Dual biologic or small molecule therapy may benefit highly selected, refractory inflammatory bowel disease (IBD) patients at specialized centers, a meta-analysis suggested.
In a review of 30 studies reporting on 288 trials, Robert Battat, MD, of Weill Cornell Medicine in New York City and colleagues found pooled clinical and endoscopic remission rates of 58.8% (95% CI 42-74.5) for dual biologic therapy and 34.3% (95% CI 23.5-46.1) for small molecule therapy.
In the study, online in Clinical Gastroenterology and Hepatology, the pooled endoscopic response rate was 42.9% (95% CI 26.9-59.6) and the pooled extra-intestinal manifestations (EIMs) response rate in patients with baseline activity was 49.9% (95% CI 14.2-85.7).
Furthermore, the vast majority of these refractory patients were able to avoid surgery, with just 12% (95% CI 4-24) requiring operations. The rates of success were higher in patients on dual therapy for EIMs, the team noted.
“While established therapies and surgery may be reasonable alternatives in those without short bowel syndrome due to recurrent bowel resections, these data suggest that further study is needed on the use of dual biologic or small molecule therapy in treating refractory patients,” the researchers wrote.
Of the 279 patients receiving either dual biologics or small molecule therapy, 76% had Crohn’s disease (CD), and the median duration of treatment was 24 weeks (IQR25-IQR75 13-32).
The main indications for either therapy included medically refractory IBD (81%) and concurrent EIMs or rheumatologic disease (12%).
The most common dual combinations were tumor necrosis factor-α antagonists plus anti-integrins (48%) and ustekinumab plus anti-integrins (19%); a total of 61% of patients had previously not responded to at least one of two therapies later used in combination.
The safety profile of the two treatment approaches were both considered acceptable, the researchers noted. Over a median follow-up of 32 weeks (IQR25-IQR75 13-32), pooled rates of adverse and serious adverse events were 31% (95% CI 13-54%) and 6.5% (95% CI 2.1-13.1%), the researchers reported.
Combination biologics, however, are known to be associated with a higher risk of adverse events in patients with rheumatoid arthritis.
While inter-study heterogeneity was not significant for endoscopic response (P=0.88, I2=0%), endoscopic remission (P=0.44, I2=0%), or malignancy (P=0.87, I2=0), significant heterogeneity existed for other outcomes, including clinical response, clinical remission, corticosteroid-free remission, end EIM response, adverse events, serious adverse events, need for surgery, and infections, the researchers reported.
They noted that despite the optimization of biologic therapies, a significant proportion of patients have a secondary loss of response or are primary non-responders to therapy, with only about 40% of patients with response to biologic therapies maintaining clinical remission at 1 year. In addition, that although data on dual therapy exist in the rheumatologic literature, with five randomized controlled trials (RCTs) completed, the data for IBD remain sparse.
In the absence of RCTs designed to assess safety and efficacy, “this strategy still requires highly specialized care and should only be individualized to select patients with close monitoring,” Battat and colleagues cautioned.
They noted that prospective clinical trials using dual biologic therapy are now ongoing in both CD and ulcerative colitis.
Offering his perspective on the review and meta-analysis, Lukasz Kwapisz, MD, of Baylor College of Medicine in Houston, who was not involved with the study, said that despite the heterogeneity of previous studies, the data from the met-analysis are encouraging.
“We are awaiting prospective data from multiple trials underway in combination biologics and this will go a long way in helping us with widespread use,” he told MedPage Today. “There remains a question: If this strategy was initiated early in the diagnosis, could it affect the natural course of the disease in a positive way and prevent hospitalizations and need for surgery? We are excited to see more data on this topic.”
Battat and co-authors noted several limitations to the meta-analysis, including the observational nature of most of the studies included, the significant inter-study heterogeneity, the inconsistent definitions in reporting patient outcomes across studies, and the greater availability of data on clinical versus endoscopic outcomes. In addition, the team said, while publication bias was not seen for endoscopic response, endoscopic remission, and malignancy, other outcomes demonstrated this bias or could not assess for it.
Battat reported having no conflicts to declare; co-authors reported financial relationships with AbbVie, Pfizer, Takeda, Janssen, Bristol Myers Squibb, AstraZeneca, Genentech, and Protagonist Therapeutics.
Kwapisz reported having no competing interests related to his comments.