Sponsored by AbbVie Medical Affairs

A JAK Inhibitor in Difficult-to-Treat Patients With RA


 

Over the last decade, Janus kinases (JAKs) have emerged as compelling therapeutic targets in rheumatoid arthritis (RA) and have been extensively studied.1 Upadacitinib (UPA) is a JAK inhibitor that has been approved by the US Food and Drug Administration (FDA) for the treatment of adults with moderately to severely active RA who have had an inadequate response or intolerance to one or more TNF blockers.2

Through binding and inactivation of JAKs, UPA prevents the phosphorylation and activation of signal transducers and activators of transcription (STATs) and thereby modulates the JAK/STAT signaling pathway.2

There are 4 different JAK isoforms (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]), and these JAK enzymes transmit cytokine signaling through their pairing (eg, JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2).2,3

aThe IC50 represents the concentration of UPA required to inhibit JAK function by 50%. The lower the IC50, the higher the potency. IC50 values represent the mean ± SEM from ≥3 independent studies.
bEnzyme reactions were conducted at 0.1 mM ATP.

ATP=adenosine triphosphate; EPO=erythropoietin; GH=growth hormone; GM-CSF=granulocyte macrophage colony stimulating factor; IC50=inhibitory concentration at which there is 50% effect; IFN=interferon; IL=interleukin; SEM=standard error of the mean; TPO=thrombopoietin.

Figure adapted from: Choy EH. Rheumatology (Oxford). 2019;58(6):953-962.

1. Bellinvia S, et al. EMJ Rheumatol. 2018;5(1):59-65.
2.
RINVOQ (upadacitinib) [package insert]. North Chicago, IL: AbbVie Inc.; 2022.
3. Choy EH. Rheumatology (Oxford). 2021;58(6):953-962. 4. Parmentier JM, et al. BMC Rheumatol. 2018;2:23.


 

As a rheumatologist, how do you manage patients who remain in moderate or high disease activity despite receiving ≥1 bDMARDs?

Please click on the player below to listen to Dr. Tesser’s perspective

 

 

“With my patients, I’m careful to establish our treatment goal of remission… I set the expectation that the first medication we use might not be enough, and that another advanced therapy may be needed.” – Dr. John Tesser


Upadacitinib Was Assessed in Patients Who Failed bDMARDs in a Phase 3 Trial

Upadacitinib, or UPA, is an oral, small-molecule Janus kinase (JAK) inhibitor for adults with moderately to severely active RA who have had an inadequate response (IR) or intolerance to one or more TNF blockers. UPA is approved as a 15-mg once-daily tablet that can be used in combination with MTX or other nonbiologic DMARDs or as monotherapy. Use of UPA in combination with other JAK inhibitors, bDMARDs, or with potent immunosuppressants, such as azathioprine and cyclosporine, is not recommended.1

In the SELECT Phase 3 clinical program, the safety and efficacy of UPA was investigated in patients with moderate to severe RA. These studies were performed across patient populations ranging among patients who were MTX-naive, conventional synthetic DMARD (csDMARD)-IR, MTX-IR, and bDMARD-IR (including TNF-IR).1-7UPA is only approved for patients who have had an inadequate response or intolerance to one or more TNF blockers.1

Specifically, in the SELECT-BEYOND Phase 3 trial, UPA was investigated in patients with RA who were bDMARD-IR over a 24-week, double-blind period vs placebo, and all patients received background csDMARDs.2,3

 

aUPA 30 mg QD is not an approved dosing regimen.
bFull analysis set; NRI was used for the primary endpoint and the analysis was controlled for multiple comparisons. 

ACR20=20% improvement in American College of Rheumatology score; NRI=nonresponder imputation; PBO=placebo; QD=once daily.

1. RINVOQTM (upadacitinib) [package insert]. North Chicago, IL: AbbVie Inc.; 2022.
2. Genovese MC, et al. Lancet. 2018;391(10139):2513-2524.
3.
Weinblatt ME, et al. Poster FRI0171. EULAR 2019. June 12-15, 2019; Madrid, Spain.
4. Van Vollenhoven R, et al. Arthritis Rheumatol. 2020;72(10):1607-1620.
5. Fleischmann R, et al. Arthritis Rheumatol. 2019;71(11):1788-1800.
6. Smolen JS, et al. Lancet. 2021;393(10188):2303-2311.
7. Burmester GR, et al. Lancet. 2018;391(10139):2503-2512.

