Picking Apart the SERENE-CD Study & Constipation Vibrating Capsule FDA Approved

Several recent letters to the editor provide some insight into some of the shortcomings of the SERENE-CD study which reported that higher adalimumab induction dosing and proactive therapeutic drug monitoring (TDM) were not associated with improved outcomes.

“The rerandomization design of SERENE CD, which selectively enrolled patients with clinical response at week 12 to the TDM vs CA part of the study, may have resulted in the exclusion of those who would have benefited the most from early adjustment of their anti-tumor necrosis factor (TNF) dose. The rerandomization design and the late adaptation of the proactive strategy at week 12 were 2 significant aspects of the design that may have led to the negative results. On the other hand, PAILOT, which showed beneficial effects of proactive TDM, randomized patients as early as week 4 and assessed the outcome at week 72. This is distinct from the 1-year time frame used in most other studies, including SERENE CD.8 A properly designed, adequately powered clinical trial is needed before we can make a judgement on the use of proactive TDM in patients with inflammatory bowel disease. Until then, the jury remains out.”

“The study design only allowed patients in the TDM group with adalimumab concentrations of ≥5 and ≤10 μg/mL to be escalated to 40 mg every week if their CD activity index was ≥220 or their high-sensitivity C-reactive protein level was ≥10 mg/L.. The goal of proactive TDM is to attain a threshold concentration regardless of disease activity. This design probably led the 2 groups to have similar drug concentrations at week 56…

Second, a rather low targeted drug concentration of 5 μg/mL was used, although previous studies have suggested that higher concentrations are more appropriate.5678 A study from Ungar et al5 showed that adalimumab concentrations of 8–12 μg/mL are required to achieve mucosal healing in 80%–90% of patients with IBD, and the prospective PANTS (The Personalised Anti-TNF Therapy in Crohn’s Disease Study) study identified an adalimumab concentration of 12 μg/mL at week 14 associated with remission at both week 14 and week 54.8..

Third, dose escalation for the TDM group could only happen at weeks 14, 28, or 42 (and not earlier and more often). In the PAILOT RCT, proactive TDM based on adalimumab concentration evaluations started as early as week 4 followed by week 8 and every 8 weeks thereafter until the end of the follow-up at week 72.3 Fourth, there was a rather short follow-up of the patients (44 weeks).”

” Even with the assumption of a 30% benefit of proactive TDM and that 20% of patients would have low drug levels in the absence of symptoms, the sample size for 80% power would range from 1228 to 2170. Thus, although SERENE CD1 and other clinical trials3,4 have suggested a lack of benefit of proactive TDM in adults with inflammatory bowel disease, all were likely substantially underpowered to do so.”

My take: While the SERENE-CD results have suggested that a strategy of proactive TDM may not be helpful, there are a lot of reasons to disregard these findings. Achieving a therapeutic level is a fundamental principle and proactive TDM, particularly in pediatrics, is well-supported by other studies.

Related blog posts:

Also noted:

Adalimumab Biosimilars on the Horizon (Finally) Plus Two Studies

GoodRx Health (Jan 3, 2023): Humira Biosimilar Boom: 8 Meds Launching in 2023 There are more than 17 billion reasons why there are 8 new adalimumab (Humira) biosimilars coming to the market.

Excerpts:

1. Amjevita

Amjevita (adalimumab-atto) will be available in prefilled autoinjector pens (40 mg) and prefilled syringes (20 mg, 40 mg). Amjevita products will come in low-concentration forms, but they will be citrate-free. It’s expected to launch on January 31, 2023.

2. Cyltezo

Cyltezo (adalimumab-adbm) became the first biosimilar to be designated as interchangeable with HumiraInterchangeable biosimilars go through additional studies to determine whether you can switch back and forth between the biosimilar and the original product without issues. Biosimilars without this designation haven’t gone through these same studies. 

Cyltezo will only be available in a prefilled syringe and will come in two doses: 20 mg and 40 mg. Both are low-concentration forms and citrate-free. Cyltezo is expected to launch in the U.S. as early as July 1, 2023.

3. Hyrimoz

Hyrimoz (adalimumab-adaz): a 40 mg dose will be available in both a pen and a syringe. A 10 mg syringe will also be available. Both are low-concentration forms. These products contain citric acid, which is closely related to citrate. Citric acid can also make injections more painful. A citrate-free high-concentration form of Hyrimoz is currently under FDA review. Hyrimoz is expected to launch in the U.S. on September 30, 2023.

