Treatment Satisfaction with Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary Immunodeficiency: a Pooled Analysis of Six Hizentra® Studies

Primary immunodeficiency diseases (PIDDs) consist of a heterogenous group of disorders in which there is an intrinsic impairment in the body’s immune system [1, 2]. While up to 300 types of PIDD are recognized, common variable immunodeficiency and X-linked agammaglobulinemia are two of the most common [1, 2]. The true prevalence of PIDD is not well established, but estimates suggest that PIDD affects 1 in 2000 children, 1 in 1200 individuals of any age, and 1 in 600 households in the United States (equivalent to 150,000–360,000 patients) [3].

PIDD imposes a significant disease burden on patients, including limitations in work, play, and normal physical activity [4]. In comparison with healthy children and adults, patients with PIDD experience measurably lower general health with higher hospitalization rates and increased physical, school, and social activity limitation [5‐7]. Further, patients with PIDD fare even worse than those with other chronic conditions with respect to general health perceptions [8, 9].

Fortunately, effective treatment of PIDD is available and associated with patient benefit. Most patients with PIDD require life-long immunoglobulin G (IgG) replacement therapy, which has been directly shown in longitudinal studies to decrease not only the rate of life-threatening bacterial infections and related hospitalizations [10, 11], but also improve health-related quality of life (HRQOL) [12].

Since IgG therapy can be administered either intravenously (IVIG) or subcutaneously (SCIG) [13‐16] and constitutes life-long treatment, the choice of modality of administration can have major implications for patient well-being over their lifetime [17]. Evidence suggests that the efficacy of IgG therapy is similar whether it is administered as SCIG or IVIG [18, 19], yet compared to IVIG, SCIG offers the benefits of more stable serum IgG levels, increased patient flexibility due to self-administration and flexible dosing schedules, and a lower rate of systemic adverse events (AEs) [20, 21]. Furthermore, pharmacokinetic modeling has previously shown that doses can be administered at varying intervals (daily to biweekly) with little impact on serum IgG levels [22, 23].

SCIG, which has been gaining significant favor as an administration route [22, 23], is almost always administered in a home setting. It has the potential to improve several important aspects of HRQOL in patients with PIDD, including fewer limitations with regard to work or other daily activities and reduced impact of treatment on everyday life [21].

There are a variety of SCIG formulations available, including those with IgG concentrations of 10%, 16%, or 20%, and a recombinant human hyaluronidase-facilitated SCIg (fSCIg) [18, 24, 25]. Hizentra® (IgPro20, CSL Behring, Bern, Switzerland) was the first 20% liquid IgG product for subcutaneous administration [26]. The high IgG concentration in Hizentra® allows for a small infusion volume and a short infusion time, thereby further increasing flexibility of dosing and potentially patient HRQOL [21, 27, 28].

Herein, we report results from a pooled analysis of HRQOL results from two pivotal Phase 3 studies and four follow-up/extension studies in patients with PIDD from Europe (EU), the United States (US), and Japan (JP), upon switching from IVIG or another SCIG to Hizentra® and during long-term maintenance Hizentra® treatment.

This analysis of six Phase 3 clinical studies showed meaningful improvement for several relevant aspects of IgG treatment-specific HRQOL (as measured by the LQI) and health status (as measured by SF-36v2) in patients with PIDD upon switching from IVIG or another SCIG to Hizentra®, which was maintained for up to 3 years. Specifically, in two studies (EU and JP) involving a switch from IVIG to SCIG, LQI and SF-36v2 domain scores improved significantly from initial Screening, as early as Week 12 with sustained improvement through Week 24. In the EU switch study, where patients had an option to switch from either IVIG or another SCIG to Hizentra®, these improvements were almost exclusively driven by patients switching from IVIG to SCIG. In fact, there were no statistically significant changes observed in patients who switched from another SCIG to Hizentra®.

These results on improvement following a switch from IVIG to SCIG are consistent with past studies that have also demonstrated an improvement in health status and IgG-specific HRQOL perceptions, as measured by SF-36 and LQI questionnaires [20, 21, 33, 34]. In one study, significant improvements were seen from baseline to month 10 in the SF-36 domains of Vitality, Mental Health, and Social Functioning in patients switching from IVIG to SCIG [20]. Improvements in other SF-36 domains, including Role Physical, Bodily Pain, Role Emotional, Health Transition, and General Health have also been shown following a switch from IVIG to SCIG [21, 33]. Furthermore, significant improvements in both the LQI summary score and individual LQI domains have also been reported [20, 21, 33, 34]. In our switch studies, the domains most favorably impacted were Therapy Setting and Treatment Interference, and to a smaller extent, Therapy-Related Problems, for the LQI questionnaire, and Physical Function, General Health, and to a lesser extent, Role Emotional for the SF-36v2 questionnaire. Most improvements on the above domains were at or near magnitudes of what is considered at least moderately meaningful change.

