A Phase 3 Trial of a JAKi in Patients With Giant Cell Arteritis Sponsored by AbbVie Medical Affairs + Health Impact Save
Listen as coinvestigator and rheumatologist Dr. Andrea Rubbert-Roth reviews this Phase 3 trial of a JAKi in patients with giant cell arteritis. Dr. Rubbert-Roth discusses the latest results, including efficacy and safety outcomes.
Transcription
Welcome to RheumNow. This podcast is sponsored and developed by AbbVie US Medical Affairs and Health Impact. Today, we will discuss key outcomes from the Phase three SELECT GCA trial. This trial compared the efficacy and safety of upadacitinib, an oral selective JAK inhibitor, to placebo, both in combination with the glucocorticoid taper for the treatment of patients with active giant cell arteritis, or GCA. Upadacitinib is indicated for the treatment of adults with giant cell arteritis.
Limitations of use: Upadacitinib is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. Joining me today to review the SELECT GCA trial is Doctor Andrea Rupert Roth, senior physician and rheumatologist at Cantonspetal St. Gallen in Switzerland. Doctor Rupert Roth is one of the investigators in the SELECT GCA trial. To view the data being discussed today, visit the latest Rx update at roomnow.com, a phase three trial in patients with giant cell arteritis.
Welcome to the podcast, Doctor. RheumNow.
Hello, I'm very glad to be here. Thanks for the invitation and I'd like to say hello to the colleagues who listen to that podcast, particularly of the RheumNow audience.
To get us started, could you give us an introduction to GCA and the current treatments?
GCA is a well known disease. It's a vasculitis giant cell vasculitis that's called sometimes it may involve cranial arteries that may eventually even lead to blindness that's mainly cranial or can also involve large vessels meaning the aorta, as well as some of the arteries that descend from the aorta like the carotid, the subclavian arteries, and others. Parrotreatment options for GCA are quite limited. I think that's fair to say. And the main stone of treatment are glucocorticoids.
However, we all know that the glucocorticoid treatment comes along with a significant risk of glucocorticoid related toxicity. So efforts have been made to look for glucocorticoid saving drugs.
Doctor. Rupert Roth, could you tell us how the SELECT GCA trial was designed?
The SELECT GCA trial was designed in a way that patients were able to be enrolled if they were at least 50 years old. It was possible to enroll patients who were either experiencing relapsing disease or patients with newly diagnosed disease. Once GCA is diagnosed, the patients are starting on a certain dose of glucocorticoid. It's going to be decreased and while the patients are hopefully off symptoms and feeling better, then there are screened and eventually randomized in the trial, meaning that the patients who were receiving upadacitinib that was used in two different doses versus placebo, that some patients were able to reduce the corticosteroids relatively quickly after around half a year. The other patients were maintained on glucocorticoids for a whole year, and the primary outcome was a proportion of patients on sustained remission.
And so some patients were having longer time periods and higher doses of glucocorticoids, whereas the patients on upadacitinib had a lower amount of glucocorticoids in a shorter time period. And the question, of course, was, is it possible to substitute for glucocorticoids with all the well known toxicities, in particular the elderly patient population? Is this possible, and can we ultimately achieve sustained remission? And we do have now the results of the first part of the trial. The trial concept was over two years.
It's now the first part of the trial. It will be very interesting to move on also in the second year when some patients stop the uBradacid and others are going to be discontinuous. But I think it's worth to look at the first part in that regard right now.
Before we get into the study findings, could you give us an overview of the patients enrolled in Select GCA, including baseline demographics and disease characteristics?
A total of four twenty eight patients were randomized and treated. Most of these patients were female over the age of 65 and had not been previously receiving IL-six inhibitors. That's important, only five percent had those. We know that there may be a common pathway between IL-six inhibitors and JAK inhibitors. Seventy percent had new onset disease, thirty percent had relapsing disease, and the mean baseline glucocorticoid dose by the time that the patients were enrolled in the trial was around thirty five mg per day.
Well, you for that overview. Can you also give us an overview of the endpoints in the SELECT GCA trial?
Overall, ubitisertin at fifty milligram together with a twenty six week glucocorticoid taper met its primary endpoint. There were a variety of secondary endpoints. These were grouped in a hierarchical order, and nine of the 11 endpoints were also achieved. And unfortunately, we don't have the time to go over this in detail, but I think that's also a significant success.
