Millie Long, MD, on JAK Inhibitors: The Real Deal

Janus kinase (JAK) inhibitors hold great promise for the future in clinical terms because of their strong efficacy and fast onset of action, along with long-term achievement of clinical remission, Millie Long, MD, said in her presentation at the Advances in Inflammatory Bowel Disease Regionals virtual regional meeting, August 27.

Dr Long is a professor of medicine in gastroenterology and hepatology at the University of North Carolina.

Her presentation focused on understanding the JAK and signal transducer and activator of transcription (STAT) signaling pathway, evaluating the efficacy and safety of JAK inhibitor therapies for treating patients with inflammatory bowel diseases (IBD), and exploring upcoming small molecule medications and mechanisms.

Dr Long spoke about the 2 most approved oral JAK inhibitors—tofacitinib and upadacitinib—in the treatment of ulcerative colitis (UC) and Crohn disease (CD). Citing the OCTAVE studies comparing tofacitinib to placebo, tofacitinib showed greater efficacy than placebo with greater numerical values of patients in clinical remission. In OCTAVE 1, 18.5% of the patients taking tofacitinib achieved clinical remission compared to only 8.2% of patients who took a placebo. Similarly, in OCTAVE 2, more patients achieved clinical remission in the tofacitinib group than in the placebo group (16.6% vs 3.6%). The OCTAVE Sustain study demonstrated that tofacitinib 10mg 2 times daily showed more improvement in UC (40.6% of patients) than tofacitinib 5mg 2 times daily (34.3% of patients).

Similar numerical values were seen in mucosal healing with tofacitinib. While tofacitinib 5mg per day produced better results than placebo, tofacitinib 10 mg per day achieved even greater results in managing UC. “Mucosal healing data are very important for me as these numbers give me a better idea of whether the inflammation along the lining of the bowel has in fact, improved or not,” she explained.

Dr Long spoke about considering other biomarkers such as stool frequency and rectal bleeding. She cited studies that provided evidence that tofacitinib is not only effective but also safer and faster. “This drug is fast (as fast as 3 days) in terms of the onset of disease and the posteffects. We can avoid a lot of concurrent steroids since tofacitinib is rapidly effective,” she said.

Dr Long explained that the most recently approved JAK inhibitor, upadacitinib, has repeatedly shown great efficacy in treatment of UC. At weeks 8 and 52, upadacitinib presented impressive remission results among patients with UC, with results consistently better with upadacitinib 30mg and 45 mg vs upadacitinib 15 mg. Whether gauged by endoscopic and histological endpoints or secondary endpoints, upadacitinib 15mg and 30mg have both produced robust results compared to placebo in quick clinical response and long-term clinical remission.

However, Dr Long, noted, JAK inhibitors should be used with awareness of their potential side effects . “Adverse effects such as herpes zoster, lipid abnormalities, increased serum creatinine kinase, nasopharngitis, and venous thromboembolic events have been reported at induction levels and maintenance levels, too.” However, shedding light on the data pulled from OCTAVE 7-year study, she said, “while there were some incidents of herpes zoster and venous thromboembolic events, overall, these events were relatively low. The event rates were not very high and somewhat expected.”

While tofacitinib and upadacitinib have both been approved by the US Food and Drug Administration, there are many other JAK inhibitors are in various phases of approval for treatment of UC and CD, including:

• Filgotnib in phase 3
• Peficitnib in phase 2b for UC
• TD-1473 in phase 3 for UC and phase 2 for CD
• PF-06700841 in phase 2
• PF-06651600 in phase 2
• BMS-986165 in phase 2

Dr Long explained how selective JAK inhibitors have different safety profiles. Infections are potentially increased with JAK1 and JAK 3 inhibitors but not with TYK2 inhibitors. Increases in low-density lipoprotein and high-density lipoprotein typically do not change with most JAK inhibitors, but have shown minor changes in levels with TD 1473, which is a gut-selective JAK inhibitor. Creatinine kinase levels, and reticulocyte and neutrophil counts have remained somewhat similar with most JAK inhibitors, as well. “We definitely need more real-world data and long-term trial data to help us understand whether there may be any difference in the selective agents.”

In conclusion, Dr Long vouched for JAK inhibitors tofacitinib and upadacitinib. “I have used both of these drugs extensively in my practice and I can say they are very efficacious.”

She emphasized the importance of considering any cardiovascular complications and risk of infections before administering a particular type of inhibitor to patients. She is confident of the additional small molecules that are in the pipeline for development and approval, including other selective JAKs. “The future is potentially quite bright for this mechanism as we learn more,” she concluded.

—Priyam Vora

Reference:

Long M, JAK inhibitors in 2022. Presented at: Advances in Inflammatory Bowel Disease Regionals Virtual; August 27, 2022.