A few recent articles provide a lot of practical information regarding implementation of tofacitinib into treatment regimens for ulcerative colitis (UC).
- S Danese et al. Inflamm Bowel Dis 2018; 24: 2106–12. Review article on Tofacitinib.
- J-F Colombel. Inflamm Bowel Dis 2018; 24: 2173–80. Review article on Herpes Zoster due to JAK Inhibitors (eg Tofacitinib).
- KL Winthrop et al. Inflamm Bowel Dis 2018; 24: 2258-65. Clinical study detailing the risk of Herpes Zoster in patients with UC receiving Tofacitinib.
The first of these articles reviews the mechanism of action of tofacitinib (TFB) and the relevant studies showing efficacy for UC. A summary of the results are listed in Table 1. Some of the reported results –with TFB dosed at 10 mg BID:
- In 2012, Sandborn et al: clinical response in 61% at wk 8 and clinical remission of 48% at wk 8.
- In 2017 (OCTAVE Induction 1): clinical response in 18.5% at wk 8 and clinical remission of 31.3% at wk 8.
- In 2017 (OCTAVE Induction 2): clinical response in 16.6% at wk 8 and clinical remission of 28.4% at wk 8.
- In 2017 (OCTAVE Sustain):clinical response in 40.6% at wk 8 and clinical remission of 45.7% at wk 8.
- In all of these studies, TFB outperformed the placebo arm and has had a good safety profile
Most common adverse effects had similar rates in the placebo arm:
Other adverse effects have included pneumonia, herpes zoster (HZ) infection, and increased lipid levels (more common than with placebo group). Trials in patients with rheumatoid arthritis have indicated an increased incidence of nonmelanoma skin cancer, lymphoma, breast cancer, lung cancer, and gastric cancers.
Preclinical studies have shown that TFB could cause fetal malformations when given at much higher doses. Though, clinical experience in humans have not found teratogenic effects; this is based on one study with 9815 RA/psoriasis patients and 47 women who became pregnant.
Role for tofacitinib:
- “Tofacitinib could be used in patients suffering mild, moderate and severe UC…after aminosalicylates (5-ASA)…and as second-line therapy in patients who have been treated with TNF inhibitors.”
Advantages of tofacitinib:
- Oral administration with rapid absorption
- Short serum half-life
- Good experience in large number of patients with rheumatoid arthritis
- No immunogenicity.
- Effective in patients who have had previous anti-TNF agents
More on Herpes Zoster Infection:
- The other two references detail the risk of Herpes Zoster infections with TFB usage.
- Winthrop et al identified 65 (5.6%) of patients developed HZ among phase II/III open-label, long-term extension trials.
- The review by Colombel notes that patients with UC have “an increased risk of HZ compared with the general population, and this risk can be increase by the use of immunosuppressive therapy. JAK inhibitors, including tofacitinib, have been associated with HZ risk…The majority of HZ casees are noncomplicated.”
- In this review, Colombel details an algorithm for treatment of HZ cases and indicates that adults receiving TFB should consider vaccination to lower the risk of HZ.
My take: A significant portion of patients with UC either do not respond to anit-TNF agents or lose response. Tofacitinib provides an alternative treatment with a different mechanism of action. Given the few other non-surgical treatment options, I expect it will be rapidly incorporated into treatment algorithms.
Related blog posts:
W Sandborn et al. N Engl J Med 2017; 376:1723-1736 May 4, 2017DOI: 10.1056/NEJMoa1606910
Abstract from NEJM:
Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy.
We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks.
In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels.
In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo.
From Gastroenterology & Endoscopy News July 2016: Tofacitinib Effective in Refractory and Severe UC
Tofacitinib (Pfizer), an oral agent already approved for certain patients with rheumatoid arthritis, can induce clinical remission in up to 25% of individuals with moderate to severe, refractory ulcerative colitis (UC) and clinical response in as many as 60% of these patients.
The results, based on two placebo-controlled trials involving more than 1,100 patients, showed the drug also increased the risk for serum lipid elevations but was otherwise safe. Researchers presented the data at the 2016 annual meeting of the European Crohn’s and Colitis Organization (ECCO; oral presentation 019)…
The new data are from the OCTAVE Induction 1 and Induction 2 trials, identically designed, randomized, double-blind and placebo-controlled Phase III studies…In the OCTAVE 1 trial, 476 patients received 10 mg of tofacitinib orally twice daily for eight weeks and 122 received an oral placebo. In OCTAVE 2, 429 and 112 patients were randomized to receive the two regimens, respectively.
