Tag Archives: Upadacitinib

Upadacitinib Works Quickly and with High Response

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D Ahuja et al. Am J Gastroenterol 2023; Open Access! Comparative Speed of Early Symptomatic Remission With Advanced Therapies for Moderate-to-Severe Ulcerative Colitis: A Systematic Review and Network Meta-Analysis Thanks to Ben Gold for this article.

Key findings:

  • On network meta-analysis of 14 RCTs, upadacitinib was more effective than all agents in achieving symptomatic remission at weeks 2 (range of RR, 2.85–6.27), 4 (range of RR, 1.78–2.37), and 6 (range of RR, 1.84–2.79). 

This study has a number of limitations including the following:

  • Potential differences in patient-level characteristics between these trials
  • Symptoms may not always correlate with endoscopic findings
  • Data from some medications (eg. tofacitinib) were incomplete and not included

My take: This study indicates an impressive early symptomatic response to upadacitinib compared to other agents for ulcerative colitis.

Related blog posts:

CCFA 2023 (Atlanta) Part 3

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This is third day summarizing some of the talks at the regional CCFA conference. Erin Forster presented on Treatment with Oral Advanced Therapy. Below are my notes and some of the slides; my notes may have errors of omission or transcription. Can get access to full slide set: (n=22) here: Treatment with Oral Advanced Therapy

  • JAK inhibitors (Tofacitinib, Upadacitinib) have rapid onset of action and are taken orally
  • Tofacitinib (Xeljanz) -concern about cardiovascular events was derived from elderly rheumatologic patients.  Cardiovascular events are rare. Higher dose (TID) (in the hospital) associated with lower colectomy rates in acute severe ulcerative colitis.
  • Upadacitinib (Rinvoq) -now approved for CD and UC. Higher dosing could affect liver function (especially if underlying liver disease).  Also, JAK inhibitors as a class have similar safety concerns: increased herpes zoster and concerns for cardiovascular concerns (esp if >50 years)..
  • S!P receptor modulators: Oznaimod, Etrasimod & Amiselimod. Can cause bradycardia -have to check EKG prior.
  • None of the oral agents are safe in pregnancy

More Data: Upadacitinib “is Effective and Safe” Plus 2 in Kids

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S Friedberg et al. Clin Gastroenterol Hepatol 2023; 21: 1913-1923. Open Access! Upadacitinib Is Effective and Safe in Both Ulcerative Colitis and Crohn’s Disease: Prospective Real-World Experience

Methods: “We performed a prospective analysis of clinical outcomes on upadacitinib in patients with UC and CD using predetermined intervals at weeks 0, 2, 4, and 8 as part of a formalized treatment protocol.” 84 met inclusion criteria  (44 UC patients, 40 CD patients) -though complete data was available for only a fraction of these. All of the patients had received prior anti-TNF therapy and 89% had received 2 or more advanced therapies. 

Key findings:

  • Ulcerative colitis: At 4 and 8 weeks of treatment, 19 of 25 (76.0%) and 23 of 27 (85.2%) achieved clinical response and 18 of 26 (69.2%) and 22 of 27 (81.5%) achieved clinical remission, respectively. Of those who previously were tofacitinib-exposed, 7 of 9 (77.8%) achieved clinical remission by 8 weeks.
  • Crohn’s disease: In CD, 13 of 17 (76.5.%) achieved clinical response and 12 of 17 (70.6%) achieved clinical remission by 8 weeks. Of those with increased fecal calprotectin and C-reactive protein levels, 62% and 64% normalized by week 8, respectively. 
  • Results were seen as early as week 2 in both UC and CD, with clinical remission rates of 36% and 56.3.%,
  • Acne was the most commonly reported adverse event, occurring in 24 of 105 patients (22.9%) (Table 4). Six patients stopped upadacitinib due to adverse effects.

My take: “In this large real-world experience in medically resistant patients with UC or CD, we report that upadacitinib is rapidly effective and safe, including in those who had prior tofacitinib exposure.” In pediatrics, the effectiveness of this upadacitinib is a logical target for ImproveCareNow. More pediatric data will be needed to garner FDA approval.

