs where decrease in effectiveness is undesirable Use in pregnancy.

The available data with Actemra in pregnant women are insufficient to draw conclusions about drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. You may report side effects to the FDA at eight hundred FDA1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 88888352555. Please see additional important safety information in full prescribing information, including boxed warning.