Reports

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15th United European Gastroenterology Week

Paris, France / October 27-31, 2007

Editorial Overview:

Brian G. Feagan, MD, FRCPC

Once reserved for inflammatory bowel disease (IBD) refractory to other options, tumour necrosis factor alpha (TNF-a) inhibitors are being considered earlier in the treatment of mild-tomoderate Crohn’s disease and ulcerative colitis on the basis of evidence that they reduce long-term morbidity, particularly the need for subsequent s u rg e ry. While there is still debate about how soon to initiate TNF-a inhibitors, new agents are yielding insight about how differences in their structure and their relative molecular activities influence antiinflammatory effects. Although there are no large studies directly comparing TNF-a inhibitors for clinical outcomes, there are data suggesting that patients who do not respond to one may respond to another. With new TNF-a inhibitors in development ,there is major potential to reveal more about the significance of the unique characteristics of these agents as well as expanding therapeutic options within a potent drug class.

A PRECiSE Analysis

A pegylated humanized TNF-a inhibitor, certolizumab pegol is the newest compound within this class to complete phase III testing in Crohn’s disease. In the pivotal placebo-controlled maintenance program called PRECiSE 2 (Pegylated Antibody Fragment Evaluation in Crohn’s Disease: Safety and Efficacy), 63% of those randomized to active therapy vs. 36% of those receiving placebo (P<0.001) maintained a response, defined as a =100-point reduction in the Crohn’s Disease Activity Index (CDAI), at week 26 (Schreiber et al. N Engl J Med 2007;357:239-50). This degree of response is along the same order of benefit previously re p o rted in phase III studies with the TNF-a inhibitors infliximab and adalimumab.

The newest data from the PRECiSE trials program substantiate the activity of certolizumab pegol beyond 26 weeks. Patients who completed PRECiSE 2 were entered into PRECiSE 3, an open-label study of certolizumab pegol 400 mg administered every four weeks for up to five years. Patients who relapsed during PRECiSE 2 (defined as a =70-point increase in CDAI or an absolute CDAI =350 points) were entered in PRECiSE 4 and received a re-induction with certolizumab pegol 400 mg consisting of three doses administered at weeks 0, 2 and 4 followed by a maintenance dose every four weeks. In placebo patients who relapsed during PRECiSE 2 maintenance, a single dose of certolizumab was administered in PRECiSE 4. The objective in each follow-up was to evaluate safety and long-term efficacy according to the Harvey-Bradshaw Index (HBI).

At the end of 26 weeks in PRECiSE 2, 48.4% of certolizumab patients were in remission as defined by the HBI. At the end of 12 months in PRECiSE 3, 41.9% remained in remission using the same definition; by 18 months, 37.2% were still in remission. In PRECiSE 4, 29% of those who received a three-dose re-induction regimen achieved remission despite relapsing on certolizumab during PRECiSE 2. The remission rate at month 12, the latest point of follow-up so far, was 35%. In the placebo group that received a single dose of certolizumab in PRECiSE 4, the initial remission rate was 44% and remained at 44% at month 6 of follow-up, falling to 36% by month 12.

Prolonged Treatment Without Dose Increase

These data appear to differ from the experience with infliximab in ACCENT (A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen) (Lancet 2002;359 [9317]:1541-9) and adalimumab in CHARM (Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance) (Gastroenterology 2007;132[1]:52-65). In both these studies, a doubling of dose was required to regain response in patients who failed initial treatment, whereas re-induction with certolizumab pegol in PRECiSE 4 achieved successful sustained responses without a dose increase.

Prolonged treatment with certolizumab pegol did not raise any new safety issues. As observed with other TNF-a inhibitors, the most frequently reported adverse events were gastrointestinal side effects and an i n c reased risk of infectious diseases. There were no serious adverse events considered by the investigators to be related to the study medication. Although there was one death from Pneumocystis carinii infection in PRECiSE 4, it occurred 12 weeks after the last dose of certolizumab pegol and was not considered medication-related.

Inducing Remission in Unresponsive Patients

These results support the long-term efficacy and safety of certolizumab pegol, but the unique characteristics of drugs in this class suggest that they may not be interchangeable. For example, certolizumab pegol is pegylated, thereby slowing its elimination and increasing its half-life. In addition, it does not have the Fc portion of the antibody. Unlike other TNF-a inhibitors, this agent has not induced complement activation, antibody-dependent cytotoxicity, or apoptosis in mechanistic studies. In vitro studies have indicated that it has a high affinity for TNF-a relative to other TNF-a inhibitors. Like adalimumab but unlike infliximab, certolizumab is administered subcutaneously, which circumvents the risk of acute or delayed infusion reactions. The effect of these differences, if any, on clinical activity relative to other agents that target TNF-a will require a randomized trial, but there are data, including those presented at the UEGW, that lack of response to one agent does not preclude lack of response to another despite their common molecular target.

