Weekly Adalimumab Dosing in Ulcerative Colitis
Weekly Adalimumab Dosing in Ulcerative Colitis
Treatment options for patients with refractory UC have improved greatly with the approval and use of anti-TNF agents. The efficacy of every other week dosing with adalimumab as maintenance therapy for patients with moderately to severely active UC who have failed conventional therapy has been demonstrated in the ULTRA 2 trial. Results from this post hoc analysis using patient data from ULTRA 2 suggest that escalation from every other week to weekly maintenance dosing of adalimumab may be beneficial in treating patients who either do not initially respond to induction therapy or who initially respond, but later lose response. We selected week 8 as the time point to stratify patients by response to induction therapy (using partial Mayo score) and analysed these subgroups separately. At 1 year, of the patients who escalated to open-label weekly dosing, 45% of patients with week 8 response had regained clinical response and 45% had mucosal healing. The corresponding rates for patients without week 8 response after induction dosing were 25% and 29.2%, respectively. Furthermore, clinical remission was achieved with open-label weekly dosing in 2% of patients who did not respond to induction therapy and in 20% of patients who responded early, but later lost response. No new safety signals or increase in adverse events were reported with weekly dosing.
Clinical factors that predict lack or loss of response to anti-TNF therapy are of particular interest for physicians who treat patients with UC. In ULTRA 2, patients with response at week 8 were approximately half as likely to move from blinded to open-label therapy or to escalate to weekly dosing as patients without early response. A logistic regression analysis of demographical and disease-related factors in all adalimumab-randomised patients in ULTRA 2 identified only previous anti-TNF use as a significant predictor of escalation to weekly dosing for patients with UC. Interestingly, factors which have been shown to influence the pharmacokinetics of monoclonal antibodies, including CRP, albumin level (which may be a marker for the neonatal Fc receptor salvage pathway), concomitant thiopurine use and weight, were not significantly associated with escalation to weekly dosing. Patients with week 8 response were more likely to be taking concomitant corticosteroids at the beginning of ULTRA 2. The reason for this finding is unclear, and the baseline use or non-use of steroids was not associated with the eventual need for escalation to weekly dosing.
The package labelling for adalimumab in both the US and Europe limits the use of adalimumab maintenance therapy to patients who have shown signs of efficacy by week 8 after induction dosing of 160/80 mg followed by 40 mg every other week. These data are based upon the favourable results observed at 1 year in patients with response at week 8 relative to the overall adalimumab-treated population. While the data presented here suggest that escalation to weekly dosing has the greatest benefit in patients with early response and subsequent loss of response in terms of achieving response, remission or mucosal healing, a substantial benefit in terms of mucosal healing was also observed with weekly dosing for week 8 nonresponders. It is possible that some of the patients who escalated to weekly dosing had symptoms that were not due to UC-related inflammation, since assessment of mucosal ulcers was not required at the time of escalation to weekly dosing in ULTRA 2. While UC-related inflammation typically is not considered to lead to irreversible damage, certain patients experience dysmotility, anorectal dysfunction or alterations in mucosal permeability with associated symptoms due to UC-related structural and functional damage beyond the mucosal layer. Physicians should consider these issues as well as other potential causes of symptom activity (e.g. gastroenteritis, functional symptoms or irritable bowel syndrome) when evaluating a patient's therapy for UC.
The stringent definition of remission used in this trial (a full Mayo score ≤2, no subscore >1) may explain the greater rates of response and mucosal healing than remission observed in patients who escalated to open-label weekly dosing. Achieving remission required both symptomatic control and mucosal healing in a study population with an average baseline Mayo score of approximately 9 who failed conventional immunosuppressive therapy and may have had previous anti-TNF treatment. Although remission rates of 20% or less were observed for patients who escalated to weekly dosing, disease burden should be considered when evaluating these rates in both week 8 response groups.