Can you tell us a little bit more about the key efficacy outcomes from upadacitinib fifteen mg group in the SELECT GCA trial and why are they clinically important?
The primary endpoint of the SELECT GCA trial is the proportion of patients achieving sustained remission. The definition of sustained remission is the absence of signs and symptoms of GCA between week twelve 50 two and adherence to the protocol defined glucocorticoid table regimen. A significantly higher percentage of patients on ubetasidenib fifty mg plus the twenty six week glucocorticoid taper achieved sustained remission. These were forty six point four percent of patients compared to twenty nine percent of patients on placebo plus a fifty two week glucocorticoid taper. The proportion of patients achieving sustained remission as well as sustained complete remission is very important because it characteristically means that the patients do not experience a relapse.
Looking at the proportion of patients achieving sustained complete remission, these were thirty seven point one percent on upadacitinib fifty mg compared to sixteen point one percent on placebo and this was statistically significant. Sustained complete remission was defined as achieving sustained remission together with normalization of the erythrocyte sedimentation rate, the ESR, and high sensitivity C reactive protein from week twelve to week fifty two. GCA is a disease that tends to relapse once the corticosteroids are down or even stopped, and so we do see a statistically significant difference despite the placebo patients had significantly longer and more glucocorticoids.
Are there any other ranked secondary efficacy outcomes from select GCA our audience should be aware of?
I'd like to mention some results with regard to the glucocorticoid exposure and we know that the normal treatment of GCA would cover a 52 glucocorticoid treatment, and what was measured in the trial was a total cumulative exposure to glucocorticoids within the trial in the different treatment arms. And what was lower, not surprisingly, with upadacitinib fifty mg was the total amount of glucocorticoids. This was sixteen fifty mg versus two thousand eight hundred and eighty two milligram in patients receiving the glucocorticoids over fifty two weeks. In addition, in a post hoc analysis, the median additional glucocorticoid dose at week fifty two was greater with placebo and those patients, to remind you, already received fifty two weeks of glucocorticoids taper compared to upadacitinib fifteen mg plus a twenty six week glucocorticoid taper and to speak of some numbers in the placebo group, it was five hundred and twelve point five mg versus twenty mg in the upadacitinib fifty mg group.
Well thank you for that review. Now, let's discuss the safety outcomes of Select GCA. What are the key safety outcomes from the trial?
That safety is very important, in particular in an elderly patient population. I think we are all aware of this. We have to keep in mind that the majority of patients enrolled in Select GCA were newly diagnosed disease, so those patients didn't have a long standing history of using corticosteroids. And it's really very surprising that the rates of serious infection were lower with bupasitamab fifty mg plus the twenty six week glucocorticoid taper versus the placebo patients who received the fifty two week glucocorticoid taper, namely 12.7 events per 100 patient years with placebo compared to 7.9 events per 100 patient years with ubradacitinib fifteen mg. We also observed a higher rate of hepatocellular surgery with ubatacitinib fifteen milligram plus the twenty six week glucocorticoid taper.
That's something that we know is being encountered more frequently with JAK inhibitors, and in the group of patients receiving upadacitinib fifteen mg, we observed 7.3 events per 100 patient years compared to placebo with 4.2 events per 100 patient years. Two adjudicated major adverse cardiac events, so called MACE, occurred in the placebo plus fifty two week glucocorticoid table route. And, think of note, no MACE was reported in the glucocorticoid twenty six week group with upadacitinib. Moving to the venous thromboembolism, they were also adjudicated and rates were similar across different treatment groups. Non melanoma skin cancer is also very important with these kinds of treatments.
Rates were similar between the upadacitinib fifteen mg and the placebo group. Of note, rates of other malignancy without non melanoma skin cancer were similar between the upadacitinib fifteen mg and the placebo group. In addition, no active events of tuberculosis, lymphoma, or gastrointestinal perforations were reported in any of the treatment groups.
To wrap up, could you give us some final thoughts summarizing the SELECT GCA trial?