Related articles:

LV Collen. Inflamm Bowel Dis 2023; 29: 1175-1176. Rapid Clinical Remission With Upadacitinib in a Pediatric Patient With Refractory Crohn’s Disease A pediatric patient with Crohn’s disease refractory to anti-tumor necrosis factor therapy, vedolizumab, ustekinumab, and 6-mercaptopurine achieved rapid clinical remission with upadacitinib.

A Bousvaros, BAR Schmidt, M Kurtz. Gastroenterology & Hepatology 2023; 19: 401-403. Open Access! “Treatment of Genital Crohn’s Disease with Upadacitinib in a Male Child: A Case Report”. This report describes the rapid response to upadacitinib in a 12 yo with refractory Crohn’s ileocolitis (x 5 yrs) with associated “granulomatous lymphangitis” affecting the penis and scrotum. It notes that “anti-TNF therapy was described as the most effective treatment, with either improvement or resolution of scrotal swelling in most patients. However, intermittent penile swelling persisted in a subset of the patients.18“…”Although data on the use of JAK inhibitors to treat pediatric IBD are limited, the fact that these are small molecules with wide systemic effects suggests that JAK inhibitors may be useful in the treatment of extraintestinal manifestations of IBD….[and]  that JAK inhibitors such as upadacitinib may play an important role in the treatment of such refractory patients.”

Related blog posts:

On an adventurous day, we climbed the Nietzsche trail to get from the coast to the top of Eze, France.

Landmark Study: Oral Biologic for Crohn’s –Upadacitinib

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EV Loftus et al. N Engl J Med 2023; 388:1966-1980. Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease

This study is the basis for the FDA’s approval of updacitnib (Rinvoq) for Crohn’s disease in adults: New FDA Rinvoq (upadacitinib) Indication: Oral Treatment For Crohn’s

This publication describes the results of two multicenter, double-blind, randomized, placebo-controlled induction trials (n=1021 adults,U-EXCEL, U-ECEED) and one maintenance trial (n=502, U-ENDURE) with Upadacitinib (Rinvoq). The induction trials involved an early mandatory glucocorticoid taper.

Key findings:

  • A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons).
  • There was a rapid onset of action with a difference in clinical response compared to placebo at 2 weeks
  • Maintenance Trial of clinical responders: At week 52 in U-ENDURE, a higher percentage of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons).
  • Adverse effects included gastrointestinal perforations (6 in study medication, 1 in placebo), neutropenia in up to 2.6%, and increased Herpes Zoster infections in patients receiving study medication (1.5% to 3%).

A good commentary of this study is in the same issue: M Abreu. N Engl J Med 2023; 388:2005-2009. It is noted that upadacitinib showed a good response even though a different JAK inhibitor, tofacitinib, had disappointing results for patients with Crohn’s disease. Other points:

  • “It is hard to compare findings across studies because of differences in the characteristics of patients and end points. That being said, the incidences of clinical remission observed by Loftus et al. were greater than those observed in most studies of biologic drugs to treat Crohn’s disease. Moreover, upadacitinib was more likely than placebo to resolve extraintestinal manifestations.”
  • “They did not find evidence of cardiovascular or thromboembolic complications, which were previously observed in patients with rheumatoid arthritis treated with tofacitinib and which led to a black-box warning.10 However, the treatment of greater numbers of patients for a longer duration will be required to determine whether upadacitinib is asssociated with a risk of such complications.”
  • “Among the most common upadacitinib-specific adverse events were anemia [6.9%] and acne [6.3%]. The increase in anemia may be due to off-target effects of upadacitinib on erythropoietin signaling through JAK2.”

My take: This is great news for patients with Crohn’s disease. In addition to having a new option for refractory disease, this option does not require IV administration. When will pediatric data be available?

New FDA Rinvoq (upadacitinib) Indication: Oral Treatment For Crohn’s

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5/18/23: FDA approves first oral treatment for moderately to severely active Crohn’s disease

“Patients should start with 45 mg of Rinvoq once daily for 12 weeks. Following the 12-week period, the recommended maintenance dosage is 15 mg once a day. A maintenance dosage of 30 mg once daily can be considered for patients with refractory, severe, or extensive Crohn’s disease.”

“The most common side effects of Rinvoq as indicated for Crohn’s disease are upper respiratory tract infections, anemia, fever, acne, herpes zoster, and headache…. Serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis have occurred with JAK inhibitors such as Rinvoq.”