Screenshot from gastroendonews.com
Also from Gastroenterology & Endoscopy News August 2016: Update on Diagnosis and Treatment for Ulcerative Colitis This article provides a succinct summary regarding diagnosis and treatments of ulcerative colitis; treatments discussed include emerging therapies like tofacitinib.
This blog entry has abbreviated/summarized this terrific presentation; most of the material has been covered in this blog in prior entries (can use search function to find additional relevant material) but still this was a useful review. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.
Emerging Therapies in IBD –Dr. Gary Lichtenstein
Background: This lecture started with a review of current therapies. We have learned how to use our current therapies better. There still remain a large number of patients that face surgery with IBD; though there has been improvement (?50% reduction).
Issues with thiopurines were reviewed. May take 2-6 months to take effect, though monotherapy with thiopurines are fairly ineffective for Crohn’s disease as initial therapy.
Leukocyte Trafficking Agents:
- AJM300 –oral agent. Initial safety data were fine.
- AMG 181
- Etrolizumab (Vermeire S Lancet 2014) –low rates of endoscopic healing, but better than placebo
Ozanimod (RPC1063) (oral agent, fairly rapid onset) causes S1P-r on lymphocytes to be internalized –more selective than Fingolimod. Good safety has been noted thus far. No notable cardiac problems. Infrequent elevations of transaminases; this issue will need to be followed.
Tofacitinib oral Janus Kinus (JAK) Inhibitor (Sanborn WJ et al. NEJM 2012; 367: 616-24). Dr. Lichtenstein thinks 10 mg will be recommended dose. Follow lipids. For UC
Mongerson related post: Mongerson -Phase II Data Available in NEJM | gutsandgrowth
Related article from GI & Hep News: Ustekinumab for complex Crohn’s from ECCO conference/UNITI-1 Study (n=741)
FMT. Further studies are needed
As noted in a previous blog (see below for link), tofacitinib, an oral Janus Kinase Inhibitor has shown promise as an agent for ulcerative colitis. However, its results thus far for Crohn’s disease (CD) have been discouraging. Another study (Clin Gastroenterol Hepatol 2014; 12: 1485-93) reiterates that message.
In brief, 139 patients with moderate-to-severe active CD were randomly assigned to 3 dosage groups of tofacitinib (1-, 5-, and 15-mg) and compared with placebo. There were no significant differences in response or remission between tofacitinib and the placebo group, though there were reductions in both C-reactive protein and fecal calprotectin among patients given the 15-mg dose.
Related blog posts:
Previously Tofacitnib, an oral Janus kinase inhibitor, has shown promise as an emerging treatment for inflammatory bowel disease (Tofacitinib –a JAK Inhibitor for UC | gutsandgrowth). So, a recent large study in tofacitinib use in rheumatoid arthritis caught my attention, specifically with regards to the potential risks of treatment (NEJM 2014; 370: 2377-86).
This double-blind study randomly assigned 958 patients (mean age ~49 years) to receive 5 mg or 10 mg of tofacitinib twice daily or weekly methotrexate. This study, called ORAL Start, examined the effectiveness of these drugs over a 24 month period in patients with active moderate-to-severe rheumatoid arthritis naive to therapeutic doses of methotrexate.
- Among tofacitinib patients, 25.5% (5 mg group) and 37.7% (10 mg group) had an ACR 70 response at 6 months compared with 12.0% of methotrexate patients. Results at 12 and 24 months were similar (Figure 1)
- Adverse effects:
- 4% of tofacitinib patients developed herpes zoster compared with 1.1% of methotrexate patients
- 5 tofacitinib patients developed cases of cancer (three cases of lymphoma) compared with 1 case among patients receiving methotrexate
- Tofacitinib was associated with decreases in neutrophil/lymphoctye counts, increases in creatinine levels, increases in aminotransferases, and increases (16-22%) in LDL/HDL cholesterol levels
- Four deaths were noted among patients treated with tofacitinib compared with none in the methotrexate patients.