Among presentations on second- and third-line TNF-a inhibitors at the UEGW was a collaborative study between institutions in France and Belgium. It was not controlled or systematic and evaluated response in only 49 Crohn’s disease patients, but it did provide preliminary evidence that a third agent can induce remissions even in patients previously unresponsive to infliximab or adalimumab. In those e n rolled, the median duration of Crohn’s disease was six years and 37% of the patients were female. About 75% of patients had involvement of the ileum and colon, and slightly more than half had anal lesions. Forty per cent had a previous surgical resection. All patients had experience with azathioprine and twothirds had been previously treated with methotrexate. Almost 60% of patients received infliximab first followed by adalimumab and then certolizumab pegol. Most of others received adalimumab first then infliximab and finally certolizumab pegol. Only 4% of patients received certolizumab pegol first.

On the third anti-TNF-a agent, a >3-point reduction in the HBI was achieved in 55% of patients at six weeks. When response was evaluated in the context of the reason for failure of the second-line agent, response was observed in 66% of those with primary failure, 53% of those who had lost efficacy, and 43% of those who were intolerant. These results build on previously reported studies, such as the GAIN (Gauging Adalimumab Efficacy in Infliximab Nonresponders) study, which has demonstrated efficacy for a second TNF-a inhibitor after the failure of the first (Ann Intern Med 2007; 146:829-38).

More Productive Workdays

New data from the PRECiSE studies program has re i n f o rced the benefits on quality of life and work productivity reported earlier in studies of other TNF-a antagonists. In the work productivity and daily activity levels analysis, for example, work productivity increased at all time points in those taking the TNF-a inhibitor when compared to placebo. When calculated as workdays gained, the data found that those randomized to certolizumab pegol had a gain of half a fully productive workday per week, an advantage that was statistically significant and consistent with the significant improvements in quality of life.

Summary

The addition of a new TNF-a inhibitor to the therapeutic options in Crohn’s disease is a significant development. In responders, this class of drug has altered the lives of patients poorly responsive to previous agents. The introduction of a new agent has the potential to further expand the IBD population who achieve remission. These compounds, despite a common therapeutic target, do not appear to be interchangeable.

A third TNF-a inhibitor, certolizumab pegol, has demonstrated a degree of efficacy and safety that appears to be at least commensurate with that observed with two agents previously introduced in its class. Although controlled trials are needed to compare the relative attributes of TNF-a inhibitors, these drugs do have unique features. This premise is reinforced by the evidence that patients who have failed one such agent can respond to another. From the PRECiSE trials program, there are now data to confirm long-term remission of Crohn’s disease with certolizumab pegol as well as the potential to regain response in a substantial proportion of patients with a re-induction regimen.?

Questions and Answers With:

Dr. Remo Panaccione • Dr. Brian Bressler • Dr. Naoki Chiba • Dr. Richard Fedorak

Q. The current TNF-a inhibitors, which differ in structure, pegylation and route of administration, do not appear to be interchangeable. Can you discuss the reasons why it may be useful to have a selection of these agents available?

Dr. Panaccione: Although infliximab, adalimumab and certolizumab all belong to the same biological class and the target for all of these agents is the same—namely, TNF-a—these agents are quite diff e rent in their molecular structure and possibly their mode of action. We know that simple blockade of TNF-a or its receptor is not the whole story. Apoptosis has been touted as an important mechanism by which these drugs work, but by virtue that certolizumab does not appear to cause apoptosis and has still proven to be efficacious in clinical trials speaks to the fact that we do not completely understand the mode of action. That said, having a selection within the same class gives clinicians the opportunity to try another member in the class if a patient loses response or becomes intolerant to another member in the class. If there are even subtle differences in mechanisms of action of these agents, there may be room to explore the efficacy in primary non-responders. This has never been tested but some recent data presented at the ACG in Philadelphia suggested that c e rtolizumab was effective in patients who were previously thought to be primary non-responders to another anti-TNF. This came from an open-label access study but if this is indeed the case, then this is intriguing.

Dr. Chiba: It is always good to have more than one agent available. Infliximab is the one we are familiar with and it has a good track record so far with treating luminal and perianal disease in Crohn’s and now with ulcerative colitis as well. It is unclear whether we need to add in an immunosuppressive agent with infliximab, as there is a somewhat higher risk of developing antiinfliximab antibodies and if so, then this might reduce efficacy. Infliximab needs to be given in the clinic and the patient has to spend several hours there for infusion. Most patients have no problem with this. However, patients can administer themselves subcutaneous (s.c.) adalimumab injections and this is an advantage for some patients where going to a clinic is inconvenient.

