Are there data to support dose intensification of golimumab for moderate to severe inflammatory bowel disease (e.g., 100 mg every 2 weeks)?

Introduction
Inflammatory bowel disease (IBD) is a group of immune-mediated inflammatory conditions that affect all or part of the gastrointestinal tract (GI).1 There are 2 major types of IBD: ulcerative colitis (UC), which affects the inner lining of the colon and rectum, and Crohn’s disease (CD), which affects the outer lining of any part of the GI tract. The Centers for Disease Control and Prevention (CDC) reports that there are over 3 million adults living with IBD in the United States, with UC having a slightly higher prevalence than CD (approximately 1.25 million vs 1 million affected).1,2 The etiology of IBD is hypothesized to be caused by an interplay of genetics and environmental factors that trigger the immune system. Non-modifiable risk factors for IBD include non-Hispanic White race and age 45 years and older. Additionally, adults with IBD are more likely to be former smokers, sleep <7 hours daily, have inadequate physical activity, and have a history of serious psychological distress or other chronic conditions.1

Symptoms common to both UC and CD include diarrhea and other changes in bowel movement, fatigue, weight loss, nausea, and abdominal pain.1 Patients with CD often experience non-bloody diarrhea, mouth sores, and malnutrition (depending on the affected part of the GI tract), whereas those with UC are more likely to have bloody or mucus-filled stool due to ulcers, along with pain and urgency during bowel movements. In both CD and UC, the severity of symptoms may change over time, ranging from mild to severe. Many patients experience long periods of remission with proper disease state management; however, active disease flare-ups can occur unexpectedly and negatively impact the quality of life.1,3 Notably, 70% of patients with active UC in a given year will have another episode of active disease in the following year.3 For patients with CD who are in remission, relapse rates are estimated at 20%, 67%, and 76% at 1, 5, and 10 years, respectively.

Biologics in IBD
Biologics are the cornerstone of therapy for moderate to severe IBD, and include agents from several biologic therapy classes, including tumor necrosis factor-alpha (TNF) inhibitors.4-6 Nonetheless, a subset of patients experience an inadequate initial response (ie, primary non-response) or loss of response after initial success (ie, secondary non-response) to biologics.7 Secondary loss of response has been reported in up to 50% of patients, with an annual rate ranging between 5% to 20%. Proactive and reactive therapeutic drug monitoring of trough drug concentrations and anti-drug antibodies can optimize treatment and improve outcomes in patients receiving TNF inhibitors by guiding decisions on dose adjustments, addition of immunomodulators, or therapy switches within or outside the drug class. Notably, dose escalation may reduce or even reverse the loss of therapeutic response to TNF inhibitors, although specific strategies are not addressed in IBD treatment guidelines.4-6 

The remainder of this review summarizes literature describing golimumab dose escalation in UC and CD.8-10 Golimumab is approved for adults with moderately to severely active UC who are steroid-dependent or have failed or were intolerant to prior therapy.11 The labeled dosing for golimumab for UC begins with an initial subcutaneous injection of 200 mg at Week 0, followed by 100 mg at Week 2, and then 100 mg every 4 weeks thereafter. Golimumab is not approved for CD but has been used off-label, and there are other TNF inhibitors with approval for CD (eg, infliximab, adalimumab, certolizumab pegol).10,11 Of note, a separate golimumab formulation for intravenous infusion is not approved for use in patients with UC or CD.

Literature Review
Based on a PubMed literature search conducted in September 2024, golimumab dose escalation was evaluated in 2 observational studies involving patients with UC and one observational study involving patients with CD (see Table 1).8-10 In UC, dose intensification regimens included increasing the maintenance dose (eg, from 50 mg to 100 mg every 4 weeks, 100 mg to 200 mg every 4 weeks, or 100 mg every 4 weeks to 100 mg every 2 weeks).8.9 In patients with CD, the dose intensification regimens were not specifically reported, but strategies included re-induction, shortening of dose interval, or a combination of both.10 All studies demonstrated that patients who experienced secondary loss of response to golimumab achieved improved clinical response and remission rates with golimumab dose intensification.8-10

One of the UC studies had a prospective design, reducing selection and recall bias, but its follow-up period following dose intensification was the shortest at 24 weeks.8 The other 2 studies were retrospective but featured longer follow-up periods, approximately 12 months (UC) and 22 months (CD).9,10 A significant limitation of the UC studies was the use of a lower initial maintenance dose than recommended by the product label.8,9 In one study, half of the patients, and in the other study, the majority of patients, received an initial maintenance dose of 50 mg every 4 weeks instead of the recommended 100 mg every 4 weeks. Lastly, one study reported tertiary loss of response after golimumab dose escalation in 9 patients with UC.9

Table 1. Clinical studies evaluating golimumab dose escalation in UC and CD. 8-10
Study design and durationPopulation Golimumab dose intensification Results following dose escalation
Fumery 20238
 
Prospective cohort, multicenter

Follow up to 24 weeks after dose escalation		N=47 patients with UC who had loss of response after median of 20.4 months of golimumab maintenance dosing: 200 mg at week 0 and 100 mg at week 2, followed by
50 mg (n=25) or 100 mg (n=22) every 4 weeks for patients weighing <80 kg or ≥80 kg, respectively		Maintenance dose escalations (a total of 50 escalations among 47 patients)
 
50 mg every 4 weeks to 100 mg every 4 weeks (25 escalations)


100 mg every 4 weeks to 100 mg every 2 weeks (25 escalations)		Visit 2 (Weeks 2 to 4):
Clinical response: 40%
Clinical remission: 10%
Endoscopic response: 33%
Endoscopic remission: 23%

