Efficacy, Safety and Tolerability of a New 10% Intravenous Immunoglobulin for the Treatment of Primary Immunodeficiencies.

We report here the results of a phase 3 study to assess the efficacy, safety, and tolerability of GC5107, a new 10% liquid intravenous immunoglobulin (IVIG) in preventing serious bacterial infections in patients with primary immunodeficiency (ClinicalTrials.gov: NCT02783482). Over a 12-month study period, 49 patients aged 3 to 70 years with a confirmed diagnosis of primary immunodeficiency received GC5107 at doses ranging from 319 to 881 mg/kg body weight every 21 or 28 days, according to their previous IVIG maintenance therapy. A total of 667 infusions of GC5107 were administered comprising a total of 45.86 patient-years of treatment. A single acute serious bacterial infection occurred during the study, resulting in an incidence of 0.02 events per patient-year (upper 99% one-sided confidence interval limit: 0.21), meeting the prespecified primary efficacy endpoint. The mean incidence of infections other than acute serious bacterial infections was 2.9 infections per patient-year. Efficacy was also demonstrated by the low mean annualized rate of hospitalizations due to infection (0.1 day) and the mean annualized duration of hospitalizations (0.1 day). The mean rate of intravenous and oral antibiotic use was 0.1 day and 13.2 days, respectively. There was a mean of 7.1 days of missed work, school, or daycare days. The proportion of infusions with temporally associated adverse events (TAAEs) occurring during or within 72 hours after GC5107 infusion was 0.24 (upper 95% one-sided confidence interval limit: 0.31), meeting the pre-specified primary safety endpoint. Overall, 149 of 667 infusions (22%) were associated with TAAEs. The most common TAAE was headache, reported by 49% of patients. More than 98% (731/743) of all adverse events that occurred throughout the 12-month study period were mild or moderate. More than 98% of infusions were completed without discontinuation, interruption or rate reduction. There were no treatment-emergent serious adverse events related to GC5107 or study discontinuations due to an adverse event. Overall, pharmacokinetic parameters for GC5107 were within the range of those reported in studies of other marketed IVIG products. Results of the present study demonstrate that GC5107 is an effective, safe and well-tolerated treatment for patients with primary immunodeficiency.

An essential role for the Zn2+ transporter ZIP7 in B cell development.

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.

Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial.

Importance: Current treatments for long-term prophylaxis in hereditary angioedema have limitations. Objective: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks. Design, Setting, and Participants: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized. Interventions: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments. Main Outcome and Measures: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period. Results: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab). Conclusions and Relevance: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy. Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.

Efficacy and safety of an intravenous C1-inhibitor concentrate for long-term prophylaxis in hereditary angioedema.

BACKGROUND: The plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH) is approved in the United States as an intravenous (IV) on-demand treatment for hereditary angioedema (HAE) attacks, and, in Europe, as on demand and short-term prophylaxis. OBJECTIVE: This analysis evaluated Berinert Patient Registry data regarding IV pnfC1-INH used as long-term prophylaxis (LTP). METHODS: The international registry (2010-2014) collected prospective and retrospective usage, dosing, and safety data on individuals who used pnfC1-INH for any reason. RESULTS: The registry included data on 47 subjects (80.9% female subjects; mean age, 44.8 years), which reflected 4082 infusions categorized as LTP and a total of 430.2 months of LTP administration. The median absolute dose of pnfC1-INH given for LTP was 1000 IU (range, 500-3000 IU), with a median time interval between infusion and a subsequent pnfC1-INH-treated attack of 72.0 hours (range, 0.0-166.4 hours). Fifteen subjects (31.9%) had no pnfC1-INH-treated HAE attacks within 7 days after pnfC1-INH infusion for LTP; 32 subjects (68.1%) experienced 246 attacks, with rates of 0.06 attacks per infusion and 0.57 attacks per month. A total of 81 adverse events were reported in 16 subjects (34.0%) (0.02 events per infusion; 0.19 events per month); only 3 adverse events were considered related to pnfC1-INH (noncardiac chest pain, postinfusion headache, deep vein thrombosis in a subject with an IV port). CONCLUSION: In this international registry, IV pnf-C1-INH given as LTP for HAE was safe and efficacious, with a low rate of attacks that required pnfC1-INH treatment, particularly within the first several days after LTP administration.

Emerging Paradigm of Primary Immunodeficiency Disease: Individualizing Immunoglobulin Dose and Delivery to Enhance Outcomes.

An emerging paradigm for the treatment of primary immunodeficiency disease (PIDD) with immunoglobulin (IgG) replacement therapy emphasizes the tailoring of treatments to each patient with the goal of preventing infections and minimizing side effects. Increasing evidence shows that the IgG dose needed to prevent infection varies with each patient, and both intravenous immunoglobulin (IGIV) and subcutaneous immunoglobulin (IGSC) have emerged as feasible modes of delivery. Although IGIV is currently the routine treatment, IGSC is increasingly being chosen as the preferred route of delivery due to greater flexibility and reduced side effects.

