Elevating RA Treatment Expectations

NOVEMBER 11, 2019
Aileen Lorenzo Pangan, M.D., Executive Medical Director of Immunology, AbbVie
Rheumatoid arthritis (RA) is a complex, systemic autoimmune disease that is well known but not well understood. One related consequence – many people living with RA do not achieve remission. [1]

Many continue to struggle daily through painful joints and fatigue, unable to do many of the things that they used to.[2]

The good news? The heightened community focus on research and development can help change this storyline.

Remission or low disease activity are the primary goals of RA treatment as defined by the American College of Rheumatology (ACR) guidelines.[3] But not all patients can get there despite the progress in the management of RA over the last couple of decades. This challenge is what drives all of us who work in this field each day.

Early in my career as a rheumatologist, there were fewer treatment options available for moderate to severe RA. For many patients who had an RA diagnosis, chronic pain, irreversible joint deformities and loss of function are what slowly unfolded before their eyes over time. Fortunately, tumor necrosis factor (TNF) inhibitors soon came to the clinic, which helped to address these challenges. As a physician, I went from managing recurrent flares and having the difficult conversation about joint damage, to counseling patients that with these new biologic therapies, they may have a better chance of managing their RA symptoms. Having seen how achieving remission affected the lives of some of my patients, I knew the work was not done until this became a reality for more RA patients.

When I decided to join AbbVie, I was in search of an opportunity to do clinical research that would advance the care of rheumatology patients. Today, I lead a team of physicians and scientists who design and execute clinical trials that evaluate investigational new compounds to treat immune-mediated inflammatory diseases. Our mission is focused on advancing the standard of care for the treatment of the diseases for which we work. The challenge in RA was to develop a new therapy that could elevate treatment expectations and help more patients reach their treatment goals. We knew that different patients respond differently to any given therapy so we needed to better understand what new pathways we could target. 

My colleagues in drug discovery focused on the hypothesis that inhibition of certain Janus Kinases (JAK) could deliver a positive benefit-risk profile in RA patients. Years of diligent work led to the discovery of upadacitinib, now known as RINVOQ, an oral JAK inhibitor that was approved by the U.S. Food and Drug Administration (FDA) in August 2019 for the treatment of adults with moderately to severely active RA who have had an inadequate response or intolerance to methotrexate.[4]

In developing RINVOQ to treat moderate to severe RA, we knew it was necessary to design a comprehensive program so we could have a good understanding of the optimal use of this compound for various types of patients. Our team evaluated RINVOQ in one of the largest registrational Phase 3 programs in RA with approximately 4,400 patients evaluated across all treatment arms in five studies. The SELECT studies included assessments of efficacy, safety and tolerability across a variety of patients with moderate to severe disease from those who were naïve* or intolerant to methotrexate, to patients who had failed or were intolerant to biologic disease-modifying anti-rheumatic drugs. Results from the five pivotal trials showed:
  • RINVOQ met all primary (ACR20 or ACR50 at Week 12 or 14) and ranked secondary endpoints in all five studies
  • Remission rates with RINVOQ (as assessed by DAS28-CRP<2.6) were observed at week 12 or 14 with durable rates through week 26  
  • RINVOQ significantly inhibited radiographic progression with or without methotrexate at week 24 or 26*
We have made progress in our understanding of RA and in our ability to develop new effective medicines for patients living with this disease. With the multiple therapies available today, rheumatologists can better address each patient’s unique needs and more patients can reach their individual treatment goals, something I hoped for when I was still in clinic. I am fortunate and proud to have been a part of making RINVOQ a viable treatment option for many patients.   

* RINVOQ is not indicated for MTX-naive patients.

