Millie Long, MD, on New and Upcoming Small Molecule Treatment Options

Thanks to the recent approval of multiple new small molecules for treatment of ulcerative colitis (UC), the treatment landscape has changed, Millie Long, MD, explained at the April 30 Advances in Inflammatory Bowel Disease regional meeting, held virtually. With these recent advancements and more upcoming, it’s important to be aware of the efficacy and safety of all treatment options, which are unique depending upon the mechanism of action.

Dr Long is a professor of medicine in the Division of Gastroenterology and Hepatology at the University of North Carolina, as well as the Director of the Gastroenterology and Hepatology Fellowship Program.

Dr Long tracked the development of therapies for IBD, from sulfasalazine in the 1970s, thiopurines in the 1980s, and then "an explostion of options" with the run of biologics since 2000 (infliximab, adalimumab, vedolizumab, ustekinumab, and more). The last 4 years or so have seen approvals in the small molecule class for UC with tofacitinib (2018), ozanimod (2021), and upadacitinib (2022).

Dr Long explained that ozanimod, a sphingosine-1-phosphate (S1P) receptor modulator, works by internalizing S1P receptors in lymphocytes and preventing them from mobilizing to inflammatory sites. This small molecule binds "with very high-affinity to S1P subtypes 1 and 5" and the selectivity of this agent "really helps with safety," Dr Long stated. In the TRUE NORTH phase 3 trial for patients with UC, the rates of clinical remission and response, endoscopic improvement, and mucosal healing at week 10 were higher among those patients treated with ozanimod for induction than among those receiving placebo. In maintenance, ozanimod showed better clinical remission and response, endoscopic improvement, and mucosal healing, and had better rates of maintenance remission, glucocorticoid-free remission, and durable remission at week 52 than placebo. When considering positioning, Dr Long stated that without prior exposure to anti-TNF therapies who were treated with ozanimod had "a much more robust induction" at week 10 than those patients who had previously been exposed. She added, though, that at week 52, "no matter which group you're in, if you respond, you have good maintenance results."

Safety considerations for ozanimod include a risk of bradycardia, serious or opportunistic infections, macular edema, and elevated liver enzymes. Additionally, in TRUE NORTH, absolute lymphocyte count decreased by a mean of 54% from baseline to week 10, though Dr Long noted "We didn't see severe lymphopenia." Bradycardia was more common among those patients treated with ozanimod than with placebo during induction therapy (though, not during maintenance). Elevated liver aminotransferase levels were more common with ozanimod therapy than placebo, though Dr Long noted that none of the patients reached Hy’s law criteria suggestive of drug-induced liver injury or had severe liver injury.

There is also a contraindication for patients with Mobitz type II second- or third-degree atrioventricular block, sick sinus syndrome, or sinoatrial block except, with a functioning pacemaker.

Before beginning treatment with ozanimod, Dr Long recommends performing an electrocardiogram, an ophthalmological evaluation for patients at risk of macular edema, and confirming the varicella zoster vaccination status of the patient. During treatment, liver enzymes should be monitored during induction and periodically throughout. Dr Long also pointed out, "We do need better data surrounding pregnancy with ozanimod." According to animal data it may cause fetal harm. Therefore, contraception is recommended.

Next, Dr Long addressed etrasimod, a selective S1P receptor modulator currently in the pipeline. In the CULTIVATE phase 2 dose-ranging trial for treatment of UC, patients treated with etrasimod had better improvement from baseline to 12 weeks in modified Mayo Clinic Score, endoscopic improvement, and clinical remission, than patients receiving placebo. In the ELEVATE 12 phase 3 trial among patients with UC who had previously failed or were intolerant to at least 1 conventional, biologic or Janus kinase (JAK) inhibitor therapy, there was a statistically significant difference between etrasimod treatment and placebo for all primary and secondary endpoints. Full results of this study have yet to be released.

Tofacitinib is a JAK inhibitor with pan-JAK activity (with a higher affinity for JAK1 and JAK3 than JAK2 and TYK2) that was approved in 2018 for treatment of adults with moderate to severe UC. Since that approval though, tofacitinib has been positioned after TNF therapies, and there are "some safety concerns that we want more data on," Dr Long stated. In OCTAVE 1 and OCTAVE 2 (induction trials), and OCTAVE sustain (maintenance trial), patients receiving 10mg of tofacitinib did better in remission, mucosal healing, Mayo Stool Frequency Subscore, and Mayo Rectal Bleeding Subscore than those receiving placebo. Additionally, Dr Long stated that tofacitinib has "a robust timeline to improvement" which means "I may be able to induce with a JAK without using a corticoidsteroids, which would improve my safety."

