Reports

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PRIORITY PRESS - 2008 Advances in Inflammatory Bowel Diseases

Hollywood, Florida / December 4-7, 2008

According to Dr. Bruce Sands, Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts, corticosteroids may induce complete remission in the short term but at one year, only about one-third of patients continue to respond. Data from a Paris cohort also indicated that the need for surgery for Crohn’s disease (CD) patients did not change during the time they were receiving immunomodulator therapy.

Increasingly, physicians understand that the earlier they intervene with the tumour necrosis factor alpha (TNF-a) inhibitors, the more likely patients will achieve a good response. This was demonstrated in CHARM (Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance) where Crohn’s Disease Activity Index (CDAI) remission rates were over 50% among anti-TNF-a recipients with a disease duration of less than two years vs. approximately 33% for those with a disease duration of five years and more. “Timing of therapy is very important to the outcome,” Dr. Sands confirmed.

The same relationship was seen in the PRECiSE (Pegylated Antibody Fragment Evaluation in Crohn’s Disease: Safety and Efficacy) 2 study where 68% of certolizumab pegol recipients with a disease duration of under one year achieved CDAI remission at week 26 compared with only about 45% of those whose disease had lasted for five years or more. The Step-Up vs. Top-Down study importantly demonstrated that 61% of CD patients who received early aggressive biologic therapy achieved remission and were not on steroids at six months compared with 41% of those treated conventionally.

While this difference had narrowed by month 12, 73% of Top-Down recipients were still in complete endoscopic remission at two years compared with only 30% of those on conventional therapy. “There seems to be a huge carry-over effect over time with regard to mucosal healing with the Top-Down approach,” Dr. Sands observed.

Concerns about safety have tended to prevent upfront use of the TNF-a inhibitors. Reassuringly, safety data from the TREAT (Crohn’s Therapy Resource, Evaluation and Assessment Tool) Registry indicate that serious infections are significantly more likely to be associated with current use of glucocorticosteroids and narcotic analgesics than the use of infliximab, as Dr. Sands remarked.

Refractory Disease

Regarding refractory CD, Dr. Stephen Hanauer, Professor of Medicine and Clinical Pharmacology, University of Chicago Medical Center, Illinois, reminded delegates that in a significant proportion of patients who achieve an initial response, the dose of infliximab or adalimumab has to be increased. In ACCENT (A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen) I, for example, approximately 25% of patients receiving infliximab at a dose of 5 mg/kg required an increase to 10 mg/kg to sustain their response (dose creep phenomenon). Similarly, “up to 50% of patients in our practices require increased dosing with adalimumab,” Dr. Hanauer told delegates.

Patients may also lose their response to a TNF-a inhibitor, either because they do not have active underlying inflammation or because a stricture or fistula is causing their symptoms. Moreover, the development of immunogenicity to some anti-TNF-a agent is not infrequent. Dr. Hanauer stated, “Immunogenicity to one agent does not imply immunogenicity to another, so if they have antibodies to one agent, switch to another.”

WELCOME Study

Unlike infliximab and adalimumab, certolizumab pegol does not contain a fragment-crystallizable (Fc) portion and therefore does not induce complement activation, antibody-dependent cellular cytotoxicity or apoptosis in vitro.

In WELCOME (26-Week Open-Label Trial Evaluating the Clinical Benefit and Tolerability of Certolizumab Pegol Induction and Maintenance in Patient Suffering from CD with Prior Loss of Response or Intolerance to Infliximab) reported here by Vermeire et al. and cited by Dr. Hanauer, a total of 539 CD patients who had previously responded to infliximab but who had lost their response or had become intolerant to it were enrolled in the open-label induction phase, during which they received certolizumab pegol 400 mg subcutaneous (s.c.) injections at weeks 0, 2 and 4.

The primary end point was clinical response, defined as a decrease in CDAI score of at least 100 points at week 6, or remission, defined as a decrease in CDAI score of at least 150 points. At week 6, 62.2% of patients in the intent-to-treat analysis had responded to treatment while almost 40% had achieved remission. Clinical response and remissions were achieved as early as week 2 in 33.4% and 18% of patients, respectively, suggesting that the majority of patients who are no longer responding to infliximab will respond to the new Fc-free TNF-a inhibitor at a relatively rapid rate.

A PRECiSE Corroboration

An extension phase of the PRECiSE studies, PRECiSE 4, involved patients who were responding but who subsequently lost response to active therapy along the way. “Instead of kicking the dose up to 400 mg every two weeks, we were allowed to give a single injection and then follow patients in the same trial,” Dr. Hanauer reported. With this single additional 400 mg s.c. dose of the new TNF-a inhibitor, “about half of the patients responded and continued to respond to treatment for the duration of the trial, so some patients on certolizumab pegol maintenance therapy may respond and continue to respond to a single additional injection,” he noted.

Patients with Fistulas

In a separate presentation, Dr. Hanauer detailed results from exploratory analyses of PRECiSE 2 data limited to patients with fistulas at study entry. Importantly, patients had all responded to active therapy during the open-label portion of PRECiSE 2, and then were randomized to either continue on active maintenance or to placebo. Response for patients with fistula at baseline was defined as closure of at least 50% of fistula at any two consecutive visits or 100% closure at week 26. Fifty-eight patients who responded to the initial infusion of the new TNF-a inhibitor were randomized, 30 to placebo and 28 to anti-TNF maintenance.

Some 53.6% in the active maintenance arm had fistula response (namely, at least 50% closure on at least two visits) vs. 43.3% of those on maintenance placebo. The proportion of those who maintained this degree of closure at week 26 was also much higher in the active maintenance arm at 73.3% vs. 38.5% in the placebo arm. At week 26, 66.7% of patients on active maintenance therapy had 100% fistula closure vs. 30.8% on placebo maintenance.

CDAI response and remission rates at week 26 were similarly much higher in the anti-TNF arm at 71.4% for the anti-TNF recipients vs. 33.3% for placebo for response, and 53.6% vs. 20% for remission rates for active therapy vs. placebo, respectively. Mean changes in Inflammatory Bowel Disease Questionnaire scores from baseline to week 26 were also significantly greater at 36.7 points for the active therapy group vs. 20.7 points for their placebo counterparts, an indication that quality of life was also improved in the Fc-free TNF-a inhibitor arm. Efficacy and tolerability of the novel agent appears to be sustained.

As reported here by Sandborn et al., 141 patients who had received certolizumab pegol in PRECiSE 2 entered into PRECiSE 3, 73% of whom were in remission at the start of the study. After 12, 18, 24 and 30 months of continued therapy, remission rates were 62.4%, 55.3%, 49.6% and 39.7%. The percentage of patients who completed assessments and achieved remission remained stable throughout the study at 74.1% at the start of the PRECiSE 3, 73.3% at 12 months, 81.3% at 18 months and 77.8% at 30 months.

The authors reported that treatment was well tolerated with no injection-site pain, and that no new safety signals emerged over the 30-month treatment interval.

A second study of the long-term safety of the same anti-TNF agent involving 2166 patients with a duration of exposure of up to 3.5 years indicated there were seven cases of a solid tumour, but as of July 2007, no cases of lymphoma had been reported.

Opportunistic infections other than tuberculosis were reported in three patients, again suggesting that unexpected safety findings have yet to emerge during long-term follow-up of this novel Fc-free TNF-a inhibitor.

Note: At press time, certolizumab pegol is not available for use in Canada.