Tucson Botanical Gardens

Upadacitinib Receives FDA Approval to Treat Adults with Ulcerative Colitis

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Pharmaceutical Technology (3/17/22): FDA grants approval to AbbVie’s Rinvoq for ulcerative colitis treatment

An excerpt:

The US Food and Drug Administration (FDA) has granted approval to AbbVie’s Rinvoq (upadacitinib) to treat adult patients with moderate-to-severe active ulcerative colitis (UC).

A selective inhibitor of Janus kinase (JAK), Rinvoq is indicated to treat UC patients who had reduced response or are not tolerant to one or more tumour necrosis factor (TNF) blockers.

Per David Rubin: This treatment is a once a day oral pill. In adults, induction consists of 45 mg daily for 8 weeks, then 15 mg or 30 mg for maintenance treatment.

Related blog post: Emerging IBD Treatment: Selective Jak Inhibitor, Upadacitinib 

Shem Creek, SC at dusk

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Emerging IBD Treatment: Selective Jak Inhibitor, Upadacitinib

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Two recent large studies examined the use of Upadacitinib, an oral JAK1 inhibitor, for Crohn’s disease and for Ulcerative Colitis.

The first study, “CELEST,” (n=220) is the “first to evaluate the efficacy, safety, pharmacokinetics, and dose-response of upadacitinib immediate-release formulation in patients with moderate to severe CD and refractory to TNF antagonist therapy using PRO-based clinical and endoscopic endpoints… Nearly half of the patients enrolled in CELEST (44% [96/220]) were taking oral corticosteroids at baseline and underwent a mandatory taper starting at week 2.” The key findings are noted in the graphical abstract (below). A couple of additional points:

  • During the induction period, the 24-mg twice-daily dose exhibited the most consistent association with meaningful improvements for multiple clinical and endoscopic endpoints at week 12 or 16
  • Clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P < .1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib
    twice daily, and by 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo.
  • Endoscopic remission was achieved by 10% (in 3 mg group) (P < .1 vs placebo), 8% (in 6 mg and 12 mg groups) (P < .1 vs placebo), 22% (in 24 mg BID group) (P < .01 vs placebo), and 14% (in 24 mg QD group) (P < .05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo
  • Upadacitinib was also associated with improvements in quality of life, based on IBDQ, observed as early as week 8
  • AEs reported in this study were consistent with those previously observed in clinical trials with JAK inhibitors. Two patients had myocardial infarction events and 1 patient had a mesenteric vein thrombosis.
  • Limitations: sample size, lack of placebo control during maintenance

The second study, “U-ACHIEVE,” for ulcerative colitis (n=250) notes that in cellular assays upadacitinib is up to 60-fold selective for JAK1 over JAK2 and >100-fold selective over JAK3.  The study incorporated a new definition for the primary endpoint of clinical remission using the adapted Mayo score with a more stringent criterion than previous studies. A consistent dose-response relationship with upadacitinib for this primary endpoint was observed. Other points:

  • Upadacitinib was more effective than placebo for inducing remission in patients with moderately to severely active ulcerative colitis
  • The onset of action was rapid, as shown by improvement in the partial
    Mayo score at week 2
  • Endoscopic improvement at week 8, defined as endoscopic subscore of 1, was achieved in 14.9%, 30.6%, 26.9%, and 35.7% of patients receiving upadacitinib 7.5 mg, 15 mg, 30 mg, or 45 mg, respectively, compared with 2.2% receiving placebo (P ¼ .033, P < .001, P < .001, and P < .001 compared with placebo, respectively)
  • Histologic improvement was demonstrated in all treatment arms
  • The types of AEs reported in this study were similar to those previously observed in clinical trials with JAK inhibitors. In the 45 mg daily arm, one patient developed herpes zoster and one participant developed deep venous thrombosis/pulmonary embolism (26 days after discontinuation of study medication)

My take: Upadacitinib looks quite promising for ulcerative colitis and is likely to be helpful in a smaller subset of patients with Crohn’s disease.  HIgher doses appear to be more effective but are likely to be associated with higher rates of adverse events. Further studies, including pediatric trials, are needed.