Adverse effects seen with tofacitinib include herpes zoster, lipid abnormalities, increased serum creatinine kinase, nasopharyngitis, and venous thromboembolic events. Dr Long stated that "the complicated we are potentially worried the most about, but don't have data yet in UC is venous thromboembolism. This concern comes from a safety study of tofacitinib among patients with rheumatoid arthritis, where the treatment arms were associated with increased risk of major cardiovascular events. "We need to consider this," Dr Long stated, "but it's not necessarily that the data are arising from UC data." 

Dr Long suggested checking the complete blood count (CBC) and liver function test (LFT) "for the first 8 weeks, every two weeks...And I do check lipid panel at the beginning and then again at eight weeks." If the lipids have elevated at week 8, a lipid-lowering agent should be added. She also noted that tofacitinib should be avoided if the patient has a lymphocyte count below 500 cells/mm3, an absolute neutrophil count below 1000 cells/mm3, a hemoglobin level below 9 g/dl, or severe hepatic impairment.

Upadacitinib is a selective JAK1 inhibitor, currently in phase 3 trials for both CD and UC. According to the U-ACCOMPLISH and U-ACHIEVE induction studies, patients with UC treated with upadacitinib had a higher rate of remission at week 8 than those in the placebo group. In the U-ACHIEVE maintenance trial, both dosing arms of upadacitinib outperformed placebo on remission at week 52. Secondary endpoints of U-ACHIEVE maintenance also found that upadacitinib was better than placebo in endoscopic remission, corticosteroid-free remission, and maintenance of clinical response.

According to a subgroup analysis, patients who had previously had an inadequate response, loss of response, or intolerance to biologic therapies, and those patients who had not previously experienced an inadequate response to a biologic, who were treated with upadacitinib, "you see a similar effect." Dr Long went on, "This drug doesn't have that loss of effectiveness in that post-TNF position. It seems to be robust across TNF-naïve or TNF-exposed populations."

Dr Long added that when it came to upadacitinib and safety, "the jury is still out." Though she noted that because it is a selective JAK inhibitor, "I think that hopefully we'll find this to be reassuring." The current safety profile for upadacitinib includes risks for herpes zoster, acne, and opportunistic infections.

For the treatment of CD, upadacitinib demonstrated dose-response for endoscopic remission at week 16, according to data from the CELEST trial. Additionally, continued clinical remission and endoscopic response were observed with upadacitinib at week 52. Over 52 weeks in CELEST, the safety profile for upadacitinib was consistent with studies for upadacitinib in rheumatoid arthritis.

Another JAK inhibitor in the pipeline is filgotinib. In the SELECTION phase 2b/3 induction trial for filgotinib for UC, both TNF-naïve and TNF-exposed patient cohorts had better rates of clinical remission at week 10 than the placebo arm. In the maintenance trial, clinical remission and steroid-free remission at week 58 were both better in the filgotinib arms than the placebo.

To demonstrate how to choose a treatment, Dr Long also presented a case. A 59-year-old woman with hyperlipidemia and hypertension presents with a 2-month history of progressive diarrhea, urgency, and mild rectal bleeding. Labs reveal that the patient has mild anemia, a slightly elevated CRP, and an albumin of 3.4. The colonoscopy confirms moderate left-sided colitis. The patient is initiated on mesalamine, both oral and topical, and a prednisone taper. While there is improvement in her symptoms, she begins to worsen with the prednisone tapered to <15 mg. Dr Long also noted that the patient prefers to have a pill option.

Because the disease is moderate and responsive to prednisone, Dr Long explained there is not a huge need for rapidity of therapy. Without prior TNF-exposure, there is no role for tofacitinib or upadacitinib. Additionally, there are risk factors for a cardiovascular event. Ozanimod or a biologic such as ustekinumab and vedolizumab are both reasonable options, Dr Long stated. Given the patient’s preference for oral therapies, though, she suggested discussing ozanimod and providing the appropriate pretreatment testing.

—Allison Casey

Reference:
Long M. What’s new in small molecules? Presented at: AIBD Regionals Meeting; April 30, 2022. Virtual.