Adalimumab Gains FDA Approval for Use in Children

Medications used in pediatrics often do not have a “pediatric indication” on their FDA-approved labeling.  Until recently, one of those medications included adalimumab (Humira).

Sept 25, 2014 (From MSN Money):  The Food and Drug Administration cleared Humira as a treatment for moderate to severe Crohn’s disease in children ages 6 and older when those children haven’t been helped by other treatments, AbbVie said. The North Chicago, Illinois, company said Humira can be administered at home, unlike similar drugs used to treat the condition. During the second quarter, revenue from Humira jumped 26 percent to $3.29 billion.

Related blog post:

Safety Signal for Anti-TNFs

In a large population of inflammatory bowel disease patients, anti-tumor necrosis factor medications (anti-TNFs) did not increase the risk of cancer in a recent study from Denmark.  This link provides a summary of the study (JAMA 2014 June 17 [doi:10.1001/jama.2014.5613]) in GI & Hepatology News: Anti-TNFs -Safety Signal

Here’s an excerpt:

This study “assessed the risks of any cancer and 11 individual cancers, including malignant melanoma, in 56,146 IBD patients aged 15 and older…during 1999-2012, of whom 4,553 took TNF-alpha antagonists.  Median follow-up was 9.3 years…A total of 6.7% of the patients who never took TNF-alpha antagonists developed cancer during follow-up compared with 1.8% of patients who took the drugs…

Stratifying for cancer risk according to years since first exposure, no specific time-dependent pattern was observed in our study…an increased risk in the long term cannot be excluded.”

In another systemic review study (Clinical Gastroenterology and Hepatology Volume 12, Issue 9, Pages 1443–1451, September 2014) focused on pediatric IBD patients (n=5528), the authors found that “Two patients developed lymphoma (2.1/10,000 PYF). This value was … lower than the population of pediatric patients receiving thiopurine monotherapy (4.5/10,000 PYF; SIR, 0.47; 95% CI, 0.03–6.44)”…”the risk of lymphoma was no greater among children with IBD who received anti-TNF therapy than those treated with other IBD therapies or adults treated with anti-TNF agents. The rate of serious infection was significantly lower among pediatric patients with IBD treated with anti-TNF agents than those treated with steroids, or adults with IBD who received anti-TNF therapy.”  Here’s the link: anti-TNF therapy with lower lymphoma risk than thiopurines in pediatrics

Monotherapy or Combination Therapy with Adalimumab?

Since the introduction of anti-tumor necrosis factor therapies (anti-TNFs), the benefit of using these agents in combination with immunomodulators or as monotherapy has shifted a few times based on the latest studies.  The most influential recent studies had been SONIC and UC Success which indicated that combination therapy for Crohn’s and Ulcerative Colitis, respectively, was more effective and without more adverse effects than monotherapy. A recent study may create some additional uncertainty in this line of thought (Gastroenterol 2014; 146: 941-49).

The author performed a pooled analysis of data from 1594 patients with Crohn’s disease (CD).  Studies included CLASSIC I and II, CHARM, GAIN, EXTEND, and ADHERE.  In total, these studies provided 3050 patient-years of exposure. For individual patients, the median followup period was 1.5 years.

Key findings:

  • “Those patients receiving combination therapy had an increased risk of malignancy (other than non melanoma skin cancer [NMSC])” with a relative risk of 2.82.
  • Adalimumab monotherapy was not associated with an increased risk of malignancy other than NMSC
  • Combination therapy was associated with relative risk of NMSC of 3.46

In the discussion, the authors state “the data suggest that the increased risk likely is attributed to the immunomodulator therapy.”

A related editorial (884-86) helps dissect the articles strengths/limitations as well as implications.

Strengths:

  • the study captured data from randomized controlled trials.