Dr. Bressler: A selection of TNF-a inhibitors is an important advancement in the treatment of Crohn’s disease. Having the option of either intravenous (i.v.) or s.c. administration of such medications significantly increases the convenience of this type of treatment. Being able to self-administer a biologic is very desirable to many patients, reducing the burden the i.v. form potentially requires. A selection of agents will allow switching within this class of biologic therapy when patients who have had a previous response to a TNF-a inhibitor can regain response with an alternative one. Potentially the different formulations of TNF-a inhibitors may act differently and result in different immunogenicity. As we learn more about the causes of Crohn’s disease and how best to use these types of biologics, certain patients may preferentially benefit from one agent based on its unique mechanism of action and immunogenic potential.

Dr. Fedorak: Clinical trial evidence has demonstrated to us that loss of response to one anti-TNF agent can frequently be overcome and the patient can enter back into remission with the use of a second or even third anti- TNF agent. The different anti-TNF agents have different routes and durations of administration. The ability to individualize administration approaches for patients will be important to compliance and ultimate efficacy.

Q. Now that patients have been followed for as long as 80 weeks on TNF-a inhibitors with acceptable efficacy and tolerability, can you explain where these fit in with strategies for long-term disease control?

Dr. Panaccione: I believe that we are all becoming more comfortable with this class of drugs, especially considering that infliximab has been on the market for over nine years and more than 1 million patients have received treatment. However, most clinicians remain reluctant to position this class of drugs before steroids and immunosuppressants. Therefore, the top-down approach has not replaced the step-up approach. This is likely not in the best interest of all patients. There are patients who would certainly benefit from early introduction of biological therapy. Recent data from France that has been corroborated by the Mayo Clinic group suggests that patients with young age of disease onset, colonic disease, presence of perianal lesions and early need for steroids constitute a group which has a high likelihood of progressing to a disabling course. If this is the case, maybe these patients should be targeted for early intervention. However, I think work needs to be done to refine which patients will not only benefit most from these therapies but also which patients would respond best. This remains an unmet research need.

Dr. Chiba: One area where these agents seem to shine is their apparent ability to heal the mucosa and so markedly reduce the relapse rate. Clearly, these agents are very effective for long-term control of Crohn’s disease in some patients, but there is clearly an issue with their very high expense and the concern for aggravating disease states such as tuberculosis and raising concerns about lymphoma. Clearly, these drugs will not be for everyone but they do represent a big advancement in helping with long-term disease control.

Dr. Bressler: The long-term efficacy and tolerability of TNF-a inhibitors adds further evidence to our understanding of the benefit this strategy of treating Crohn’s disease can have for patients. Long-term TNF-a inhibition can safely control Crohn’s disease, leading to as little impact as possible of this disease on patients, and potentially reducing complications of Crohn’s disease such as surgeries and hospitalizations.

Dr. Fedorak: Outside of clinical trials, patients have been treated continuously since 2000 with anti-TNF agents. Many of these patients have resumed work and school activities because of their use of anti-TNF agents. There is no doubt that these patients are in long-term remission because of their access and use of long-term anti TNFs.

Q. In general, what is the significance of s.c. vs. i.v. infusions for administration of TNF-a inhibitors? How may the reduced rate of injection-site reactions with certolizumab affect your treatment choice?

Dr. Panaccione: There is no doubt that s.c. injection is preferred by patients. These patients are young and at formative years in their lives with school and employment commitments. They want to have the freedom to come and go, to travel, and in certain instances, the ability to take control of their disease. A recent survey done at the University of Calgary IBD Clinic suggested that 78% of patients would prefer the s.c. route of administration. Some physicians may be leery of doing this but this should be discussed with patients. The fact that certolizumab pegol has been associated with very few injection-site reactions is a definite advantage and I believe this will be an important feature to patients.

Dr. Chiba: The biggest advantage to the s.c. administration route is that it allows the patient to have control over their disease management as they can selfadminister treatment. I have no experience with certolizumab but certainly, reduced injection-site reactions would be advantageous to the patient.

Dr. Bressler: Convenience for patients is the major significance of s.c. vs. i.v. infusions for administration of TNF-a inhibitors. The immunogenic potential of a s.c. agent may also be different compared to one administered i.v. Albeit rare, infusion reactions are also not an issue when administering these agents s.c. However, injectionsite reactions are potentially problematic when delivering TNF-a inhibitors s.c. Certolizumab has been reported to have a low rate of injection-site reactions, which would be one aspect I would consider when selecting a s.c. TNF-a inhibitor.