Visit 3 (Weeks 4 to 8):
Clinical response:44%
Clinical remission:22%
Endoscopic response:45%
Endoscopic remission:41%

Week 26:
Among 29 patients with data, 12 were still being treated with golimumab and 6 were in clinical remission. Infection and UC exacerbation and infection were reported in 1 patient each.
Taxonera 20179

Retrospective cohort, multicenter

Follow-up for the entire study period was approximately 12 months		N=142 patients with moderate-to-severe UC that were receiving golimumab as the first, second, or third TNF inhibitor at the following dosing: 200 mg at week 0 and 100 mg at week 2, followed by 50 mg (n=100) or 100 mg (n=40) every 4 weeks for patients weighing <80 kg or ≥80 kg, respectively
 
During follow-up, 50 of 114 patients (43.8%) who started maintenance therapy experienced secondary loss of response; the golimumab dose was escalated in 31 patients (62%)		Maintenance dose escalations: 
 
50 mg every 4 weeks to 100 mg every 4 weeks (n=28)
 
100 mg every 4 weeks to 200 mg every 4 weeks (n=1)
 
100 mg every 4 weeks to 100 mg every 2 weeks (n=2)		Response: 71% (22 of 31 patients)
 
Tertiary loss of response: 9 patients 
 
Colectomy: 1 patient
Greener 201810

Retrospective cohort, single center

Follow up not clearly defined but roughly at 22 months		N=45 patients with TNF inhibitor refractory CD (failed ≥2 anti-TNF agents)

First-month cumulative doses (induction plus maintenance) were at or above standard doses (ie, 400 mg) in 75% of patients.

Monthly maintenance doses of ≥200 mg were given to 52% of patients		Therapeutic dose optimization was attempted in 10 [28.5%] primary responders who relapsed while on golimumab maintenance therapy; dosing not provided but strategies were: re-induction, shortening of dose interval, and combination of both strategiesClinical improvement: 8 of 10 patients

Abbreviations: CD=Crohn’s disease; TNF=tumor necrosis factor alpha; UC=Ulcerative colitis.

Conclusion 
Golimumab is approved for use in UC and is used off-label in CD.10,11 Although literature on golimumab dose intensification in UC and CD is limited, available studies suggest that this strategy may be beneficial for inducing clinical response and remission in patients with secondary loss of response to the drug.8-10 In 2 studies of patients with UC, dose intensification strategies involved increasing the maintenance dose beyond typical doses (eg, 100 mg every 2 weeks or 200 mg every 4 weeks), while 1 study in patients with CD used strategies such as re-induction and shortening of dose interval. Tertiary loss of response has been reported after golimumab dose escalation in UC.

Prepared by:
Ama D Coffie
PharmD Candidate Class of 2024

Kathy Sarna, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois Chicago College of Pharmacy

October 2024

The information presented is current as September 1, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

Resources 

  1. Inflammatory bowel disease (IBD). Centers for Disease Control and Prevention. Accessed September 24, 2024. https://www.cdc.gov/inflammatory-bowel-disease/index.html
  2. Lewis JD, Parlett LE, Jonsson Funk ML, et al. Incidence, prevalence, and racial and ethnic distribution of inflammatory bowel disease in the United States. Gastroenterology. 2023;165(5):1197-1205.e2. doi:10.1053/j.gastro.2023.07.003
  3. The Facts About Inflammatory Bowel Diseases. Crohn’s & Colitis Foundation of America. November 2014. Accessed September 24, 2024. https://www.crohnscolitisfoundation.org/sites/default/files/2019-02/Updated%20IBD%20Factbook.pdf.  
  4. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG clinical guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019;114(3):384-413. doi:10.14309/ajg.0000000000000152
  5. Feuerstein JD, Isaacs KL, Schneider Y, et al. AGA clinical practice guidelines on the management of moderate to severe ulcerative colitis. Gastroenterology. 2020;158(5):1450-1461. doi:10.1053/j.gastro.2020.01.006
  6. Feuerstein JD, Ho EY, Shmidt E, et al. AGA clinical practice guidelines on the medical management of moderate to severe luminal and perianal fistulizing Crohn’s Disease. Gastroenterology. 2021;160(7):2496-2508. doi:10.1053/j.gastro.2021.04.022
  7. Marsal J, Barreiro-de Acosta M, Blumenstein I, Cappello M, Bazin T, Sebastian S. Management of non-response and loss of response to anti-tumor necrosis factor therapy in inflammatory bowel disease. Front Med (Lausanne). 2022;9:897936. doi:10.3389/fmed.2022.897936
  8. Fumery M, Nancey S, Filippi J, et al. Effectiveness of golimumab intensification in ulcerative colitis: A multicentric prospective study. Aliment Pharmacol Ther. 2023;57(11):1290-1298. doi:10.1111/apt.17421
  9. Taxonera C, Rodríguez C, Bertoletti F, et al. Clinical Outcomes of Golimumab as First, Second or Third Anti-TNF Agent in Patients with Moderate-to-Severe Ulcerative Colitis. Inflamm Bowel Dis. 2017;23(8):1394-1402. doi:10.1097/MIB.0000000000001144
  10. Greener T, Boland K, Steinhart AH, Silverberg MS. The unfinished symphony: golimumab therapy for anti-tumour necrosis factor refractory Crohn’s Disease. J Crohns Colitis. 2018;12(4):458-464. doi:10.1093/ecco-jcc/jjx176
  11. DailyMed. National Library of Medicine. Accessed September 24, 2024. https://dailymed.nlm.nih.gov/dailymed/