The study design of ULTRA 2 included an intermediate step from blinded to open-label adalimumab 40 mg every other week for lack of response, before allowing escalation to weekly dosing for continued or subsequent inadequate response. Of the patients randomised to adalimumab in ULTRA 2, 48.7% of week 8 responders and 37.7% of nonresponders who moved from blinded to open-label adalimumab continued to receive the same dose of 40 mg every other week and did not escalate to weekly dosing. Approximately 40% of patients in each group achieved response at week 52 with open-label 40 mg every other week dosing. Although similar rates of efficacy were achieved for patients who stayed on every other week dosing and for those who subsequently escalated to weekly dosing, these results should not be interpreted as a lack of potential benefit for weekly over every other week dosing; patients escalated to weekly dosing by protocol design because of inadequate response to open-label every other week dosing and were not randomised to weekly dosing. The reasons for the achievement of response in the patients who moved from blinded to open-label every other week dosing and remained at that dose are unknown. While some of the improvements may be related to the change from blinded to open-label therapy, it is also possible that symptoms which led to the move to open-label therapy were either transient or not related to the patient's underlying UC. In addition, it is also important to consider that some week 8 nonresponders may have experienced a delayed response to adalimumab, which was achieved after week 12 with open-label every other week dosing.
The use of therapeutic drug monitoring (i.e. trough concentrations of anti-TNF agents) is increasingly being advocated to guide therapy for patients with inflammatory bowel disease who experience a loss of response. This strategy is based upon the findings observed in several cohort studies that patients treated with anti-TNF agents who achieve efficacy generally have higher median trough serum drug concentrations than those who do not respond. A recent exposure-response analysis from the ULTRA 2 study found that patients with higher adalimumab trough concentrations (grouped by quartiles) had greater rates of remission at week 8. In addition, patients with remission at week 52 in ULTRA 2 had higher serum adalimumab trough concentrations than patients not in remission at 1 year. In this analysis, median serum adalimumab concentrations nearly doubled in both week 8 responders and nonresponders after escalation to weekly dosing, and median serum adalimumab concentrations after escalation to weekly dosing were slightly higher for patients who achieved clinical response and mucosal healing at week 52 relative to patients who did not achieve these endpoints. The similarity of the serum adalimumab trough concentrations in week 52 responders and nonresponders suggests that there are nonpharmacokinetic factors (including relative amounts of inflammation, the presence of scarring, or differences in individual responsiveness to anti-TNF therapy) that influence response to therapy. Further analyses of adalimumab pharmacokinetic data collected in ULTRA 2 are ongoing.
Data from several observational retrospective studies support our results that weekly adalimumab dosing can be an effective strategy for patients who do not demonstrate early response or who lose response to treatment. In a large case series of patients with active UC treated with adalimumab from 22 IBD centres in Italy, approximately one-third of patients required escalation to weekly dosing and greater than 40% of those patients could de-escalate therapy after a median of 5 months. In the retrospective cohort study based on data from ENEIDA registry (multicenter Spanish database of patients with IBD), 37.5% of patients escalated to weekly dosing and 44% of those patients achieved remission and an additional 42% achieved response after escalation to weekly dosing. Although remission rates were higher in the observational studies than those reported here and the decision to dose escalate was at the discretion of the investigator and not according to pre-defined criteria of nonresponse, these 'real-life' clinical practice experiences are consistent with our results that weekly dosing of adalimumab can be a favourable treatment option for patients who lose response to therapy on every other week maintenance dosing. The Italian series also suggests that returning to every other week dosing (which was not allowed per the ULTRA 2 protocol) may be an option in some patients. More information regarding patient characteristics associated with a successful return to every other week dosing is needed.
Our analysis has several limitations. As mentioned earlier, the decision to move from blinded to open-label therapy and subsequent escalation to weekly dosing was based on patient symptoms assessed using the partial Mayo score, which is based largely on patient-reported stool frequency and rectal bleeding, and not documented objective evidence of ongoing inflammatory activity. Furthermore, the results of this post hoc analysis were based on patients receiving open-label therapy, which could influence the response rates observed. Lastly, this analysis included a relatively small number of patients and only included data up to 1 year.
The results presented here have important implications in the treatment of patients with UC. This is the first report from a prospective clinical study which demonstrates that escalation to weekly dosing with anti-TNF therapy is beneficial for patients with UC. In real-world clinical practice, physicians have three options when deciding on a treatment course for patients who lose response or do not respond to anti-TNF therapy. These include switching therapy, adjusting the dosage, or discontinuing anti-TNF treatment. The results presented here suggest that escalation to weekly dosing is a safe and potentially beneficial strategy for patients losing response on every other week adalimumab therapy. Long-term data showing the durability of escalation to weekly dosing are needed and will provide further insight into the benefit of dose adjustment for patients with UC who do not respond or who have lost response to anti-TNF therapy.
