GUSELKUMAB (TREMFYA)
Guselkumab (Tremfya) injection for intravenous (IV) use is a fully human, dual-acting monoclonal antibody that blocks interleukin (IL)-23 while also binding to CD64, a receptor on cells that produce IL-23. IL-23 is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Guselkumab inhibits the release of proinflammatory cytokines and chemokines.
Guselkumab (Tremfya) is available in two forms: injection for IV use and injection for subcutaneous (SC) use. The lowest effective dosage should be used to maintain therapeutic response.
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal (GI) tract of unknown etiology. IBD has two major categories: ulcerative colitis (UC) and Crohn disease (CD).
ULCERATIVE COLITIS
The most common symptoms of UC are diarrhea, rectal bleeding, urgency to have bowel movements, abdominal cramps, pain, fever, and weight loss. UC primarily causes inflammation of the mucosal lining and is generally limited to the colon and rectum. The treatment of UC is focused on stopping the inflammation and preventing flare-ups. The type of treatment depends on the type and severity of symptoms. Mild symptoms may respond to an antidiarrheal medicine such as loperamide (e.g., Imodium). Treatment for individuals who may be having mild-to-moderate symptoms include aminosalicylates and antibiotics, whereas individuals with severe symptoms may be treated with:
- Immunomodulators/disease-modifying antirheumatic drugs (DMARDs) (e.g., azathioprine, 6-mercaptopurine, methotrexate)
- Demonstrated dependence on corticosteroids (e.g., budesonide [Entocort EC], prednisone, hydrocortisone, methylprednisolone)
- Tumor necrosis factor (TNF) blocker (e.g., adalimumab [Humira®])
- Biologics for the treatment of UC (e.g., ustekinumab [Stelara], risankizumab [Skyrizi], Golimumab [Simponi®])
- Janus kinase (JAK) inhibitors (e.g., tofacitinib [Xeljanz], Upadacitinib [Rinvoq])
- Sphingosine-1 phosphate (S1P) receptor modulator (e.g., Zeposia, Velsipity)
DMARDs can be subdivided into the traditional small-molecular-mass, chemically synthesized nonbiologic DMARDs (such as, but not limited to, methotrexate, sulfasalazine, azathioprine, leflunomide, hydroxychloroquine sulfate, and cyclosporine) and biologic DMARDs. Examples of biologic DMARDs include, but are not limited to, infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira), anakinra (Kineret), golimumab (Simponi, Simponi Aria), tocilizumab (Actemra), and rituximab (Rituxan).
The American Gastroenterological Association (AGA) and the American College of Gastroenterology (2019) have clinical practice guidelines on the management of moderate to severe UC and make recommendations for the use of biologics for induction and maintenance of remission in adults (AGA, 2020; ACG, 2019). Generally, TNF inhibitors such as Entyvio® (vedolizumab IV infusion/SC injection), Stelara® (ustekinumab IV infusion/SC injection), or Xeljanz®/Xeljanz® XR (tofacitinib tablets, tofacitinib extended-release tablets) are recommended for induction treatment of moderate to severe disease (strong recommendations, moderate quality of evidence).
CROHN DISEASE
CD is characterized by inflammation in the digestive tract, anywhere from the mouth to anus, but most commonly in the small intestine and the beginning of the large intestine. Individuals may experience flares, when symptoms are present, followed by periods of remission, lasting weeks to years, where the symptoms disappear. The symptoms usually start slowly and can get worse over time. Common symptoms are diarrhea, abdominal pain and cramping, and weight loss. Outside of the GI tract, symptoms can include joint pain or arthritis, painful skin rashes or bumps, eye irritation, the development of kidney stones, inflammation of the lungs that can lead to difficulty breathing, or inflammation of the liver and bile ducts that can cause primary sclerosis cholangitis. It is estimated that 1 million individuals in the US have CD. CD is more common in individuals between the ages of 13 to 30, have a family member with IBD, smoke cigarettes, or are of Jewish descent. Complications of CD can include anemia, osteoporosis or osteopenia, delayed growth and development, or malnutrition. Serious complications can include intestinal obstruction, the formation of fistulas, or the development of abscesses, anal fissures, or ulcers anywhere along the GI tract. Individuals with CD are also more likely to develop colorectal cancer (CRC). There is no cure for CD, so the goal of treatment is to maintain remission. Treatments may include medication with or without surgery.
Commonly used medications for the treatment of CD are similar to those used for UC, and can include corticosteroids, immunosuppressants, and biologics. However, not all medications that treat UC can also be used to treat CD. For example:
- Immunomodulators (e.g., azathioprine, 6-mercaptopurine, methotrexate)
- Demonstrated dependence on corticosteroids (e.g., budesonide [Entocort EC], prednisone, hydrocortisone, methylprednisolone)
- TNF blocker (e.g., adalimumab [Humira®])
- Biologics for the treatment of CD (e.g., ustekinumab [Stelara], risankizumab [Skyrizi])
PEER-REVIEWED LITERATURE
SUMMARY
The UC approval for guselkumab (Tremfya) for IV use is based on data from the phase 2b/3 QUASAR (A Study of Guselkumab in Participants With Moderately to Severely Active Ulcerative Colitis) study (NCT04033445), which evaluated the safety and efficacy of guselkumab, an interleukin-23 antagonist, in individuals with moderately to severe active UC who had an inadequate response, loss of response, or intolerance to corticosteroids, immunomodulators, biologic therapy, and/or Jak inhibitors. During the 12-week induction study, participants were randomly assigned to receive guselkumab 200 mg (n=421) or placebo (n=280) by IV infusion at week 0, week 4, and week 8. The primary endpoint was clinical remission per modified Mayo Score, defined as stool frequency subscore of no more than 1 and not greater than baseline, rectal bleeding subscore of 0 and endoscopic subscore of no more than 1 without friability at week 12. Results showed 23% of participants treated with guselkumab achieved clinical remission at week 12 compared with 8% of participants who received placebo (treatment difference, 15% [95% CI, 10–20]; P<0.001). Moreover, 27% of guselkumab-treated participants achieved endoscopic improvement at week 12 compared with 11% of participants on placebo (P<0.001). The most common adverse reaction reported was respiratory tract infection.
The expanded approval for CD was supported by data from the Phase 3 GALAXI (A Study of the Efficacy and Safety of Guselkumab in Participants With Moderately to Severely Active Crohn's Disease) and GRAVITI (A Study of Guselkumab Subcutaneous Therapy in Participants With Moderately to Severely Active Crohn's Disease) studies. In the GALAXI 2 and GALAXI 3 studies, individuals who received 200 mg of guselkumab (Tremfya) IV at Weeks 0, 4, and 8 showed statistically significantly higher rates of clinical remission and endoscopic response at Week 12 than individuals who received placebo. Additionally, guselkumab (Tremfya) demonstrated superiority to Johnson & Johnson's ustekinumab (Stelara) across all pooled secondary endoscopic endpoints. Of the randomized individuals, 52% had previously failed at least one biologic therapy. In the GRAVITI study, guselkumab (Tremfya) at 400 mg SC at Weeks 0, 4, and 8 met the coprimary endpoints of clinical remission and endoscopic response at Week 12 versus placebo.
OFF-LABEL INDICATIONS
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company's off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
