Category Archives: inflammatory bowel disease

NY Times: Humira’s Best-Selling Drug Formula: Start at a High Price. Go Higher.

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NY Times: Humira’s Best-Selling Drug Formula: Start at a High Price. Go Higher.

An excerpt:

Humira is the best-selling prescription drug in the world…The price of Humira, an anti-inflammatory drug dispensed in an injectable pen, has risen from about $19,000 a year in 2012, to more than $38,000 today, per patient, after rebates, according to SSR Health, a research firm. That’s an increase of 100 percent…

How much you actually pay out of pocket, and whether you can afford Humira at all, depend on your insurance and eligibility for discounts…

Humira, which accounted for nearly two-thirds of AbbVie’s $25.6 billion in revenue in 2016, was not simple to develop. It is among a new class of drugs known as biologics, which are made from living cells rather than synthetic chemicals…

Looking at the international picture tells its own story about drug costs. A prefilled carton with two syringes costs $2,669 in the United States, compared with $1,362 in Britain, $822 in Switzerland and $552 in South Africa…

An analysis by the Institute for Clinical and Economic Review found that Humira’s list price would need to be discounted by at least 55 percent to be cost effective for rheumatoid arthritis, its originally approved use.

Dr. Steven D. Pearson, the founder of the institute, which provides cost benefit data to health plans, said competing drugs were overpriced as well.

“Even in a space like this, where there is a lot of competition, we don’t see the prices coming down,” he said. “That speaks to the fact that it doesn’t often function like a free market usually would.”..

AbbVie joined a few of its rivals in saying it would limit price increases to single digits this year, and so only raised Humira by another 9.7 percent this month, roughly four and a half times the inflation rate. For the drug industry, that counts as generosity.

My take: Humira is a very important and effective medication, particularly for inflammatory bowel disease and rheumatoid arthritis. I infer from this article which compares the Humira pricing strategy to that used by Martin Shkreli that if U.S. consumers are to have more affordable pharmaceuticals, government intervention will be needed. AbbVie, like many other pharmaceutical companies, will continue to aggressively price Humira; after all, 8 billion in profits is not as good as 10 billion.

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Therapeutic Drug Monitoring for Vedolizumab

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A recent observational study (N Williet et al. Clin Gastroenterol Hepatol 2017; 15: 1750-7) provides some important information about where we are heading with regard to therapeutic drug monitoring (TDM) with vedolizumab (VDZ).

This study enrolled 47 consecutive patients with either Crohn’s disease (CD, n=31) or ulcerative colitis (UC, n=16). In those without a clinical response at week 6, an additional dose of 300 mg of VDZ was administered at week 10.

Key findings:

  • VDZ levels were higher in responders than in nonresponders, which is in agreement with previous studies ( (NEJM 2013; 369: 711-21, NEJM 2013; 369: 699-710)
  • A low therapeutic drug level as early as week 2 (<24.5 mcg/mL) and at the end of induction (week 6) (<18.5 mcg/mL) was associated with the need for drug optimization within 6 months in all patients
  • All patients with a level <19.0 mcg/mL at week 6, regained a secondary response after optimization at week 10.
  • The authors note that in the GEMINI trial, anti-VDZ antibodies were detected in 56 of 1434 patients (3.7%).  In this cohort, no anti-VDZ were detected using the same methods.

My take: Low trough levels of VDZ at week 6 are associated with the need for drug optimization/increased dosing.

Fatty Acid Intake and Risk of Ulcerative Colitis Flare

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A recent study (Barnes EL et al. Clin Gastroenterol Hepatol 2017; 15: 1390-6) found an association between the intake of certain fatty acids and the risk of an ulcerative colitis flare.  This is nicely summarized in the AGA Journals Blog.

Here’s the link: Does Consumption of Certain Fatty Acids Increase Risk of Ulcerative Colitis Flares?