 

Baseline Demographics and Disease Characteristics

Within the SELECT-BEYOND trial, baseline demographics and disease characteristics were similar between treatment arms. Key characteristics that are of special interest in patients who failed bDMARDs are highlighted in the table below.

.

aValues are mean ± SD unless noted.
bData available for 163 patients.
cIR defined as patients who did not show an adequate response after ≥3 months of treatment and/or had to discontinue due to intolerability or toxicity, irrespective of treatment duration.
dLOE (lack of efficacy) defined as patients who did not respond to therapy or had loss of response to treatment.

ACPA=anti-citrullinated protein antibodies; CDAI=Clinical Disease Activity Index; CRP= C-reactive protein; HAQ-DI=health assessment questionnaire–disability index; IL-6=interleukin-6; MOA=mechanism of action; PtGA=patient’s global assessment of disease activity; RF=rheumatoid factor; SD=standard deviation; SJC66=swollen-joint count based on 66 joints; TJC68=tender-joint count based on 68 joints; TNFi=tumor necrosis factor inhibitor; VAS=visual analogue scale.

1. Genovese MC, et al. Lancet. 2018;391(10139):2513-2524.
2. Weinblatt ME, et al.
Poster FRI0171. EULAR 2019. June 12-15, 2019; Madrid, Spain.

 

UPA + csDMARDs Showed Significant Improvement vs PBO + csDMARDs in the Change From Baseline in DAS28-CRP at Week 12

 

Remissiona Measures at Week 12

 

Nominal p-values: #p>0.05, p<0.05, ††p<0.01, †††p<0.001 vs PBO + csDMARDs.

aRemission does not mean drug-free remission or complete absence of disease activity.
bAdditional endpoint; not controlled for multiple comparisons; nominal p-value is provided.
cBoolean-based criteria consist of TJC 1, SJC 1, CRP 1 mg/dL, and patient’s global assessment 1 (scale 0-10).6
dPost hoc analysis; not controlled for multiple comparisons; nominal p-value is provided.

Full analysis set (NRI).

DAS28-ESR=28-joint Disease Activity Score based on erythrocyte sedimentation rate; RAPID3=Routine Assessment of Patient Index Data 3; SDAI=Simple Disease Activity Index; SJC=swollen joint count; TJC=tender joint count.

1. Hall S, et al. Poster THU0174. EULAR 2019. June 12-15, 2019; Madrid, Spain.
2. Data on File. AbbVie. ABVRRTI70198.
3. Data on File. AbbVie. ABVRRTI68842.
4. Bergman MJ et al. Poster THU0192. EULAR 2020 E-Congress; June 3-6, 2020
.
5.
Data on File. AbbVie. ABVRRTI72785.
6. 
Felson DT, et al. Ann Rheum Dis. 2011;70(3):404-413.

 

According to the ACR recommendations, LDA should be set as the minimal treatment goal, as remission may not be achievable in some patients, such as those with refractory disease.

Fraenkel L, et al. Arthritis Rheumatol. 2021;73(7):1108-1123.

Please click on the player below to listen to Dr. Tesser’s perspective

 

 

“Sometimes we must accept that the goal of remission is not attainable. We then strive for the next best outcome, which is LDA.” – Dr. John Tesser

 

DAS28-CRP ≤3.2 (LDA) at Week 12

a††††p≤0.0001 vs PBO + csDMARDs; DAS28-CRP ≤3.2 at Week 12 (UPA + csDMARDs vs PBO + csDMARDs) was a ranked key secondary endpoint and was controlled for multiplicity. Full analysis set (NRI).

1. Genovese MC, et al. Lancet. 2018;391(10139):2513-2524.
2. Data on File. AbbVie. ABVRRTI68842.

 

CDAI ≤10 (LDA) Responses at Week 12 Across Patient Populations

Irrespective of the number or type of bDMARDs previously received, patients with RA who were bDMARD-IR achieved improvement in signs and symptoms with UPA.