IMPORTANT SAFETY INFORMATION FOR RINVOQ
SERIOUS INFECTIONS
Patients treated with RINVOQ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt RINVOQ until the infection is controlled.
Reported infections include:
  • Active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease. Test patients for latent TB before RINVOQ use and during therapy. Consider treatment for latent infection prior to RINVOQ use.
  • Invasive fungal infections, including cryptococcosis and pneumocystosis.
  • Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.
Carefully consider the risks and benefits of treatment with RINVOQ prior to initiating therapy in patients with chronic or recurrent infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with RINVOQ, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.
MALIGNANCY
Lymphoma and other malignancies have been observed in patients treated with RINVOQ. Consider the risks and benefits of treatment with RINVOQ prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or in patients who develop a malignancy. NMSCs have been reported in patients treated with RINVOQ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
THROMBOSIS
Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients treated with Janus kinase inhibitors used to treat inflammatory conditions. Many of these adverse events were serious and some resulted in death. Consider the risks and benefits prior to treating patients who may be at increased risk. Patients with symptoms of thrombosis should be promptly evaluated.
GASTROINTESTINAL PERFORATIONS
Gastrointestinal perforations have been reported in clinical studies with RINVOQ, although the role of JAK inhibition in these events is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). RINVOQ should be used with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation.
LABORATORY ABNORMALITIES
Neutropenia
Treatment with RINVOQ was associated with an increased incidence of neutropenia (absolute neutrophil count [ANC] <1000 cells/mm3). Treatment with RINVOQ is not recommended in patients with an ANC <1000 cells/mm3. Evaluate neutrophil counts at baseline and thereafter according to routine patient management.
Lymphopenia
Absolute lymphocyte counts (ALC) <500 cells/mm3 were reported in RINVOQ clinical studies. Treatment with RINVOQ is not recommended in patients with an ALC <500 cells/mm3. Evaluate at baseline and thereafter according to routine patient management.
Anemia
Decreases in hemoglobin levels to <8 g/dL were reported in RINVOQ clinical studies. Treatment should not be initiated or should be interrupted in patients with hemoglobin levels <8 g/dL. Evaluate at baseline and thereafter according to routine patient management.
Lipids
Treatment with RINVOQ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Manage patients according to clinical guidelines for the management of hyperlipidemia. Evaluate 12 weeks after initiation of treatment and thereafter according to the clinical guidelines for hyperlipidemia.
Liver enzyme elevations
Treatment with RINVOQ was associated with increased incidence of liver enzyme elevation compared to placebo. Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) are observed during routine patient management and drug-induced liver injury is suspected, RINVOQ should be interrupted until this diagnosis is excluded.
EMBRYO-FETAL TOXICITY
Based on animal studies, RINVOQ may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RINVOQ and for 4 weeks after the final dose. Verify pregnancy status of females of reproductive potential prior to starting treatment with RINVOQ.
VACCINATION
Use of live, attenuated vaccines during, or immediately prior to, RINVOQ therapy is not recommended. Prior to initiating RINVOQ, patients should be brought up to date on all immunizations, including prophylactic zoster vaccinations, in agreement with current immunization guidelines.
LACTATION
There are no data on the presence of RINVOQ in human milk, the effects on the breastfed infant, or the effects on milk production. Available data in animals have shown the excretion of RINVOQ in milk. Advise patients that breastfeeding is not recommended during treatment with RINVOQ and for 6 days after the last dose.
HEPATIC IMPAIRMENT
RINVOQ is not recommended in patients with severe hepatic impairment.
ADVERSE REACTIONS
The most common adverse reactions in RINVOQ clinical trials (≥1%) were: upper respiratory tract infection, nausea, cough, and pyrexia.

Please see full Prescribing Information.
 
 
[1] Medicines Matter Rheumatology. JAK inhibitors: The next generation of drugs for treating rheumatoid arthritis? https://rheumatology.medicinematters.com/rheumatoid-arthritis-/jak-inhibitors/jak-inhibitors-the-next-generation-of-drugs-for-treating-rheumat/12336972. Accessed June 18, 2019
[2] American College of Rheumatology. Rheumatoid Arthritis. Available at: https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Rheumatoid-Arthritis. Accessed on June 7, 2019.
[3] American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care and Research, 2015. https://www.rheumatology.org/Portals/0/Files/ACR%202015%20RA%20Guideline.pdf. Accessed on May 21, 2019
[4] RINVOQ™ (upadacitinib) [Package Insert]. North Chicago, Ill.: AbbVie Inc.
 


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