Here’s an excerpt:

Diets with high levels of fatty acids such as myristic acid (found in palm oil, coconut oil, and dairy fats) increased risk of flare in patients with ulcerative colitis (UC), researchers report in the September issue of Clinical Gastroenterology and Hepatology. Their findings, from a prospective study of more than 400 patients in remission during treatment with aminosalicylates, could guide future studies of supplements or compounds that reduce risk of flares in patients with UC in remission…

Edward L. Barnes et al performed a prospective study of dietary patterns among 412 patients, from 25 sites, with UC in remission during monotherapy with an aminosalicylate (mesalamine, sulfasalazine, or balsalazide for at least 3 months before enrollment). Patients completed a validated food frequency questionnaire (on consumption of dairy, fruits, vegetables, eggs, meat, fish, cereals, breads, and starches, beverages, sweets, and baked goods) at enrollment and were followed for 12 months…

Forty-five patients (11%) had a relapse of UC within 1 year of study enrollment… In multivariable analysis, higher intake of myristic acid (odds ratio, 3.01) and alpha linolenic acid (odds ratio, 5.50) were associated with increased risk of relapse, although a dose–response relationship was retained only for myristic acid intake.

Other foods previously implicated in flares of UC, such as processed meat, alcohol, and foods high in sulfur, were not associated with an increased risk of flare.

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From Andy Warhol Exhibit at the High Museum

Costs of Biologics for Inflammatory Bowel Disease

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A recent study examines the market share and costs of biologic therapies for inflammatory bowel disease:

Excerpt from abstract:

The average biologic-taking patient accounted for $25 275 PMPY in 2007 and $36 051 PMPY in 2015. The average paediatric biologic-taking patient accounted for $23 616 PMPY in 2007 and $41 109 PMPY in 2015. In all patients, the share of costs for biologics increased from 72.9% in 2007 to 85.7% in 2015 (81.7% in 2007 to 94.9% in 2015 in paediatrics).

Conclusion

The vast majority of costs allocated to out-patient IBD medications in the USA is attributed to increasing use of biologic therapies despite the relative minority of biologic-taking patients.

My take: Biologic therapies are costly but also very effective.

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The Original Anti-TNF Therapy: Thalidomide

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A recent study (M Lazzerini et al. Clin Gastroenterol Hepatol 2017; 15: 1382-9) used data from 2 multicenter trials of 70 children to assess the efficacy of thalidomide in pediatric patients with refractory inflammatory bowel disease (37 with Crohn’s disease, 23 with ulcerative colitis)

Key findings:

  • 42 patients (60%) had clinical remission & 45 (64%) had clinical response at week 8
  • 38 patients (54%) had clinical remission or response at week 52. 29 of these patients had mucosal healing (no erosions or ulcerations) & 20 patients had histologic healing
  • 7 patients dropped out from study prior to 52 weeks due to side effects (n=5) or clinical relapse (n=2)

My take: I have not used thalidomide therapy and remain concerned about long term side effects (eg. peripheral neuropathy).  Though, the authors are correct that its safety “may be acceptable compared with the safety of other” treatments, especially if there are few remaining options.

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IBD Short Takes -Fall 2017

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From ImproveCareNow: Real-World Experience with Adalimumab

An excerpt:

A total of 174 children and adolescents were treated with adalimumab as their first anti-TNF therapy…The mean age at the time of Crohn’s disease diagnosis was 13 years and, on average, they started adalimumab at 14.5 years of age…

  • At 3 months after adalimumab was started, all 174 were still on the medication, and 69-71% were in steroid-free remission
  • At 6 months after adalimumab was started, of the 174 who had a clinic visit, 95% were still on the medication, and 75-77% were in steroid-free remission
  • At 12 months after adalimumab was started, of the 154 who had a clinic visit, 94% were still on the medication, and 79-80% were in steroid-free remission
  • At 24 months after adalimumab was started, of the 71 who had a clinic visit, 97% were still on the medication, and 91-94% were in steroid-free remission
  • At 36 months after adalimumab was started, of the 39 who had a clinic visit, 80-86% were still on the medication, and 81-86% were in steroid-free remission

No positive or negative effect on remission was seen with concomitant immunomodulator therapy. However, the number of patients studied during the retrospective analysis is too small to detect all but the greatest impact of this approach.

EC Maxwell et al. JPGN 2017; 65: 299-305  CHOP experience with diverting ileostomy for severe IBD (2000-2014).