4. Hadlima

Hadlima (adalimumab-bwwd) will be available in both an autoinjector and a syringe in a 40 mg dose. And it will come in both low- and high-concentration forms. The high-concentration form will be citrate-free. Hadlima is expected to launch in the U.S. on or after July 1, 2023.

5. Abrilada

Abrilada (adalimumab-afzb) will be available in a prefilled pen (40 mg) and in a syringe (10 mg, 20 mg, 40 mg). All Abrilada products will be low-concentration forms and citrate-free. Abrilada’s manufacturer has applied for interchangeable status with Humira. Abrilada is expected to launch in the U.S. as early as July 1, 2023.

6. Hulio

Hulio (adalimumab-fkjp) will be available in a prefilled pen (40 mg) and in a syringe (20 mg and 40 mg). All forms are low-concentration and citrate-free. Hulio is expected to launch in the U.S. on or after July 1, 2023.

7. Yusimry

Yusimry (adalimumab-aqvh) will only be available in a 40 mg prefilled syringe. It will be in a low-concentration form and citrate-free. Yusimry is expected to launch in the U.S. on or after July 1, 2023.

8. Idacio

Idacio (adalimumab-aacf) will be available in a 40 mg dose in both a pen and a syringe. Both forms will be low-concentration and citrate-free. Idacio is expected to launch in the U.S. as early as July 1, 2023.

My take: In high school, one of math teachers used to call me Hochman sub-1 and my twin brother Hochman sub-2. Perhaps, we can start designating biosimilars in a similar fashion?

Related blog posts:

Two other important studies I wanted to cite -both studies have Benjamin Gold, one of my better-known partners, as one of the authors:

  • KA Chien, C Thomas, V Cooley, T Weinstein, KF Murray, L Muir, C Hayes, BD Gold, LM Gerber, CG Sauer, G Tomer. JPGN 2023; 76: 25-32. Physician Burnout in Pediatric Gastroenterology In this survey with 408 responses (23% response rate), the authors found 29% reported high risk for emotional exhaustion, 18% reported high risk for depersonalization, and 33% reported overall burnout.
  • VC Cohran, BD Gold, DJ Spencer, CR Cole. JPGN 2022; 75: 689-691. Health Care Disparities in Gastroenterology: The Pediatric Gastroenterology Perspective This commentary reviewed survey results highlighting healthcare disparities which have been identified in IBD, NALFD, and liver transplantation. The authors outline some of the steps that NASPGHAN has taken as well as some of the work that is needed.

Coming to a GI Clinic Near You? Intestinal Ultrasound for Ulcerative Colitis

F De Voogd, et al. Gastroenterol 2022; 163: 1569-1581. Intestinal Ultrasound Is Accurate to Determine Endoscopic Response and Remission in Patients With Moderate to Severe Ulcerative Colitis: A Longitudinal Prospective Cohort Study

27 patients with moderate to severe ulcerative colitis (UC) completed followup in this single-center, prospective, longitudinal cohort study. Key findings:

  • Bowel wall thickness (BWT) correlated with endoscopic Mayo score. “The most accurate cutoff for BWT was 2.8 mm for endoscopic remission, 3.9 mm for improvement, and a decrease of 32% for response.”

The associated editorial (C Palmela, C Maaster. Gastroenterol 2022; 163: 1485-1487. Open Access! The Use of Intestinal Ultrasound in Ulcerative Colitis-More Than a Mucosal Disease?) details other studies showing the utility of intestinal ultrasound, including the TRUST%UC study which enrolled 253 patients with UC. “. At baseline, 88.5% of patients had increased bowel wall thickness (BWT). Response to therapy could be detected as early as 2 weeks after initiation of therapy, as shown by reduction of abnormal BWT.” In anothre study with severe UC, “BWT reduction of >20% being an excellent predictor of response to intravenous steroids at 48 hours, as shown recently by Ivemark et al.10

The editorial notes that intestinal ultrasound “is often thought as being operator dependent. Nonetheless, several studies have shown an excellent inter-observer agreement in IUS, especially for the assessment of BWT,7,12 as was also found in this [De Voogd] study.” An additional finding in the De Voogd study was that the “the submucosa was the most thickened layer, and after 8 weeks of therapy it was also the most responsive layer;” thus, UC is not simply a mucosal disease.

My take: This study shows that with more widespread adoption, many UC patients could be followed non-invasively with intestinal ultrasound (and calprotectin).