Discussion
Treatment options for patients with refractory UC have improved greatly with the approval and use of anti-TNF agents. The efficacy of every other week dosing with adalimumab as maintenance therapy for patients with moderately to severely active UC who have failed conventional therapy has been demonstrated in the ULTRA 2 trial. Results from this post hoc analysis using patient data from ULTRA 2 suggest that escalation from every other week to weekly maintenance dosing of adalimumab may be beneficial in treating patients who either do not initially respond to induction therapy or who initially respond, but later lose response. We selected week 8 as the time point to stratify patients by response to induction therapy (using partial Mayo score) and analysed these subgroups separately. At 1 year, of the patients who escalated to open-label weekly dosing, 45% of patients with week 8 response had regained clinical response and 45% had mucosal healing. The corresponding rates for patients without week 8 response after induction dosing were 25% and 29.2%, respectively. Furthermore, clinical remission was achieved with open-label weekly dosing in 2% of patients who did not respond to induction therapy and in 20% of patients who responded early, but later lost response. No new safety signals or increase in adverse events were reported with weekly dosing.
Clinical factors that predict lack or loss of response to anti-TNF therapy are of particular interest for physicians who treat patients with UC. In ULTRA 2, patients with response at week 8 were approximately half as likely to move from blinded to open-label therapy or to escalate to weekly dosing as patients without early response. A logistic regression analysis of demographical and disease-related factors in all adalimumab-randomised patients in ULTRA 2 identified only previous anti-TNF use as a significant predictor of escalation to weekly dosing for patients with UC. Interestingly, factors which have been shown to influence the pharmacokinetics of monoclonal antibodies, including CRP, albumin level (which may be a marker for the neonatal Fc receptor salvage pathway), concomitant thiopurine use and weight, were not significantly associated with escalation to weekly dosing. Patients with week 8 response were more likely to be taking concomitant corticosteroids at the beginning of ULTRA 2. The reason for this finding is unclear, and the baseline use or non-use of steroids was not associated with the eventual need for escalation to weekly dosing.
The package labelling for adalimumab in both the US and Europe limits the use of adalimumab maintenance therapy to patients who have shown signs of efficacy by week 8 after induction dosing of 160/80 mg followed by 40 mg every other week. These data are based upon the favourable results observed at 1 year in patients with response at week 8 relative to the overall adalimumab-treated population. While the data presented here suggest that escalation to weekly dosing has the greatest benefit in patients with early response and subsequent loss of response in terms of achieving response, remission or mucosal healing, a substantial benefit in terms of mucosal healing was also observed with weekly dosing for week 8 nonresponders. It is possible that some of the patients who escalated to weekly dosing had symptoms that were not due to UC-related inflammation, since assessment of mucosal ulcers was not required at the time of escalation to weekly dosing in ULTRA 2. While UC-related inflammation typically is not considered to lead to irreversible damage, certain patients experience dysmotility, anorectal dysfunction or alterations in mucosal permeability with associated symptoms due to UC-related structural and functional damage beyond the mucosal layer. Physicians should consider these issues as well as other potential causes of symptom activity (e.g. gastroenteritis, functional symptoms or irritable bowel syndrome) when evaluating a patient's therapy for UC.
The stringent definition of remission used in this trial (a full Mayo score ≤2, no subscore >1) may explain the greater rates of response and mucosal healing than remission observed in patients who escalated to open-label weekly dosing. Achieving remission required both symptomatic control and mucosal healing in a study population with an average baseline Mayo score of approximately 9 who failed conventional immunosuppressive therapy and may have had previous anti-TNF treatment. Although remission rates of 20% or less were observed for patients who escalated to weekly dosing, disease burden should be considered when evaluating these rates in both week 8 response groups.