  • In this retrospective study, a diverting ileostomy in 24 patients had improvement: 71% –>22% on chronic steroids, improved growth, hemoglobin, blood transfusion and hospitalization.
  • 10 patients underwent subsequent colectomy, 7 had successful reanastomosis, and 7 remain diverted.
  • Diversion allowed a definitive diagnosis in 7 subjects (initially 13 patients were considered IBD-U).
  • Surgical complications were common (n=13 in 7 subjects) and included stoma obstruction, stoma prolapse, and resection of ischemic bowel.
  • One notable feature regarding this cohort was that 50% were 5 or younger when diagnosed with IBD.
  • The authors conclude that a diverting ileostomy can induce clinical stability and allow time to clarify diagnosis.

A Assa et al. JPGN 2017; 65: 293-98. In this study involving findings from 234 patients extracted from the ImageKids database (prospective multicenter cohort), the authors found that pediatric patients with perianal Crohn’s disease have a greater inflammatory burden; however, this was driven mainly by those who had fistulizing disease.

L Lian et al. Clin Gastroenterol Hepatol 2017; 15: 1226-31. This retrospective study from the Cleveland Clinic compared outcomes of endoscopic balloon dilation (EBD) (n=176) or surgery (n=131) for Crohn’s disease-related strictures (1998-2013). Patients who had EBD had an “average time to surgery delayed by 6.45 years.” Immediate success rate for EBD was 91.3%; the perforation rate was 1.1%.. Ultimately, 52% of patients who had EBD required surgery.  Earlier surgery lowered the risk of further surgery but also was associated with significant perioperative complications. In the operative group, 8.8% of patients experienced complications, mainly intra-abdominal abscesses and enterocutaneous fistula. Thus, in the right hands and with careful selection, EBD may be useful.

I Lawrance et al. Clin Gastroenterol Hepatol 2017; 15: 1248-55. This study reported the results of 11 patients who received rectal tacrolimus for resistant ulcerative proctitis. Dosing: The concentration of tacrolimus was 0.5 mg/mL and 3 mL was administered twice a day.Clinical response, using the Mayo Clinic score, was achieved in 73% of tacrolimus subjects compared with 10% (n=1) of placebo-treated subjects.  Mucosal healing at week 8 was noted in 73% of tacrolimus-treated patients, as well.

Soapes Creek Trail

Therapeutic Drug Monitoring: Ustekinumab (Stelara)

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The ability to measure drug levels has changed how we think about refractory medical disease, particularly in patients with inflammatory bowel disease.  Prior to the availability of therapeutic drug monitoring (TDM), in some situations poor response to therapy could be ascribed to variability in host immune response. Now, it is clear that many cases of refractory medical disease are due to insufficient drug level.  TDM allows for dose individualization to target the right amount of medication.

TDM has an accepted role in anti-TNF therapy.  Now, a study (R Battat et al. Clin Gastroenterol Hepatol 2017; 15: 1427-34) extends the concept of TDM to ustekinumab.  This study which took place between 2014-2015 examined ustekinumab use in 62 patients with refractory Crohn’s disease (CD).  Ustekinumab dosing: 90 mg SC at weeks 0, 1, and 2 for induction, then 90 mg every 4 or 8 weeks for maintenance.

Key findings:

  • At week 26, 80.7% of patients had a clinical response, 66.1% had a clinical remission, and 58.9% had an endoscopic response.
  • In those with an endoscopic response, the mean trough concentration of ustekinumab was 4.7 mcg/mL compared with 3.8 mcg/mL those without an endoscopic response.
  • Using a trough threshold of 4.5 mcg/mL at week ≥26, 75.9% had an endoscopic response whereas those with a level below this trough had a 40.7% endoscopic response
  • The authors did not detect antibodies to ustekinumab in any patient. The authors note that ustekinumab has low immunogenicity and prior UNITI studies indicated antibody formation in 0.2% after induction and 2.3% at 1 year.
  • Unlike combination therapy with anti-TNF therapy, “concurrent immunosuppressive therapy does not explain low immunogenicity, as only 25.8% of patients received these and had neither improved clinical outcomes nor higher drug concentrations.”