Related blog post: Source Article: Methotrexate Safety | gutsandgrowth
At a recent group dinner meeting, we had the opportunity to review therapeutic anti-TNF monitoring. In addition, we discussed emerging treatments for inflammatory bowel disease, like golimumab, tofacintinib and vedolizumab.
As noted in previous blog entries (see below), therapeutic anti-TNF monitoring can help adjust treatment. Namely, if a patient loses response to therapy and has low trough levels of anti-TNF (Infliximab ❤ μg/mL, Adalimumab <8 μg/mL, or certolizumab <27.5 μg/mL) without antidrug antibodies (ADAs), then increasing the dose is likely to be effective. However, if a patient has a therapeutic level and is not responding, changing to another agent and/or further investigation is worthwhile.
So, what information is new?
- Only about 20% of patients who lose clinical response develop ADAs. So, drug level, rather than ADAs, is most helpful.
- For infliximab, adjusting dose 14 weeks into therapy to achieve a target trough level between 3-7 mcg/mL may be helpful.
- Severe colitis patients may need higher initial doses (?as high as 20 mg/kg) due to potential for ‘antigen sink.’ This is due to notably higher clearance in the presence of low albumin, and high CRP. Other factors that increase clearance include higher BMI and male gender.
- About 1/2 of patients who receive higher doses due to severe disease may be able to deescalate dosage when improved. (?which half)
- Currently, a reactive approach to checking levels is common in U.S. in part due to costs associated with checking trough levels and ADAs (as much as $2500). That is, most commonly checking levels is undertaken in patients with suboptimal clinical response. A proactive approach to achieve target levels may be shown to be helpful.
- While studies have not shown higher adverse reactions with higher trough levels, there are a few clinical situations in which lower trough levels can be important. In patients with psoriatic skin lesions and arthralgias, if trough levels are elevated, lowering the dose may be helpful.
- Should patients have drug levels checked when they are asymptomatic?
- How does a practitioner account for variability among different laboratory assays?
- What is the optimal target level for each anti-TNF agent? Is this different in Crohn disease compared with ulcerative colitis? Is the trough target level different in adults than children?
- Is there a toxic level?
- If a rapid test response were available, would checking drug levels be needed for hospitalized patients to assess anti-TNF rescue therapy?
Related blog links:
Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition
There are definitely a lot of new therapies on the horizon for inflammatory bowel disease. One of these agents is likely to be tofacitinib which has shown efficacy for active ulcerative colitis (NEJM 2012; 367: 616-24).
Background: Tofacitinib is a selective oral inhibitor of Janus kinase (JAK) which mediates activity for multiple cytokines, including interleukins 2, 4, 7, 9, 15, and 21. Blockage of a common signaling molecule by these cytokines “should result in suppression of both T and B cells while maintaining regulatory T-cell function. It has shown efficacy for organ allograft rejection, rheumatoid arthritis, and psoriasis.” A previous small study by these investigators did not demonstrate efficacy in Crohn’s disease (Gastroenterology 2011; 140: Suppl: S124 Abstract).
Design: In this study which began as a double-blind, placebo-controlled, phase 2 trial, tofacitinib or placebo was given to 194 adult patients (from 51 centers in 17 countries) with moderate-to-severe active ulcerative colitis. Dosing for tofacitinib included groups receiving 0.5 mg, 3 mg, 10 mg, or 15 mg (all BID). “The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system.” Most of these patients had failed conventional therapy, including mesalamine, corticosteroids, immunosuppressants, and anti-TNF agents.
Results: At 8 weeks, the primary outcome with the highest doses (10 mg & 15 mg) of tofacitinib had clinical response rates of 61% (p=0.1) and 78% (p<0.001) respectively compared with a 42% placebo response. Clinical remission (Mayo score ≤ 2) occurred in 48% and 41% respectively (both p<0.001) compared with 10% in placebo group. Endoscopic remission was noted in 30% and 27% respectively (both p<0.001) compared with 2% of placebo group.
In addition, tofacitinib administration improved CRP values and fecal calprotectin concentrations (Figure 2 of article).
Potential adverse effects included the following
- neutropenia (ANC 1000-1500) observed in three treated patients
- two tofacitinib patients (10 mg group) developed abscesses
- mild increases in LDL and HDL were noted and dose-related (these changes have been seen in rheumatoid arthritis patients as well)
- N Engl J Med 2012; 367:495-507 | August 9, 2012. Tofacitinib for rheumatoid arthritis