Dr. Fedorak: S.c. administration has the distinct advantage of relieving patients from the necessity of attending i.v. infusion centres to receive a four-hour infusion of the anti-TNF agent. The infusion reactions associated with i.v. administration of an anti-TNF are more frequent and more severe than those with s.c. administered agents.

Q. By pegylation, certolizumab appears to provide favourable pharmacokinetics, avoiding dose creep. Can you comment on dose creep with infliximab and whether this concerns you for long-term safety?

Dr. Panaccione: With increasing experience with infliximab, it is evident that a certain proportion of the responders will require more intense dosing which may take the form of decreased interval or increased dose. In the clinical trials, this happened approximately 28% of the time; however, the majority were rescued with the 10-mg/kg dose. That said, this adds considerable cost to maintenance dosing. I don’t necessarily believe this will affect long-term safety. There simply isn’t any data to suggest this. However, it appears that pegylation with certolizumab pegol has translated into a favourable pharmacokinetic profile with more sustainable drug levels. Also, the data that a single re-induction dose of certolizumab can re-establish response in patients without the need for a permanent dosing intensification is an important feature.

Dr. Chiba: I have not really had a problem with dose creep with infliximab. The only thing I’ve had to do is decrease the interval between injections. So far, the biologicals appear safe but we must continue careful surveillance.

Dr. Bressler: Despite our best efforts to maintain remission with infliximab, such as using maintenance dosing as opposed to episodic treatment, pretreating with hydrocortisone and using concomitant immunosuppressants, a significant proportion of patients require either shortening of their interval or increased dosing of infliximab to stay in remission. In my experience, once one of these strategies is necessary, the expected longterm remission rate for these patients drops off. I don’t feel the requirement of higher doses of infliximab affects long-term safety, in that circulating levels probably remain similar to levels when patients were responding to lower doses. The excess infliximab is necessary to overcome the antibody-induced clearance of the medication.

Dr. Fedorak: Dose escalation with infliximab occurs, particularly following episodic [on-demand] therapy, as a consequence of the development of antibodies to infliximab. The rate of antibody to infliximab formation has been estimated at between 40% and 60%. The antibodies to infliximab will subsequently translate into a secondary loss of response to infliximab and dose escalation. In some cases, dose escalation does not overcome the loss of response and the patient has a flare of their disease. It is this secondary loss of response to infliximab that limits its long-term use.

Q. There are now data suggesting that one TNF-a inhibitor may provide control of Crohn’s disease after failure of another drug within this class. Can you comment about what is known about treating a patient who has failed a previous TNF-a inhibitor with a second or third TNF-a inhibitor?

Dr. Panaccione: It is important to define what we are talking about. There is enough evidence out there suggesting that in those patients who have previously responded and lost response to a previous anti-TNF (secondary non-responders) and/or become intolerant to an anti-TNF that coming back with another drug in class is beneficial. This was shown in the GAIN study with adalimumab and there is no reason why I think this should be different with the other members of the class. Primary non-responders are an interesting group which needs more investigation. However, emerging data from the ACG and UEGW suggest that even primary nonresponders may benefit from switching within class. These reports are based on open-label exposure in very small numbers of patients. I believe only time and clinical experience will provide the true answer to this question.

Dr. Chiba: There is not much data for this but because these biological agents are all different, there is rationale for using a different agent and there is some data to support this. However, we must keep in mind that the treatment benefit of these biologicals vs. placebo in treatment-naive patients is modest and the treatment success in patients who have received a previous biological is even smaller.

Dr. Bressler: Indeed, we are acquiring more experience with treating patients who have failed a previous TNF-a inhibitor with a subsequent TNF-a inhibitor. However, I first want to point out that our experience is predominantely in patients who initially responded to a TNF-a inhibitor and over time lost response or became intolerant of their TNF-a inhibitor. We have very limited data on the efficacy of a second TNF-a inhibitor when a patient never responded initially to their TNF-a inhibitor. In patients who have lost response or have become intolerant to their initial TNF-a inhibitor, a certain proportion of patients will respond to an alternative TNF- a inhibitor. In patients who have become intolerant of a TNF-a inhibitor, we are not seeing this intolerance cross over to an alternative agent. Using an alternative TNF-a inhibitor is effective to induce a clinical response or remission, but the likelihood of achieving such results is approximately 10% to 15% less than one would expect in TNF-a inhibitor-naive patients.

Dr. Fedorak: Treatment with a second anti-TNF frequently results in another induction of remission in a patient who has lost response to the first anti-TNF. I have personal experience with using a second or third anti-TNF in these clinical situations. It can be an extremely effective therapeutic approach.?