Thus far, no clinical studies have demonstrated improved clinical outcomes with dose escalation in the setting of low ustekinumab levels.  A prospective trial would be helpful.

My take: This study shows promising results for ustekinumab for refractory CD.  The low immunogenicity indicates that monotherapy is likely appropriate.  A target level of >4.5 mcg/mL indicates a higher likelihood of response.

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#NASPGHAN17 Therapeutic Drug Monitoring Associated with Increased Clinical Remission

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In support of Dr. Baldassano’s talk (NASPGHAN17: Treat to Target and Tight Control), this poster from the Cincinnati group (A Mulgand et al) showed that therapeutic drug monitoring has been associated with improved clinical remission scores (80% to 87%).  Correlation with a more objective marker of remission along with longer followup is now needed. One of the authors, Dana Dykes, has joined our group in Atlanta!

 

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#NASPGHAN 17 More Abstracts

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This link for the NASPGHAN abstracts :NASPGHAN 2017 Scientific Abstracts

The following slides are from some of the abstract posters. This first poster (next 5 pics) showed that symptom association with meals is not predictive of aspiration among a selected group of children who underwent swallow study evaluations. In the figures, the blue bars are children who passed the swallow study whereas the red bars indicate the children who failed the swallow study.

This next slide demonstrated that a six food diet for EoE could be administered blenderized via a gastrostomy tube.

The next slide showed that irritable bowel syndrome was more frequent (overall hazard ratio of 1.52) following a urinary tract infection in the first year of life.

The next pictures are from a poster discussing high rates of recurrent C difficile infection following fecal microbial transplantation in pediatric patients with inflammatory bowel disease (mainly ulcerative colitis).  An inference from this study would be that many cases of C difficile that were attributed as causing symptoms could in fact have been from a flare up of their IBD.  More details about the diagnosis of C difficile (based on PCR or ELISA) would be helpful

The next poster provides data from CHOP experience with Ustekinumab.  Overall, in this highly-selected (refrcactory) population the long term improvement was low; while one-third had steroid-free remission at week 8, this was not maintained at week 16 and week 24.  In addition, among the 22 patients, one developed transverse myelitis.

This study that follows (next two pics) documented the relative safety of liver biopsies (mainly percutaneous without interventional radiology) in the post-transplant period.  The two most serious adverse events, cholangitis and bile leak, helped identify biliary strictures.

The following collaborative study examined the neurocognitive status of children with Alagille syndrome.  Overall, this study shows that children with Alagille syndrome are at increased risk of low IQ compared to children with other cholestatic diseases.

 

 

#NASPGHAN17 IBD Treat to Target and Tight Control

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More information from this year’s annual NASPGHAN meeting.

This blog entry has abbreviated/summarized these presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

IBD Treat to Target: Treat the Patient or Treat the Disease

Robert Baldassano  Children’s Hospital of Philadelphia

I missed the first few minutes of this presentation, even though I had highlighted this as one of my top priorities.  So, if anyone reading this post has some additional comments, they are certainly welcome.

Key points:

  • Do not rely on symptoms alone to assess patient improvement.
  • Best surrogate marker: calprotectin.  Frequent calprotectin levels can help determine objective improvement; it is much more helpful than CRP as ~25% of patients do not elevate their CRP levels
  • Therapeutic drug monitoring is important in improving outcomes. Dose optimization improves response rate and durability of infliximab response.
  • Evolving targets in ulcerative colitis.  Even histologic activity, in the absence of endoscopic activity, is associated with relapsing disease
  • Dr. Baldassano indicated that he no longer is starting patients on thiopurine therapy. There are “36 phase 3 trials underway.” Thus, many promising options for those who may burn through current treatments
  • This lecture reviewed data from the RISK study showing that early (1st 90 days w/in diagnosis) TNF therapy helps prevent penetrating disease (related post: CCFA Update 2017/RISK study)

Another presentation by Philip Minar et al (Cincinnati Children’s Hospital Medical Center) shows that CD64 suppression is an early biomarker of response to infliximab therapy.