Limitations:

  • median followup of 1.5 years –may not be long enough to detect a malignancy signal from anti-TNF therapy
  • unclear how many adalimumab monotherapy patients had been on a thiopurine previously

Implications:

  • “Even if Osterman et al are correct, is this information clinically meaningful enough to swing the mono-combo pendulum back to mono therapy?”
  • “The clinical relevance of the increase in absolute cancer risk from 4 in 1000 with adalimumab monotherapy to 10 in 1000 with combination therapy for cancers other than NMSC is unclear”
  • This difference of 6 in 1000 “translates to 167 patients who are treated before seeing 1 excess cancer”
  • “Most (if not all) of the cancer risk is associated with thiopurine exposure…induction therapy is more effective with combination treatment–>”we propose that we should induce patients into remission with combination therapy, and then consider withdrawing thiopurines at some point.
  • “Consider treating younger males with thiopurines short term, or alternatively with methotrexate.”  Though the authors note that data from rheumatology brings some concern to methotrexate cancer risk (Semin Arthritis Rheum 2014; 43: 489-97). Source Article: Methotrexate Safety | gutsandgrowth
  • “Consider treating elderly patients with anti-TNF monotherapy to decrease their risk of serious infections”

Also noted: “Risk of Cancer in Patients with Inflammatory Bowel Diseases: A Nationwide Population-based Cohort Study with 30 Years of Follow-up Evaluation” (Clin Gastroenterol Hepatol 2014; 13: 265-73). n=13,756 patients with CD and 35,152 with UC. Key findings –among CD patients, the excess risk was largely due to extra-intestinal cancers such as hematological malignancies (SIR 1.9) and smoking-related malignancies (SIR 1.5).  Associations between UC and gastrointestinal/extraintestinal cancers were weaker (both SIRs were 1.1); the risk of gastrointestinal cancers decreased over the course of the study.

Related blog posts:

Sticky Decisions with IBD Therapy – When an Infection or Malignancy Develops

A recent review article provides advice for management of biologics and immunomodulators when an infection or malignancy develops (Inflamm Bowel Dis 2014; 20: 926-35).  Serious infections are noted in 3-5% of adults receiving either thiopurines or anti-tumor necrosis factor agents (anti-TNFs); less than 0.1% of adults develop treatment-related lymphoma.  The recommendations are provided in 5 separate tables.

Table 1 addresses the issue of bacterial infectionsFor mild infections, the authors recommend that thiopurines (azathiopurine, 6-mercaptopurine) as well as anti-tumor necrosis factor agents (infliximab, adalimumab, certolizumab, golimumab) be continued.  Examples of these ‘mild’ infectious included E. coli UTI and strep pharyngitis.  For severe bacterial infections (eg. pneumococcal pneumonia), for both these therapies, the authors recommend: “stop, but may restart once treated.”  For bacterial opportunistic infections (eg. mycobacterium), for latent infections, “do not start until 2 to 4 wk INH” whereas for active infections, the authors recommend (for anti-TNFs) “stop, only restart after full treatment, and if IBD is severe.”

  • Table 2 addresses fungal infections.
  • Table 3 addresses viral infections (eg. CMV, EBV).  For EBV, the authors recommend stopping thiopurines and not restarting in male patients.
  • Table 4 addresses malignancy: solid tumors, hepatosplenic T-cell, EBV-associated lymphoma, and lymphoproliferative lymphoma.
  • Table 5 addresses skin cancers.

Towards the end of the review, the authors provide some context for the risks with thiopurines and anti-TNFs.  “The majority of side effects associated with thiopurines and anti-TNFs are mild, self-limited and reversible…the risk of a lymphoma developing on AZA/6-MP (4/10,000 patient-years) is comparable with the lifetime risk of dying from drowning (1/1112) or dying in a bicycle accident (1/5000).  The risk is much less than the risk of dying in an automobile accident (1/108).  Patients are willing to accept risks..if their disease is severe and the chance of a clinical response outweighs the risk.”