I think SELECT GCA really shows that it is possible to reduce the amount and the length of glucocorticoid treatment in patients with either way relapse of GCA are patients with a newly diagnosed GCA, and in the context of using upadacitinib fifty milligram together with a twenty six week glucocorticoid labor, it was even shown that this was superior with regard to efficacy, also a glucocorticoid dose reduction compared to patients receiving placebo while on a fifty two week tapering. The primary endpoint was sustained remission from week twelve to 52, and nine out of a total of 11 ranked secondary endpoints were also achieved. We observed an overall higher serious infection rate in patients on placebo, and it's likely due to the higher and longer use of corticosteroids. So, in conclusion, I think the data shows that ubatacitinib fifty mg plus twenty seconds week glucocorticoid table provides a favorable benefitrisk profile and is the first oral targeted therapy for patients with GCA.
Thank you for that summary, and thank you for joining us today to speak about Select GCA.
Thank you for the invitation.
Listeners, please listen to the following about important safety considerations for upadacitinib. If you would like to learn more about Select GCA, take some time to visit roomnow.com and view the Rx update titled A Phase three Trial in Patients with Giant Cell Arteritis. There, you will find the data we discussed today. It is important to note that upadacitinib has a boxed warning for serious infections, mortality, malignancies, major adverse cardiovascular events, and thrombosis. Patients treated with upadacitinib are at increased risk for developing serious infections that may lead to hospitalization or death.
Malignancies have been observed in upadacitinib treated patients. In RA patients treated with another JAK inhibitor, a higher rate of lymphomas and lung cancers was observed when compared with TNF blockers. Non melanoma skin cancers have also been reported. Periodic skin examinations are recommended in patients at increased risk, and patients should wear protective clothing and use sunscreen. Additionally, a higher rate of all cause mortality, including sudden cardiovascular death as well as major adverse cardiovascular events, pulmonary embolism, and venous and arterial thrombosis were observed with another JAK inhibitor compared with TNF blockers in RA patients 50 years of age and older with at least one cardiovascular risk factor.
Thromboses have also been observed in upadacitinib treated patients. Avoid upadacitinib in patients at risk of thrombosis. Consider the individual patient's risks and benefits prior to initiating or continuing therapy. The most common adverse reactions are upper respiratory tract infections, headache, fatigue, peripheral edema, cough, anemia, rash, herpes zoster, and nausea. Please also read the additional safety information within the Rx update on roomnow.com titled A Phase III Trial in Patients with Giant Cell Arteritis Regarding Hypersensitivity Reactions, Other Serious Adverse Reactions, Avoiding Live Vaccines and the importance of immunizations, and medication residue in stool.
Review upadacitinib full prescribing information for additional information at www.rxabvi.com/pdf/rinvokepi.pdf.
Limitations of use: Upadacitinib is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. Joining me today to review the SELECT GCA trial is Doctor Andrea Rupert Roth, senior physician and rheumatologist at Cantonspetal St. Gallen in Switzerland. Doctor Rupert Roth is one of the investigators in the SELECT GCA trial. To view the data being discussed today, visit the latest Rx update at roomnow.com, a phase three trial in patients with giant cell arteritis.
Welcome to the podcast, Doctor. RheumNow.
Hello, I'm very glad to be here. Thanks for the invitation and I'd like to say hello to the colleagues who listen to that podcast, particularly of the RheumNow audience.
To get us started, could you give us an introduction to GCA and the current treatments?
GCA is a well known disease. It's a vasculitis giant cell vasculitis that's called sometimes it may involve cranial arteries that may eventually even lead to blindness that's mainly cranial or can also involve large vessels meaning the aorta, as well as some of the arteries that descend from the aorta like the carotid, the subclavian arteries, and others. Parrotreatment options for GCA are quite limited. I think that's fair to say. And the main stone of treatment are glucocorticoids.
However, we all know that the glucocorticoid treatment comes along with a significant risk of glucocorticoid related toxicity. So efforts have been made to look for glucocorticoid saving drugs.
Doctor. Rupert Roth, could you tell us how the SELECT GCA trial was designed?
The SELECT GCA trial was designed in a way that patients were able to be enrolled if they were at least 50 years old. It was possible to enroll patients who were either experiencing relapsing disease or patients with newly diagnosed disease. Once GCA is diagnosed, the patients are starting on a certain dose of glucocorticoid. It's going to be decreased and while the patients are hopefully off symptoms and feeling better, then there are screened and eventually randomized in the trial, meaning that the patients who were receiving upadacitinib that was used in two different doses versus placebo, that some patients were able to reduce the corticosteroids relatively quickly after around half a year. The other patients were maintained on glucocorticoids for a whole year, and the primary outcome was a proportion of patients on sustained remission.