Related blog post:

Vancomycin for Chronic Pouchitis & ASPEN Infant Formula Resources

G Lupu et al. Inflamm Bowel Dis 2022; 28: 1610-1613. Vancomycin Is Effective in the Treatment of Chronic Inflammatory Conditions of the Pouch

In this retrospective study of 41 adults with history of ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC), the authors evaluated the clinical response (subjective judgement of provider) to chronic vancomycin therapy (125 mg twice a day).

Key findings:

  • At 4 weeks, 21 (51%) of patients had a clinical response. 16 of these patients maintained a clinical response at 3 and 6 months (remained on treatment).
  • 6 additional patients demonstrated a later response. In total 22 (54%) were considered clinical responders at 3 and 6 months.
  • The mean number of antibiotics utilized prior to vancomycin was 4, including ciprofloxacin, metronidazole, levofloxacin, rifaximin, sulamethoxazole-trimetoprim, amoxicillin, and amoxicillin-clavulanic acid

My take: Since vancomycin has poor enteral absorption, it’s side effect profile is very favorable. More prospective and objective data is needed; however, vancomycin’s high cost will likely limit frequent use.

Related blog posts:

Link: ASPEN Formula Resource Practice Tool (sponsored by ByHeart)

Which Diet is Best for Irritable Bowel Syndrome? A Randomized Trial

A Rej et al. Clin Gastroenterol Hepatol 2022; 20: 2876-2887. Open Access! Efficacy and Acceptability of Dietary Therapies in Non-Constipated Irritable Bowel Syndrome: A Randomized Trial of Traditional Dietary Advice, the Low FODMAP Diet, and the Gluten-Free Diet

Methods: In patients (n=99) with Rome IV–defined non-constipated IBS, outcomes after randomization to one of three diets were compared. The “traditional dietary advice” group: “Its principles include adopting healthy, sensible eating patterns such as having regular meals, never eating too little/too much, maintaining adequate hydration, and reducing the intake of (1) alcohol/caffeine/fizzy drinks, (2) fatty/spicy/processed foods, (3) fresh fruit to a maximum of 3 per day, (4) fiber and other commonly consumed gas-producing foods (eg, beans, bread, sweeteners, etc), and (5) addressing any perceived food intolerances (eg, dairy).” (Link: National Institute for Health and Care Excellence advice on IBS mgt). The Gluten-Free diet allowed for cross-contamination. All patients had specialist dietary counseling.

Key findings:

  • All three diets resulted in improvement. The primary end point of ≥50-point reduction in IBS-SSS was met by 42% (n = 14/33) undertaking TDA, 55% (n = 18/33) for LFD, and 58% (n = 19/33) for GFD (P = .43)
  • Alterations in stool dysbiosis index were similar across the diets, with 22%–29% showing reduced dysbiosis
  • “The pragmatic study design, whereby the responsibility was left on patients to undertake the diets following appropriate education, means our findings can be generalized”

My take: All three diet approaches would be appropriate to reduce IBS symptoms, thought the TDA is the easiest for patients.

Related blog posts:

Favorite Posts 2022

Thank you to those who have helped me this past year with this blog –colleagues, friends and family. Wishing all of you a good 2023. Here are some of my favorite posts from this past year:

GI:

Nutrition:

Liver:

Endoscopy:

Health Policy:

Humor:

Most Popular 2022 Posts

The list of the most viewed gutsandgrowth blog posts in 2022.

Links to Posts:

Updated Nomenclature for Eosinophilic Gastrointestinal Diseases

ES Dellon et al. Clin Gastroenterol Hepatol 2022; 20: 2474-2484. Open Access! International Consensus Recommendations for Eosinophilic Gastrointestinal Disease Nomenclature

This article has 91 authors! Using Delphi surveys, the authors recommend the following:

  • “EGID” was the preferred umbrella term for disorders of gastrointestinal (GI) tract eosinophilic inflammation in the absence of secondary causes
  • Involved GI tract segments will be named specifically and use an “Eo” abbreviation convention: eosinophilic gastritis (now abbreviated EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC)
  • For EoN, “it is desirable, but not required, to name specific locations of small bowel involvement, if these are known…The abbreviation for eosinophilic duodenitis should be “EoD”… for eosinophilic jejunitis should be “EoJ”….eosinophilic ileitis should be “EoI”
  • The term “eosinophilic gastroenteritis” is no longer preferred as the overall name (but can be used to indicate involvement of both the stomach and small bowel)
  • When >2 GI tract areas are involved, the name should reflect all of the involved areas

IBD Updates: Dietary Patterns and Disease Activity, Ustekinumab in SUSTAIN study, INSPECT Study for Perianal Fistulas