With regard to dual therapy, the authors note, “it has been our practice to lower the concomitant AZA/6-MP in patients on combination therapy with anti-TNF and then to stop the thiopurine in patients in deep remission for 3 years. However, this decision must be individualized, and for patients with severe, disabling disease, we generally do not alter treatment.”

Bottomline: This is a useful advice/handy reference for the sticky situation of managing IBD in the face of infections and malignancy.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.

 

Comparing Biologics for Ulcerative Colitis

A recent study has reviewed biologic therapies for ulcerative colitis (Ann Intern Med. 2014;160(10):704-711). Here’s the abstract link: bit.ly/1o5PpRX.

Data Synthesis: ..There were 7 double-blind, placebo-controlled trials that were rated as low risk of bias and showed that all biological agents (adalimumab, golimumab, infliximab, and vedolizumab) resulted in more clinical responses, clinical remissions, and mucosal healings than placebo for induction therapy. The results of network meta-analysis suggested that infliximab is more effective to induce clinical response (odds ratio, 2.36 [95% credible interval, 1.22 to 4.63]) and mucosal healing (odds ratio, 2.02 [95% credible interval, 1.13 to 3.59]) than adalimumab. No other indirect comparison reached statistical significance. For maintenance, 6 double-blind, placebo-controlled trials that were rated high risk of bias showed that all biological agents have greater clinical efficacy than placebo. The occurrence of adverse events was not different between biological agents and placebo.

Limitation: Few trials, no head-to-head comparisons, and inadequate follow-up in maintenance trials.

Conclusion: Biological agents are effective treatments for UC, but head-to-head trials are warranted to establish the best therapeutic option.

Related blog posts:

 

Infliximab Compared to Adalimumab -Which is Better?

Pharmaceutical companies are not motivated to provide a definitive answer on the title question.  A recent study (Clin Gastroenterol Hepatol 2014; 12: 811-17) states that “head-to-head clinical trials of anti-TNF therapies are unlikely to ever be undertaken because of the extreme cost to conduct such studies and the financial risk that such trials would entail for the manufacturers.”  The two most popular biologics, infliximab (IFX) and adalimumab (ADA), for inflammatory bowel disease have been incredibly successful (Multi-billion dollar biologics | gutsandgrowth).

The current study is “one of the first to directly compare the effectiveness” of IFX and ADA for Crohn’s disease.  The authors retrospectively examined a U.S. Medicare data cohort from 2006-2010 and identified new users with 1459 IFX and 871 ADA patients.  While 94% of Medicare enrollees are >65 years, this study had a range of patient ages due to those who received Medicare due to disability.  In fact, in the ADA group, ~60% were between 30-60 years and in the IFX group, ~44% were in this age group.

Key result:

  • After 26 weeks of treatment, 49% of patients receiving IFX remained on drug compared with 47% of those receiving ADA.
  • Fewer patients with IFX underwent surgery (5.5 vs 6.9 surgeries per 100 person-years) but this did not reach statistical significance.
  • Rates of hospitalization did not differ among the two groups

While persistence is an imperfect measure of effectiveness, the fact that surgeries and hospitalizations were similar indicates that the medications are likely to have similar clinical effectiveness, at least in this population.  Data on mucosal healing, more direct measures of effectiveness, and longer followup certainly would strengthen this conclusion.

My First Take: It is Hard to Save $$$ at a Rolls-Royce Dealership

A recent article looked at a crucial issue –trying to deliver “best care at lower cost” (Inflamm Bowel Dis 2014; 20: 946-51).  “The goal of this report is to answer the primary question: What are implementable strategies and exploratory considerations for cost-efficient anti-TNF use while maintaining the highest quality of IBD care?”