Nominal p-values: p>0.05, p<0.05, ††p<0.01, †††p<0.001 vs PBO + csDMARDs.

aPre-specified analyses; not controlled for multiple comparisons. Nominal p-values are provided. P-value not reported for the intolerance subgroup due to low patient numbers. Full analysis set (NRI).

1. Weinblatt ME, et al. Poster FRI0171. EULAR 2019. June 12-15, 2019; Madrid, Spain.

 

Long-term Safety Analysis of UPA Up to ~4.5 Years From the SELECT Phase 3 Program

Any UPA 15 mg QD Exposure Across All 6 Phase 3 Trials in the SELECT Program

As of June 30, 2020, a total of 3209 patients with RA received ≥1 dose of UPA 15 mg QD across all 6 Phase 3 trials, representing a total of 7023.8 PYs of exposure, with a mean duration of 114 weeks (median duration of 136 weeks).1

.

aIncludes UPA monotherapy and combination therapy with csDMARDs across 6 Phase 3 studies.
bExcludes TB, oral candidiasis, and herpes zoster.
cVTE includes DVT and PE.
dAll CV events, including VTE, across the clinical program were adjudicated by a blinded external CV adjudication committee.
eMACE is defined as CV death, nonfatal myocardial infarction, and nonfatal stroke.
fPooled 12-month data from 1213 patients who received ≥1 dose of UPA 15 mg.
*Event rates per 100PY are shown in 4.5 year integrated data set while incidence rates per 100PYs are shown in 12-month data set from EARLY, MONOTHERAPY, NEXT and BEYOND studies.

SELECT-BEYOND Safety Summary Through Week 12 (PBO-Controlled Period)5

Throughout the 12-week PBO-controlled period of SELECT-BEYOND, serious infections occurred in 1 patient (1%) receiving UPA (15 mg QD + csDMARDs). Opportunistic infections occurred in 1 patient (1%) receiving UPA (oral candidiasis). Herpes zoster infections occurred in 1 patient (1%) receiving UPA and 1 patient (1%) receiving PBO (+ csDMARDs). Hepatic disorders occurred in 2 patients (1%) receiving UPA and 2 patients (1%) receiving PBO. One MACE was reported with UPA. One VTE was reported in the UPA group (pulmonary embolism).

The trials in the SELECT program were not designed to demonstrate statistically significant differences in AE rates between treatment arms.

AE=adverse event; CV=cardiovascular; DVT=deep vein thrombosis; GI=gastrointestinal; MACE=major adverse cardiovascular event; NMSC=nonmelanoma skin cancer; PE=pulmonary embolism; PYs=patient years; TB=tuberculosis; VTE=venous thromboembolic event.

1. Cohen SB, et al. Poster POS0220. 2021 EULAR Annual Congress; June 2-5, 2021; virtual e-congress.
2. Data on File. AbbVie. ABVRRTI71618.
3. RINVOQ
™ (upadacitinib) [package insert]. North Chicago, IL: AbbVie Inc.; 2022.
4. Data on File. AbbVie. ABVRRTI69047.

5. Genovese MC, et al. Lancet. 2018;391(10139):2513-2524.

 

Summary

A Rheumatologist's Challenge 

Despite the numerous DMARDs available for treating patients with RA, many may not adequately respond to 1 or even multiple csDMARDs or bDMARDs. Managing these patients can be challenging for a rheumatologist.1,2

UPA in Patients Who Are bDMARD-IR

  • UPA was assessed in patients with inadequate response to bDMARDs in the SELECT-BEYOND Phase 3 trial vs PBO2,3
  • Efficacy data shows that patients who are bDMARD-IR, including those who have failed multiple bDMARDs with either the same or different MOAs, may benefit from treatment with UPA2-6

UPA Safety Profile

  • Across ~4.5 years of UPA 15 mg QD exposure in a long-term integrated safety analysis, no new safety signals were observed7,8
  • In SELECT-BEYOND, throughout the 12-week PBO-controlled period, summary of adverse events of interest occurring in patients treated with UPA 15 mg and PBO is presented above. 1 MACE and 1 VTE were reported in the UPA 15 mg QD group.2

1. Strand V, et al. Rheumatol Ther. 2017;4(2):489-502.
2. Genovese MC, et al. Lancet. 2018;391(10139):2513-2524.
3. Rubbert-Roth A, et al. N Engl J Med. 2020;383(16):1511-1521.
4. Supplement to: Genovese MC, et al. Lancet. 2018;391(10139):2513-2524
.
5.
Rubbert-Roth A, et al. Poster POS0671. 2021 EULAR Annual Congress; June 2-5, 2021.
6. Weinblatt ME, et al. Poster FRI0171. EULAR 2019. June 12-15, 2019; Madrid, Spain.
7.
Cohen SB, et al. Poster POS0220. 2021 EULAR Annual Congress; June 2-5, 2021; virtual e-congress.
8. Data on File. AbbVie. ABVRRTI71618.

 

Upadacitinib Indication, Important Safety Considerations, and Boxed Warning

INDICATION

Upadacitinib is a Janus kinase (JAK) inhibitor indicated for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more tumor necrosis factor (TNF) blockers.

Limitation of Use: Use of upadacitinib in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

IMPORTANT SAFETY CONSIDERATIONS AND BOXED WARNING

Serious Infections: Patients treated with upadacitinib are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include tuberculosis (TB), invasive fungal, bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids. Test for latent TB before and during therapy; treat latent TB prior to use. Consider the risks and benefits prior to initiating therapy in patients with chronic or recurrent infection. If a serious infection develops, interrupt upadacitinib until the infection is controlled.

Mortality: In a postmarketing safety study in RA patients ≥ 50 years of age with at least one cardiovascular (CV) risk factor comparing another JAK inhibitor to TNF blockers, a higher rate of all-cause mortality, including sudden CV death, was observed with the JAK inhibitor.

Malignancies: 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. Patients who are current or past smokers are at additional increased risk. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with upadacitinib, particularly in patients with a known malignancy (other than a successfully treated non-melanoma skin cancer), patients who develop a malignancy when on treatment, and patients who are current or past smokers.

Major Adverse Cardiovascular Events (MACE): In RA patients who were ≥ 50 years of age with at least one CV risk factor treated with another JAK inhibitor, a higher rate of MACE (CV death, myocardial infarction, and stroke) was observed compared with TNF blockers. Patients who are current or past smokers are at additional increased risk. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with upadacitinib. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. Discontinue upadacitinib in patients that have experienced a myocardial infarction or stroke.

Thrombosis: Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated with JAK inhibitors, including upadacitinib. Many of these adverse events were serious and some resulted in death. In RA patients who were ≥ 50 years of age with at least one CV risk factor treated with another JAK inhibitor, a higher rate of thrombosis was observed when compared with TNF blockers. Avoid upadacitinib in patients at risk. Patients with symptoms of thrombosis should discontinue upadacitinib and be promptly evaluated.

Hypersensitivity Reactions: Upadacitinib is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients. Serious hypersensitivity reactions such as anaphylaxis and angioedema were reported in patients receiving upadacitinib in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue upadacitinib and institute appropriate therapy.

Other Serious Adverse Reactions: Patients treated with upadacitinib also may be at risk for other serious adverse reactions, including gastrointestinal perforations, neutropenia, lymphopenia, anemia, lipid elevations, liver enzyme elevations, and embryo-fetal toxicity.

Vaccinations: Avoid use of live vaccines during, or immediately prior to, upadacitinib therapy. Prior to initiating upadacitinib, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current immunization guidelines.

Common Adverse Reactions: The most common adverse reactions (≥1%) are upper respiratory tract infections, herpes zoster, herpes simplex, bronchitis, nausea, cough, pyrexia, and acne.

RINVOQ (upadacitinib) [package insert]. North Chicago, IL: AbbVie Inc.; 2022.

 

Review accompanying upadacitinib full Prescribing Information for additional information, visit www.rxabbvie.com or contact AbbVie Medical Information at 1-800-633-9110.

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AbbVie Inc. JAKa-US-00027-MC        Approval Date: 03/2022 v1.0