BN Limketkai et al. Inflamm Bowel Dis 2022; 28: 1627-1636. Open Access! Dietary Patterns and Their Association With Symptoms Activity in Inflammatory Bowel Diseases. This retrospective study with dietary surveys of 691 participants found the following:

  • Compared with WD1 (typical Western Diet), PB2 (Plant-based diet 2) was associated with lower odds of active symptoms for CD (odds ratio [OR], 0.32
  • PB1 (Plant-based diet 1) was associated with lower odds of active symptoms for participants with UC (OR, 0.45; 95% CI, 0.23-0.90) but not for participants with CD (OR, 0.95

Diet PB1 (“Plant-based Diet 1”) was characterized by much higher intake of fruits, vegetables, plant-based proteins, and cooked grains than most other dietary clusters. There was low water intake in favor of juices and other beverages. There was otherwise average intake of added fats and oils, sugars, seafood, and dairy products, and modest intake of meats, eggs, mixed grains, and breads.

Diet PB2 (“Plant-based Diet 2”) was characterized by high intake of fruits, vegetables, plant proteins, and cooked grains and low intake of animal proteins (especially red and cured meats), added fats, sweetened beverages, sweet bakery products, other desserts, eggs, and breads. There was also a reduction of other beverages in favor of water. There was otherwise an average intake of seafood and dairy products.

M Chaparro et al. Inflamm Bowel Dis 2022; 28: 1725-1736. Open Access! Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study In this retrospective study, 97% of the 463 patients had received prior biological therapy.

  • At week 16, 56% had remission, 70% had response
  • 26.1% required dose escalation or intensification
  • After a median follow-up of 15 months, 356 (77%) patients continued treatment.
  • Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation.
  • Neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk

J Panes et al. Inflamm Bowel Dis 2022; 28: 1737-1745. Open Access! INSPECT: A Retrospective Study to Evaluate Long-term Effectiveness and Safety of Darvadstrocel in Patients With Perianal Fistulizing Crohn’s Disease Treated in the ADMIRE-CD Trial

Background: The current chart review study evaluated the longer-term effectiveness and safety of darvadstrocel (expanded allogeneic adipose-derived mesenchymal stem cells).; n=43 treated patient and n=46 controls.

Key findings:

  • At 52, 104, and 156 weeks posttreatment, clinical remission was observed in 29 (67.4%) of 43, 23 (53.5%) of 43, and 23 (53.5%) of 43 darvadstrocel-treated patients, compared with 24 (52.2%) of 46, 20 (43.5%) of 46, and 21 (45.7%) of 46 control subjects, respectively.

Mailing Letters to People and Risk of Colorectal Cancer

A widely covered news story in October 2022 was the disappointing results/modest benefits of a colonoscopy screening study. This study actually supports the use of colonoscopy to reduce colorectal cancer deaths but shows that typical screening programs may not work well if patients don’t show up for the test.

M Bretthauer et al. NEJM 2022; 387: 1547-1556. Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death

Methods: This was “a pragmatic, randomized trial involving presumptively healthy men and women 55 to 64 years of age drawn from population registries in Poland, Norway, Sweden, and the Netherlands between 2009 and 2014. The participants were randomly assigned in a 1:2 ratio either to receive an invitation to undergo a single screening colonoscopy (the invited group) or to receive no invitation or screening (the usual-care group).”

There were 84,585 participants in Poland, Norway, and Sweden — 28,220 in the invited group,

Key findings:

  • Only 11,843 (42.0%) in the invited group underwent colonoscopy screening
  • During a median follow-up of 10 years, 259 cases of colorectal cancer were diagnosed in the invited group as compared with 622 cases in the usual-care group
  • The risk of colorectal cancer at 10 years was 0.98% in the invited group and 1.20% in the usual-care group, a risk reduction of 18%
  • The risk of death from colorectal cancer was 0.28% in the invited group and 0.31% in the usual-care group (risk ratio, 0.90; 95% CI, 0.64 to 1.16)
  • The risk of death from any cause was 11.03% in the invited group and 11.04% in the usual-care group

If all invited participants had received a colonoscopy, the authors estimate the risk of colorectal cancer would have decreased from 1.22% to 0.84% and the risk of colorectal cancer death would have been reduced from 0.3% to 0.15% (a 50% drop).

My take: Colonoscopy as a screening tool only works if it is performed. Given the low response rate for screening, other tools like an annual fecal immunochemical test (FIT) need to be considered as alternatives.

Related blog posts: