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Transitioning Between Biologics

Transitioning between biologics, also known as switching or changing between biologics, is not a new phenomenon. Since biologics for moderate to severe psoriasis have been available, physicians have been required to think about how, when, what and whom to switch. A treating physician, along with the patient, must have an agreed-upon treatment target or goal. The ultimate goal, in most cases, however, could be complete disease clearance, although PASI 75 has been considered an acceptable goal by previous authors. In order to achieve this, or at least as close as possible with the tools available, continuous, discussions, assessments and potential modifications should be done during patient visits. These modification strategies include dose adjustments, reduction of dose intervals, adjuvant topical or systemic therapies, or changing the biologic. This short paper focuses on the last strategy: ABSTRACT


INTRODUCTION
changing, switching or transition between biologics.
When considering a change, one must also consider the functional impairment of the patient, comorbidities, as well as treatment risks. 2 For instance, not all biologics are indicated for psoriatic arthritis, while others must be used with caution in patients with inflammatory bowel disease (a known comorbidity associated with psoriasis). Some biologics can be administered via alternative devices (e.g. auto-injectors) to simplify selfinjection in patients that may have dexterity issues.
Primary non-response, secondary nonresponse, adverse events, and the patientphysician decision may also be factors for switching therapy. 3 Primary non-response is also well known as a primary failure. This can occur in a small percentage of patients with any biologic. In the past, a PASI response of less than 75% improvement was considered primary failure if the success was not seen in the first six months of treatment. More recently, due to the greater efficacy of newer biologics, a PASI response of less than 90% improvement may be considered a primary failure. This can be considered as early as the first 8-12 weeks. 4,5 Some treating physicians may be a bit more patient and stretch it to the first 4-6 months. While a lack of initial efficacy during the induction period may be considered primary failure, given the variation of induction periods with many biologics, this may be an inadequate time to reach a conclusion.
Secondary non-response is also known as secondary failure, where there is a loss of efficacy over time. Several possible contributing factors include a patient's weight, previous biologic failures, and comorbidities (e.g. psoriatic arthritis, diabetes, hypertension and cardio-metabolic disease). Occasionally, optimization of the biologic, such as increasing the dose or shortening the intervals between treatments, may boost efficacy. A new concept of reinduction may also help to reverse a secondary failure. 6,7 Adverse events may necessitate a change in biologics as well. Examples include the development of tuberculosis, multiple sclerosis, congestive heart failure, recurrent candidiasis and/or sinusitis and injection site reactions. Lastly, patient-physician decision, such as a request for switching for reasons other than efficacy or safety, can occur. However, undisclosed non-adherence may be thought of as non-response to treatment and could lead to switching therapies unnecessarily. 8,9 There are differences of opinions as to whether washouts are required in-between different biologics. Appropriate washout periods minimize the potentially adverse safety effects of treating with two immunomodulatory agents at once. Evidence against a washout appreciates the risk to the patient's quality of life of waiting for 4 halflives between biologics. The latter may outweigh any perceived benefit. 10,11 The risk for psoriasis flares is generally greater than the risk for any adverse effects associated with overlapping biologic therapies. 12 While a theoretical risk for increased susceptibility to infection has been proposed if washout time is not adequate between biologic therapies, data supporting such a risk are minimal. 13

WASHOUTS
There are many published guidelines for treating psoriasis, however very few provide guidance on how to transition between biologics. The guidelines from Spanish Academy of Dermatology and Venereology (AEDV) recommend that when switching to consider the following: presence or absence of active joint disease, the clinical characteristics of the patient (weight, risk of infection, comorbidities, and contraindications related to specific biologic agents), the mechanism of action, the appropriateness of the dosage and route of administration, the additional cost of induction therapy and other pharmacoeconomic considerations, the relative risk of infections and immunogenicity and the response of the new biologic with previous exposure or failures of other biologics. However, no guidance was given on exactly how to transition. 14 The joint AAD-NPF Guidelines suggest switching biologics when there is no definitive response to treatment with anti-IL12/23, anti-IL17s and anti-IL23s ascertained after 12 weeks of continuous therapy, anti-TNFs after 12-16 weeks of continuous therapy and Infliximab after 8-10 weeks. If clinically needed, it is suggested, to switch to a different biologic agent with the possibility of improved efficacy, safety, and/or tolerability. They warn that not all switches may result in improvement. The duration of the interval between discontinuation of previous medication and initiation of a biologic may depend on the treatment that is being discontinued, disease severity, and response to prior treatment, therefore, should be assessed on a case-by-case basis. Similar to AEDV Guidelines, no direction on exactly how to switch is discussed. 15 The National Institute for Health and Care Excellence (NICE) Guidelines, recommend a switch if there is 1) no adequate response to a first biologic (at 10 weeks after starting infliximab, 12 weeks for etanercept, ixekizumab, secukinumab and brodalumab, and 16 weeks for adalimumab, ustekinumab, or guselkumab; primary failure) or 2) psoriasis initially responds adequately but subsequently loses this response (secondary failure), or 3) the 1 st biologic cannot be tolerated or becomes contraindicated. Again, there is no guidance on how to transition. 16 The most definitive guidelines on transitioning between biologics belong to the British Association of Dermatologists (BAD). 7 They suggest the following transitioning options: No washout period or a nonstandard washout period (greater than or less than three months or four half-lives). An overlap of biologic therapy or bridging with standard systemics may also be considered.
No studies comparing strategies for transitioning between biologic therapies were included in the clinical review. In those that used shorter, non-standard washout periods, there did not appear to be an increased safety risk. The BAD guidelines note factors that influence transitioning therapy strategies: drug pK/pD of the drug being stopped and the one to be started, the patient's clinical history, the disease severity and the underlying risk of infection (if biologics are overlapped). Finally, recommendation R27 suggests the following: When transitioning to a new biologic therapy (from a previous biologic therapy) consider using: a 1-month washout period or the length of the treatment cycle (whichever is longer) between the last dose of the current biologic therapy and the planned date of biologic initiation.