And so some patients were having longer time periods and higher doses of glucocorticoids, whereas the patients on upadacitinib had a lower amount of glucocorticoids in a shorter time period. And the question, of course, was, is it possible to substitute for glucocorticoids with all the well known toxicities, in particular the elderly patient population? Is this possible, and can we ultimately achieve sustained remission? And we do have now the results of the first part of the trial. The trial concept was over two years.
It's now the first part of the trial. It will be very interesting to move on also in the second year when some patients stop the uBradacid and others are going to be discontinuous. But I think it's worth to look at the first part in that regard right now.
Before we get into the study findings, could you give us an overview of the patients enrolled in Select GCA, including baseline demographics and disease characteristics?
A total of four twenty eight patients were randomized and treated. Most of these patients were female over the age of 65 and had not been previously receiving IL-six inhibitors. That's important, only five percent had those. We know that there may be a common pathway between IL-six inhibitors and JAK inhibitors. Seventy percent had new onset disease, thirty percent had relapsing disease, and the mean baseline glucocorticoid dose by the time that the patients were enrolled in the trial was around thirty five mg per day.
Well, you for that overview. Can you also give us an overview of the endpoints in the SELECT GCA trial?
Overall, ubitisertin at fifty milligram together with a twenty six week glucocorticoid taper met its primary endpoint. There were a variety of secondary endpoints. These were grouped in a hierarchical order, and nine of the 11 endpoints were also achieved. And unfortunately, we don't have the time to go over this in detail, but I think that's also a significant success.
Can you tell us a little bit more about the key efficacy outcomes from upadacitinib fifteen mg group in the SELECT GCA trial and why are they clinically important?
The primary endpoint of the SELECT GCA trial is the proportion of patients achieving sustained remission. The definition of sustained remission is the absence of signs and symptoms of GCA between week twelve 50 two and adherence to the protocol defined glucocorticoid table regimen. A significantly higher percentage of patients on ubetasidenib fifty mg plus the twenty six week glucocorticoid taper achieved sustained remission. These were forty six point four percent of patients compared to twenty nine percent of patients on placebo plus a fifty two week glucocorticoid taper. The proportion of patients achieving sustained remission as well as sustained complete remission is very important because it characteristically means that the patients do not experience a relapse.
Looking at the proportion of patients achieving sustained complete remission, these were thirty seven point one percent on upadacitinib fifty mg compared to sixteen point one percent on placebo and this was statistically significant. Sustained complete remission was defined as achieving sustained remission together with normalization of the erythrocyte sedimentation rate, the ESR, and high sensitivity C reactive protein from week twelve to week fifty two. GCA is a disease that tends to relapse once the corticosteroids are down or even stopped, and so we do see a statistically significant difference despite the placebo patients had significantly longer and more glucocorticoids.
Are there any other ranked secondary efficacy outcomes from select GCA our audience should be aware of?
I'd like to mention some results with regard to the glucocorticoid exposure and we know that the normal treatment of GCA would cover a 52 glucocorticoid treatment, and what was measured in the trial was a total cumulative exposure to glucocorticoids within the trial in the different treatment arms. And what was lower, not surprisingly, with upadacitinib fifty mg was the total amount of glucocorticoids. This was sixteen fifty mg versus two thousand eight hundred and eighty two milligram in patients receiving the glucocorticoids over fifty two weeks. In addition, in a post hoc analysis, the median additional glucocorticoid dose at week fifty two was greater with placebo and those patients, to remind you, already received fifty two weeks of glucocorticoids taper compared to upadacitinib fifteen mg plus a twenty six week glucocorticoid taper and to speak of some numbers in the placebo group, it was five hundred and twelve point five mg versus twenty mg in the upadacitinib fifty mg group.
Well thank you for that review. Now, let's discuss the safety outcomes of Select GCA. What are the key safety outcomes from the trial?
