Introduction-Biologics

Use of Biologics in IBD

When?

  • Moderately to severely active Crohn’s disease that is refractory to conventional therapy.
  • Fistulising Crohn’s disease that is refractory to conventional therapy

Clinical trials have demonstrated significant utility of infliximab for induction of remission in moderately active, steroid refractory Crohn’s disease, improvement in quality of life, and maintenance of remission in these patients for up to 54 weeks after initial infusion.

How?

2 strategies

  • Scheduled maintenance- Dose 5mg/kg. Induction doses at 0,2 and 6 weeks and then retreatment of patients who respond to initial therapy every four- to eight-week interval at 5 mg/kg  depending upon how quickly relapse of the Crohn’s disease symptoms occurs.
  • Episodic use- on demand retreatment with 5 mg/kg after a single inductive infusion of infliximab. Inductive infusion is at 0, 2 and 6 weeks for fistulising Crohn’s disease and then on demand retreatment.

Discuss episodic treatment? (NICE recommends episodic treatment)

  • Safety and cost are important aspects of all drug usage.  Toxicity is not substantially enhanced and infusion reactions are not decreased by regularly scheduled infusions.
  • Drug costs tend to decrease with time and competition and thus should not be used as a major reason for opting for an episodic regime. Further considering the costs of surgery and hospitalisations, a maintenance regime of infliximab is cost effective.
  • In ACCENT I study, the authors stress the clinical superiority of the scheduled maintenance treatment groups over the episodic strategy, with significant advantages in remission and response rates, quality of life, mucosal healing, Crohn’s disease related hospitalizations, and intra-abdominal surgery. However, regularly scheduled administration of the FDA-approved dose of 5 mg/kg infliximab was significantly better than episodic infusion in only 2 parameters (hospitalization, 23% vs. 38%; P =0.047; intra-abdominal surgeries, 3% vs. 7%; P =0.04).
  • Remission and response are the most widely accepted outcome measurements for Crohn’s disease clinical trials. ACCENT I-  only a minority of patients (44%) in the 5-mg/kg regularly scheduled group completed the study as designed; 26% discontinued treatment without crossover and 30% were crossed over to 10 mg/kg “rescue” therapy. Therefore, an alternative interpretation of these results is that on-demand retreatment with 5 mg/kg after a single inductive infusion of infliximab is comparable to the more expensive strategy of 3 inductive infusions followed by scheduled treatments every 8 weeks.
  • Certainly, a patient with luminal Crohn’s disease who requires infliximab treatment and who is not yet on immunosuppressant drugs can be induced with a single infliximab infusion after beginning maintenance 6MP, azathioprine, or methotrexate, thereby reserving regularly scheduled infliximab infusions for those patients failing optimal immunosuppressant maintenance treatment.

Discuss management strategy of patients who initially respond but then lose their response?

Antibodies to infliximab reduce infliximab blood levels and causes loss of response. This can be overcome by 4 different strategies;

  • decrease the intervals between re infusions to 7, 6, 5, or 4 week intervals
  • increase the infliximab dose to 10 mg/kg
  • Both
  • Switch to adalimumab

Discuss efficacy of infliximab treatment?

Luminal Crohn’s disease (ACCENT I data) Fistulising Crohn’s (ACCENT II data)
65% of the patients had a clinical response, including 40 percent who achieved remission. All patients initially received an initial series of infliximab (5 mg/kg) given at weeks 0, 2 and 6. Response was defined as at least a 50 percent reduction in the number of draining fistulas.

64% responded by week 14.
In patients who initially had a clinical remission, maintenance of remission (at 54 weeks) occurred in only 14 percent of patients in the single dose group compared to 28 percent of patients maintained on infliximab 5 mg/kg every eight weeks and 38 percent of patients on infliximab 10 mg/kg every eight weeks At week 54, significantly more patients assigned to maintenance therapy had complete absence of draining fistulas (36 versus 19 percent).

Adalimumab

Discuss dosing?

The approved induction dosing of adalimumab in Crohn’s disease is 160 mg given subcutaneously initially at week zero, 80 mg at week two, followed by a maintenance dose of 40 mg every other week beginning at week four. The drug is available in a single-use prefilled pen (HUMIRA Pen)

Discuss the efficacy?

Patients generally respond within the first week. Responses were maximal by three doses in the CLASSIC and CHARM studies. Patients who do not respond within this interval should not continue adalimumab.

Efficacy similar to Infliximab

Discuss the indications?

  • Same as Infliximab
  • Adalimumab can be used in patients who had lost response to or are intolerant of infliximab. Used as such in GAIN study, adalimumab was more effective than placebo at achieving clinical remission (21 versus 7 percent) and response (38 versus 25 percent)

Dosing of Adalimumab:

Starting Dose:

On day 1* 4 (four 40 mg) injections of HUMIRA. (four 40 mg injections in one day or two 40 mg injections per day for two consecutive days)
On day 15 2 (two 40 mg) injections of HUMIRA.

Continuing Dose:

On day 29 1 (one 40 mg) injection of HUMIRA.
After day 29 regular scheduled dose of one Pen (40 mg) every other week.

How to use the pen:

http://www.myhumira.com/Administering/Instructions.aspx?p=pen

How to use the syringe:

http://www.myhumira.com/Administering/Instructions.aspx?p=syringe

Patient information about Adalimumab: from NACC website

http://www.rxabbott.com/pdf/humira_medguide.pdf

Breast feeding and Adalimumab?

As the long-term effects of adalimumab on a child’s developing immune system are still not known, it is recommended that patient should not breast-feed during treatment or for six months after last dose.

Does adalimumab affect pregnancy?

There have been several reports of successful pregnancies in women with Crohn’s on adalimumab before conception or during pregnancy. Because the drug is relatively new the clinical evidence is limited therefore, the manufacturers recommend that woman of childbearing age should use adequate contraception to prevent pregnancy and continue to use it for at least 5 months after stopping taking adalimumab.

However, in many cases the risks of active Crohn’s disease outweigh the risks of the drug, even during pregnancy. In severe Crohn’s disease when patient  do not want to wait before trying for a baby the doctor and the patient together will have  to weigh up the risk of stopping against the benefits of continuing with treatment.

If the patient becomes pregnant while using adalimumab there may be reasons to continue throughout the first 6 months of pregnancy. In the last 3 months of pregnancy adalimumab should only be used with caution as it will cross the placenta and might affect the immune system of baby.

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