Further, while our findings regarding an improvement in outcomes (SF-36v2, LQI) following an IVIG to SCIG switch are consistent with past literature, to our knowledge, ours is the longest follow-up of patients with PIDD who were maintained on SCIG treatment. Generally, following improvement, there were no significant changes in these HRQOL measures during the long-term maintenance studies (conducted in EU, JP, and the US), suggesting that improvements in IgG treatment-specific HRQOL perceptions and patient health status were maintained with long-term Hizentra® treatment (up to 208 weeks). Overall, our results are consistent with a recent study that, in addition to demonstrating improvement with an IVIG to SCIG switch, showed the benefit to be maintained for up to 90 weeks [35].

Findings from our study highlight the multi-dimensional nature of PIDD and its treatment. Evidence from the switch studies demonstrated improvements in domains that reflect patient convenience, comfort, independence, treatment schedule flexibility, pleasantness of treatment setting, and less disruption of daily activities. These improvements are perhaps not surprising, given a change from treatment typically administered intravenously in a healthcare setting to home-based SCIG treatment which offers increased patient flexibility [29]. In addition, although our findings on Treatment Costs based on LQI are not meaningful as a result of the artificial nature of a clinical trial setting, evidence from real-world studies has demonstrated cost savings when switching from IVIG to SCIG for treatment of PIDD [36‐38].

The evidence also showed improvements in patient-reported Physical Function and General Health following the IVIG to SCIG switch, consistent with previously reported improvements in Vitality [20, 21]. Improvements in these domains may reflect the impact of stable serum IgG levels characteristic of SCIG treatment, including both higher IgG trough concentrations and reduced peak-to-trough variation achieved through more frequent SCIG treatments, i.e., less wear-off manifested in reduced fatigue [23, 33, 39]. In addition, patients receiving treatment at home may have a reduced exposure to nosocomial infections, further increasing the likelihood of a perceived improvement in general health. Our results therefore support the idea that maintaining stable serum IgG levels translates into improvements in physical function, and moreover, overall general health.

Consistent with the multidimensional nature of PIDD and its treatment, we observed no improvement in some domains of patient-reported outcomes. The Mental Health summary score as measured by SF-36v2 did not change after switching to SCIG. Similarly, the Treatment Costs domain on the LQI was generally not impacted. At the item level, there was lack of improvement with an IVIG to SCIG switch on the LQI items of Improved Health, Treatment Being Worthwhile, and Does Not Make Anxious or Nervous. Findings such as these, especially on the overarching LQI item Improved Health, arguably serve as reminders that PIDD is a chronic condition and may continue to exact a toll in the long run, unaffected by a switch in treatment modality. Further, domains such as emotional status are less likely to be impacted given that they are likely confounded by additional extraneous influences (not explored in these studies), consistent with the Wilson Cleary classification of health outcomes into those that are more immediately impacted by interventions (in this case, a switch from IVIG to SCIG) and those that are likely to be confounded by other factors [40]. Accordingly, it is also not surprising that while a switch in modality from IVIG to SCIG was manifested in an immediate improvement in domains that measured convenience aspects, but not so on domains and items relating to perceptions of intervention cost, as all study medication costs were covered by the study sponsor. However, in clinical practice, these factors are likely to impact patients variously, based on their healthcare system dynamics. Absence of improvement on the item Does Not Make Them Anxious or Nervous following a change to SCIG in both the switch and long-term maintenance phases may highlight the need for physicians to carefully consider those who may not be good candidates for self-infusion by encouraging shared decision making in consultation with the patient.

Finally, our findings on fatigue were somewhat mixed. In past research, patients with primary antibody deficiency have been shown to have higher fatigue levels (25.9%; 95% CI 23.7–28.3) compared with the general population (6–7.5%) [41, 42] and to patients with PIDD who had a condition different from primary antibody deficiency (6.3%; 95% CI 4.9–8.2) [43]. Moreover, patients with common variable immune deficiency, which constituted the large majority of the population in our studies, have been shown to have the highest fatigue levels of all patients with PAD [43]. Fatigue levels have also been shown to be similar regardless whether patients received IVIG or SCIG [43]. In our studies, we assessed Vitality, i.e., the obverse of fatigue, as part of the SF-36v2 and found scores to be uniformly lower (worse) than on other domains, consistent with past work. We also found only marginal improvements in Vitality in the switch studies, which were nevertheless maintained in the longer term, again potentially reflective of the chronic nature of disease and frequency of treatment.

The results from the switch (pivotal) Hizentra® studies where HRQOL was assessed showed that switching patients from IVIG to SCIG improves patient self-reported health status and IgG-specific HRQOL perception. The maintenance (extension) studies generally showed no deterioration of the improved health status achieved when switching from IVIG to SCIG treatment with Hizentra® over a long follow-up period.