That safety is very important, in particular in an elderly patient population. I think we are all aware of this. We have to keep in mind that the majority of patients enrolled in Select GCA were newly diagnosed disease, so those patients didn't have a long standing history of using corticosteroids. And it's really very surprising that the rates of serious infection were lower with bupasitamab fifty mg plus the twenty six week glucocorticoid taper versus the placebo patients who received the fifty two week glucocorticoid taper, namely 12.7 events per 100 patient years with placebo compared to 7.9 events per 100 patient years with ubradacitinib fifteen mg. We also observed a higher rate of hepatocellular surgery with ubatacitinib fifteen milligram plus the twenty six week glucocorticoid taper.
That's something that we know is being encountered more frequently with JAK inhibitors, and in the group of patients receiving upadacitinib fifteen mg, we observed 7.3 events per 100 patient years compared to placebo with 4.2 events per 100 patient years. Two adjudicated major adverse cardiac events, so called MACE, occurred in the placebo plus fifty two week glucocorticoid table route. And, think of note, no MACE was reported in the glucocorticoid twenty six week group with upadacitinib. Moving to the venous thromboembolism, they were also adjudicated and rates were similar across different treatment groups. Non melanoma skin cancer is also very important with these kinds of treatments.
Rates were similar between the upadacitinib fifteen mg and the placebo group. Of note, rates of other malignancy without non melanoma skin cancer were similar between the upadacitinib fifteen mg and the placebo group. In addition, no active events of tuberculosis, lymphoma, or gastrointestinal perforations were reported in any of the treatment groups.
To wrap up, could you give us some final thoughts summarizing the SELECT GCA trial?
I think SELECT GCA really shows that it is possible to reduce the amount and the length of glucocorticoid treatment in patients with either way relapse of GCA are patients with a newly diagnosed GCA, and in the context of using upadacitinib fifty milligram together with a twenty six week glucocorticoid labor, it was even shown that this was superior with regard to efficacy, also a glucocorticoid dose reduction compared to patients receiving placebo while on a fifty two week tapering. The primary endpoint was sustained remission from week twelve to 52, and nine out of a total of 11 ranked secondary endpoints were also achieved. We observed an overall higher serious infection rate in patients on placebo, and it's likely due to the higher and longer use of corticosteroids. So, in conclusion, I think the data shows that ubatacitinib fifty mg plus twenty seconds week glucocorticoid table provides a favorable benefitrisk profile and is the first oral targeted therapy for patients with GCA.
Thank you for that summary, and thank you for joining us today to speak about Select GCA.
Thank you for the invitation.
Listeners, please listen to the following about important safety considerations for upadacitinib. If you would like to learn more about Select GCA, take some time to visit roomnow.com and view the Rx update titled A Phase three Trial in Patients with Giant Cell Arteritis. There, you will find the data we discussed today. It is important to note that upadacitinib has a boxed warning for serious infections, mortality, malignancies, major adverse cardiovascular events, and thrombosis. Patients treated with upadacitinib are at increased risk for developing serious infections that may lead to hospitalization or death.
Malignancies have been observed in upadacitinib treated patients. In RA patients treated with another JAK inhibitor, a higher rate of lymphomas and lung cancers was observed when compared with TNF blockers. Non melanoma skin cancers have also been reported. Periodic skin examinations are recommended in patients at increased risk, and patients should wear protective clothing and use sunscreen. Additionally, a higher rate of all cause mortality, including sudden cardiovascular death as well as major adverse cardiovascular events, pulmonary embolism, and venous and arterial thrombosis were observed with another JAK inhibitor compared with TNF blockers in RA patients 50 years of age and older with at least one cardiovascular risk factor.
Thromboses have also been observed in upadacitinib treated patients. Avoid upadacitinib in patients at risk of thrombosis. Consider the individual patient's risks and benefits prior to initiating or continuing therapy. The most common adverse reactions are upper respiratory tract infections, headache, fatigue, peripheral edema, cough, anemia, rash, herpes zoster, and nausea. Please also read the additional safety information within the Rx update on roomnow.com titled A Phase III Trial in Patients with Giant Cell Arteritis Regarding Hypersensitivity Reactions, Other Serious Adverse Reactions, Avoiding Live Vaccines and the importance of immunizations, and medication residue in stool.
Review upadacitinib full prescribing information for additional information at www.rxabvi.com/pdf/rinvokepi.pdf.