The study design of ULTRA 2 included an intermediate step from blinded to open-label adalimumab 40 mg every other week for lack of response, before allowing escalation to weekly dosing for continued or subsequent inadequate response. Of the patients randomised to adalimumab in ULTRA 2, 48.7% of week 8 responders and 37.7% of nonresponders who moved from blinded to open-label adalimumab continued to receive the same dose of 40 mg every other week and did not escalate to weekly dosing. Approximately 40% of patients in each group achieved response at week 52 with open-label 40 mg every other week dosing. Although similar rates of efficacy were achieved for patients who stayed on every other week dosing and for those who subsequently escalated to weekly dosing, these results should not be interpreted as a lack of potential benefit for weekly over every other week dosing; patients escalated to weekly dosing by protocol design because of inadequate response to open-label every other week dosing and were not randomised to weekly dosing. The reasons for the achievement of response in the patients who moved from blinded to open-label every other week dosing and remained at that dose are unknown. While some of the improvements may be related to the change from blinded to open-label therapy, it is also possible that symptoms which led to the move to open-label therapy were either transient or not related to the patient's underlying UC. In addition, it is also important to consider that some week 8 nonresponders may have experienced a delayed response to adalimumab, which was achieved after week 12 with open-label every other week dosing.
The use of therapeutic drug monitoring (i.e. trough concentrations of anti-TNF agents) is increasingly being advocated to guide therapy for patients with inflammatory bowel disease who experience a loss of response. This strategy is based upon the findings observed in several cohort studies that patients treated with anti-TNF agents who achieve efficacy generally have higher median trough serum drug concentrations than those who do not respond. A recent exposure-response analysis from the ULTRA 2 study found that patients with higher adalimumab trough concentrations (grouped by quartiles) had greater rates of remission at week 8. In addition, patients with remission at week 52 in ULTRA 2 had higher serum adalimumab trough concentrations than patients not in remission at 1 year. In this analysis, median serum adalimumab concentrations nearly doubled in both week 8 responders and nonresponders after escalation to weekly dosing, and median serum adalimumab concentrations after escalation to weekly dosing were slightly higher for patients who achieved clinical response and mucosal healing at week 52 relative to patients who did not achieve these endpoints. The similarity of the serum adalimumab trough concentrations in week 52 responders and nonresponders suggests that there are nonpharmacokinetic factors (including relative amounts of inflammation, the presence of scarring, or differences in individual responsiveness to anti-TNF therapy) that influence response to therapy. Further analyses of adalimumab pharmacokinetic data collected in ULTRA 2 are ongoing.
Data from several observational retrospective studies support our results that weekly adalimumab dosing can be an effective strategy for patients who do not demonstrate early response or who lose response to treatment. In a large case series of patients with active UC treated with adalimumab from 22 IBD centres in Italy, approximately one-third of patients required escalation to weekly dosing and greater than 40% of those patients could de-escalate therapy after a median of 5 months. In the retrospective cohort study based on data from ENEIDA registry (multicenter Spanish database of patients with IBD), 37.5% of patients escalated to weekly dosing and 44% of those patients achieved remission and an additional 42% achieved response after escalation to weekly dosing. Although remission rates were higher in the observational studies than those reported here and the decision to dose escalate was at the discretion of the investigator and not according to pre-defined criteria of nonresponse, these 'real-life' clinical practice experiences are consistent with our results that weekly dosing of adalimumab can be a favourable treatment option for patients who lose response to therapy on every other week maintenance dosing. The Italian series also suggests that returning to every other week dosing (which was not allowed per the ULTRA 2 protocol) may be an option in some patients. More information regarding patient characteristics associated with a successful return to every other week dosing is needed.
Our analysis has several limitations. As mentioned earlier, the decision to move from blinded to open-label therapy and subsequent escalation to weekly dosing was based on patient symptoms assessed using the partial Mayo score, which is based largely on patient-reported stool frequency and rectal bleeding, and not documented objective evidence of ongoing inflammatory activity. Furthermore, the results of this post hoc analysis were based on patients receiving open-label therapy, which could influence the response rates observed. Lastly, this analysis included a relatively small number of patients and only included data up to 1 year.
The results presented here have important implications in the treatment of patients with UC. This is the first report from a prospective clinical study which demonstrates that escalation to weekly dosing with anti-TNF therapy is beneficial for patients with UC. In real-world clinical practice, physicians have three options when deciding on a treatment course for patients who lose response or do not respond to anti-TNF therapy. These include switching therapy, adjusting the dosage, or discontinuing anti-TNF treatment. The results presented here suggest that escalation to weekly dosing is a safe and potentially beneficial strategy for patients losing response on every other week adalimumab therapy. Long-term data showing the durability of escalation to weekly dosing are needed and will provide further insight into the benefit of dose adjustment for patients with UC who do not respond or who have lost response to anti-TNF therapy.