GUIDELINES
When switching due to efficacy, one can use no washout by switching at the next scheduled dose of the failed biologic based on the minimal or shortest dosing interval of the failed biologic with the standard induction dose schedule followed by standard maintenance dosing of the subsequent biologic. 6 However, when switching due to safety issues, one may need to use a necessary treatment-free interval until safety parameters have normalized or stabilized. 6 The washout period for biologics is usually considered to be four half-lives of the reference drug. It is important to realize that the pharmacodynamic effects of the biologic may not necessarily correlate with the pharmacokinetic effects. 7,11,17 When no washout period is required then the guide in Table 1

HOW TO TRANSITION
In general, reports show that switching between biologics whether within the same class or to a different class can be successful. 17 However, Piaserico et al. noted that individuals who experienced a secondary loss of efficacy to one TNF inhibitor or stopped treatment due to an adverse event were more likely to achieve PASI 75 at week 12 than those who were primary nonresponders. 3 The first reported transitioning between two anti-IL-17 antagonists showed similar efficacy when brodalumab patients were transitioned to secukinumab with a twomonth washout period. There was no primary, secondary, or safety issue in the brodalumab patients. The reason for the switch was due to the abrupt cessation of a clinical trial of brodalumab for administrative reasons. 18 In contrast to Piaserico et al. 3 , Georgakopoulos et al. 19 showed that the same might not be true for IL-17A antagonists, where efficacy outcomes did not correlate with reason for secukinumab discontinuation and the duration of secukinumab therapy had no effect on efficacy outcomes when switched to ixekizumab in their case series. More specifically, in this Canadian multicentre retrospective study of 17 secukinumab nonresponders, there were 4 primary secukinumab non-responders whom all responded to ixekizumab, reaching PASI75 or a physician's global assessment (PGA) of 0 or 1. There were 9 secondary nonresponders to secukinumab where 8 of the 9 responded to ixekizumab with a PASI75 or PGA of 0 or 1. There were 4 patients who stopped secukinumab due to intolerance or non-drug related reasons and 3 were able to achieve a PASI75 or PGA of 0 or 1 on ixekizumab.
Overall, their results suggested that a large proportion of secukinumab non-responders who switched to ixekizumab will experience an improved clinical response regardless of the reason or timing of secukinumab discontinuation. Not all patients who experienced an adverse event to secukinumab will experience the same issue with ixekizumab but could experience new adverse events as well. It may be worth noting, especially with the secondary nonresponders, that the primary outcome of this study was taken at the end of the ixekizumab loading phase (week 12), which is obviously a higher dose than during the maintenance phase. As secondary non-responders to secukinumab, they would have also responded well during the induction phase of this biologic and therefore it is still possible that these patients will be secondary nonresponders to ixekizumab when observed at later time points on the label maintenance dose.
Gasslitter, I., et al, 20 also recently showed successful switching in 26 patients between the three presently available anti-IL-17 agents (secukinumab, ixekizumab and brodalumab). Eighteen patients changed their treatment from secukinumab to ixekizumab and seven patients to brodalumab. Brodalumab was used in 3 cases after the failure of treatment with ixekizumab. In only one case, did the nonresponse of brodalumab result in a therapy switch to secukinumab. Overall success was seen in over 70% of patients.
Finally, a clinical benefit has also been observed among patients who switched from an anti-IL12/23 inhibitor (ustekinumab) to an anti-IL23 inhibitor (guselkumab). Specifically, a Phase 3 study showed that guselkumab WHAT TO TRANSITION TO demonstrated greater efficacy compared with ustekinumab among patients who failed to achieve an Investigator's Global Assessment score of 0 or 1 with ustekinumab therapy. For example, at week 52, greater proportions of patients treated with guselkumab achieved PASI 90 (51.1% vs. 24.1%; P < 0.001) and PASI 100 (20.0% vs. 7.5%; P = 0.003) compared with the randomized ustekinumab group. 21 Similarly, a Phase 2 study showed that patients who have been previously treated with ustekinumab, when re-treated with risankizumab, maintained or improved PASI 90 response rates. 22 Overall, regardless of the biologic, switching agents can significantly improve outcomes for patients. 23 Transitioning between biologics is now a privilege and a better way to optimize treatment for patients with moderate to severe psoriasis to improve their quality of life.