The strategies that are discussed include the following:

  • Reduce costs of avoidable dose intensification of class switching by eliminating episodic anti-TNF use and improving patient education
  • Reduce over-utilization costs by accurately determining indication for escalating anti-TNF use
  • Reduce nondrug infliximab costs through shortened infusion times after initial safety is clearly established

Exploratory considerations:

  • Self-injectable anti-TNFs
  • Combination therapy
  • Monitoring anti-TNF drug levels and autoantibodies
  • Assessing mucosal healing as a clinical endpoint

The authors discuss both the exploratory issues and the strategies.  Some of each could easily increase costs, at least in the short-term, rather than reduce them.  The authors also make note of the development of an infliximab biosimilar (Inflecta) which could be approved in U.S. by 2015.

While the review article is a good read, in my opinion the authors fail to address in a meaningful way the larger context.  The costs for hospital-based care are enormous; pediatric hospitals are like Rolls-Royce dealerships; and by the way, if you have to ask how much it costs, you probably cannot afford it.  With regard to charges/costs, there is little transparency, high variability, and little accountability.  Understanding health care costs and trying to get a good deal is much harder than buying a car.

For IBD care, as an example, the authors make note of the cost of infliximab at one pediatric tertiary care center.  At this institution, “77% of the total health care cost for each infusion encounter” was for non-drug costs.  Given how expensive the drug cost is, the expense for an infusion is very high, but probably similar to many other pediatric hospitals.

If one is interested in reducing the costs of infliximab and other infusions, the first practical step would be to consider infusion outside of a hospital-based setting, such as an infusion center.  In such a setting, the patient safety would still be excellent but the costs would be less.

In Atlanta, there have been some high-profile hospital acquisitions that have increased health care costs (When doctors sell out, hospitals cash in | www.myajc.com).  In many circumstances, when a hospital acquires a physician practice, infusion center, or endoscopy center, the charges and reimbursement increase despite no change in clinical care.  In this way and many others, the current system promotes cost-inefficient care.

Related blog entries:

Marriage, Divorce and Separation with Anti-TNF Therapy

This review article (Inflamm Bowel Dis 2014; 20: 757-66) examines the question of whether and when anti-tumor necrosis factor (anti-TNF) agents can be stopped in Crohn’s disease (CD) patients in remission.  This topic is particularly helpful since this comes up frequently in clinical practice.

As recently as a few years ago, one expert advised me that starting an anti-TNF agent (like infliximab or adalimumab) was like getting married.  Once you committed, you stayed in that relationship indefinitely.  Of course, it is well-known that individuals get divorced.  In medical terms, I guess that would be the equivalent of developing antibodies to the anti-TNF agent or other adverse reactions.  Switching from one anti-TNF to another would be equivalent to marital infidelity.

So what does this review article say about all of this?  The article examines nine studies with a little more than 500 patients.  “Current evidence suggests that a group of CD patients, possibly 30% to 40% in clinical remission while on IM (immunomodulators) and infliximab can stop the latter and maintain clinical remission for a relatively long interval.  It seems that, if followed long enough, virtually all patients (including those on IM) will eventually develop clinical recurrence.”

If tempted to separate but not divorce anti-TNF therapy, the authors recommend, in addition to clinical remission, “normal colonoscopy (and/or normal surrogate markers of disease activity) should be adopted as a criterion when stopping therapy and during follow-up….As of today, many authors do not recommend to routinely stop anti-TNF agents in patients responding to this therapy and in the absence of other issues.  Others propose to stop them after a minimum of 2 years of clinical and endoscopic remission or longer if only clinical remission can be documented…

If costs or other issues are present, we suggest to cautiously stop anti-TNF agents only in patients on combination therapy with profound (clinical, biochemical, and endoscopic) and long lasting (>1 year) remission and continuing the IM.  Such patients should be closely followed by serial determinations of fecal calprotectin and inflammatory indices, and the medication immediately restarted in the presence of a flare. When in doubt, colonoscopy should be performed.

Take-home message: Most patients are better off staying married to their anti-TNF therapy.

Also noted: Inflamm Bowel Dis 2014; 20: 742-56.  Clinical Utility of Fecal Biomarkers for the Diagnosis and Management of Inflammatory Bowel Disease.  This is a useful review with 103 references.

Superiority of Anti-TNF Therapy (Part 2)

A recent blog (Superiority of Anti-TNF Therapy in Children | gutsandgrowth) described a recent article showing that kids treated with anti-TNF therapy at the time of diagnosis had improved outcomes compared to children who were treated with other medications.  In this day of multimedia, there is a video explaining the study which may be helpful for families and clinicians alike –here’s the link:  Dr. Michael Stephens discusses the research findings: .

An excerpt from the explanation with the video:

The current research study looks at outcomes and compares three different types of treatments. The first group receives anti-TNF therapy. The second group received immune modulating therapy. The third group received no treatment within the first three months. This study was an observational study and the choice of treatment was at the discretion of the physician. In order to correct for this factor, a statistical technique was used. Patients with similar characteristics were paired within the three groups . The results showed that patients who received the anti-TNF therapy had an improved outcome, such as a higher remission rate and some indications of improved growth, at one year. All three groups had improvements in weight and body mass index but only the anti-TNF group had improvements in linear growth.

How Long Will Infliximab Work?

Given the limited therapeutic options, the question of infliximab (IFX) durability in pediatrics is quite important.  One center has published its 10-year retrospective experience (Inflamm Bowel Dis 2014; 20: 606-13).

Inclusion criteria for the 188 patients included initiating IFX prior to age 21 years and patients who had a minimum of 1-year followup.

Demographics: Median age at diagnosis was 11 years for Crohn’s disease (CD) and 12 years for ulcerative colitis (UC). Indication for IFX due to steroid refractory disease was present in 42% of UC patients compared with 14% of CD patients.  Monotherapy was more common in UC patients, 65%, compared to 35% of CD patients.

Methotrexate was administered in 69 (44%) of CD patients at time of IFX with the majority (n=56) as oral treatment (low-dose <10 mg every week).  In addition, MTX was initiated after IFX induction in another 38 (24%).  Only 36 (23%) remained on IFX mono therapy throughout the duration of treatment in CD patients.

Key findings:

  • 88% of CD patients remained on IFX at 1 year, 80% at 2 years, and 72% at 5 years.
  • Only 7 of 157 CD patients were primary nonresponders.
  • 65 of 89 CD patients who did not achieve a sustained durable remission underwent dose escalation. 40 of 65 responded to dose escalation.
  • Of those who lost response to IFX, the majority were transitioned to adalimumab (ADA) and among this group, 82% remained on ADA treatment at last followup.
  • Among UC patients (n=31), 9 were primary nonresponders. At last followup, 41% (9) remained in a durable sustained response at last followup.
  • While the authors used MTX due to favorable effects on IFX pharmacokinetics (Arthritis Rheum 1998; 41: 1552-63), there was “not a significant difference in IFX durability or efficacy between this group and patients with CD on IFX monotherapy”
  • Availability of antibodies to infliximab (ATIs) and IFX trough levels were only assessed in a subset.  However, “we did see a significant difference in those that responded to dose intensification when ATIs were undetectable.”

Bottomline: The majority of CD patients can remain on IFX for >5 years.  Among those who lose response, adalimumab was a durable alternative.  A much lower durable response was evident with the subset of patients with UC.

Related blog post:

Also noted:

Inflamm Bowel Dis 2014; 20: 614-21. In this study of 78 youth with IBD, depressive symptoms warranting additional evaluation were present in 13% which was lower than in the community comparison group.  Disease severity was noted to be inactive in 63% and mild in another 18%.

Inflamm Bowel Dis 2014; 20: 495-501. This study showed that 25 children exposed to anti-TNFs prenatally for maternal IBD seemed to show good safety.  Immunologic investigation undertaken in 17 of the children was normal.  No control group limited the ability to determine if increased infections were present.

And, here’s a link to Mar-April Circle Newsletter from ImproveCareNow -topics include group medical appointments, parent working group, dieting with IBD, and includes link to self management handbook.