Facilitating home-based treatment of hereditary angioedema.

Hereditary angioedema (HAE) is a rare disorder causing periodic attacks of nonpruritic swelling, for which highly effective subcutaneous and intravenous therapies are available. The need to seek ongoing medical attention for HAE attacks at clinics and hospitals adds to the already considerable burden of the disease. Recent international consensus treatment guidelines have emphasized home-based therapy as a preferred managed strategy whenever possible. Here, we review various strategies for facilitating home-based treatment with injectable HAE medications (plasma-derived C1 esterase inhibitor [C1-INH], ecallantide, icatibant, and recombinant C1-INH). Medical literature relating to home-based treatment of HAE is reviewed and strategies for implementing home-based therapy are presented. Home-based treatment of HAE has been shown to reduce the time to initiation of treatment, reduce the duration and severity of attacks, and improve patients' quality of life. Several options are available to facilitate home treatment of HAE. Medical staff in a primary care setting can be educated in the care of HAE patients and can teach the technique of parenteral drug administration. Home care agencies and specialty pharmacies are present in most communities and specialize in patient education. Infusion centers are skilled at working with patients with chronic diseases who perform extensive self-care. HAE comprehensive care clinics provide expert diagnosis and disease management and may become the patient's primary source of HAE care. Home-based therapy of HAE has been shown to be safe and clinically advantageous. Various strategies are available for equipping HAE patients to administer their treatments outside of a medical facility.

Training hereditary angioedema patients to self-administer intravenous C1 esterase inhibitor concentrate.

Hereditary angioedema (HAE) is a rare disorder that causes periodic attacks of sometimes painful swelling that may affect any organ system. HAE results in significant morbidity and diminished quality of life and requires patients to seek urgent medical care. HAE can be treated with C1 esterase inhibitor concentrate (C1-INH), icatibant, and ecallantide. Recent consensus guidelines recommend that all HAE patients be considered for training in self-administration of therapy to treat acute attacks or to prevent attacks. Many patients have safely and successfully self-administered intravenous infusions of C1-INH, resulting in rapid treatment, shortened attacks, and improved quality of life. With proper patient selection and adequate guidance and follow-up, self-administered C1-INH therapy is a viable and favorable option to treat HAE, particularly in patients with a moderate to high frequency of attacks.

Subcutaneous immunoglobulin therapy given by subcutaneous rapid push vs infusion pump: a retrospective analysis.

BACKGROUND: Administration of subcutaneous immunoglobulin (SCIG) via rapid push, an alternative to infusion pump delivery, can offer heightened simplicity and convenience for patients with primary immunodeficiency disease (PIDD). OBJECTIVE: To assess dosing and administration patterns, serum IgG responses, safety, and tolerability of the subcutaneous (SC) rapid push technique. METHODS: A retrospective medical record review captured data on 173 patients with PIDD (1,140 follow-up visits) who self-administered SCIG (16% or 20%) via infusion pump or SC rapid push. RESULTS: Serum IgG levels increased from a mean (SD) trough of 903.8 (285.4) mg/dL during intravenous immunoglobulin use to a steady-state mean (SD) of 1,121.6 (257.6) mg/dL on SCIG. Mean frequency of weekly SCIG administration was 2.3 days per week with pump and 2.8 days per week with SC rapid push. Mean serum IgG levels were higher among push vs pump users (1,164 vs 1,048 mg/dL). Mean (SD) SCIG volume administered per infusion site with SC rapid push was 15.0 (7.3) mL (maximum, 60.0 mL). Most patients using SC rapid push infused in 9 minutes or less; median pump infusion duration was 49 minutes. Use of 20% SCIG was associated with smaller mean weekly product volumes vs 16% SCIG (41.7 vs 51.0 mL) and fewer mean dosing days per week (2.0 vs 2.8 days). Adverse events, primarily local, were reported on fewer visits with SC rapid push (15.6%) than with infusion pump (20.7%). CONCLUSION: The SC rapid push technique is a safe, viable alternative to an infusion pump, seemingly preferred by patients and offering more rapid administration.

Subcutaneous immunoglobulin: rapid push vs. infusion pump in pediatrics.

BACKGROUND: Subcutaneous immunoglobulin (SCIG) therapy is gaining favor for the management of primary immunodeficiency disease (PIDD) in adults and children. METHODS: A retrospective chart review captured data on 96 pediatric patients with PIDD using SCIG (16% or 20%) delivered by infusion pump or SC rapid push over 620 clinic visits. Patients previously using intravenous immunoglobulin (IVIG) were converted to SCIG dosing on a 1:1 basis. Patients/caregivers voluntarily chose an administration technique. RESULTS: Although mean SCIG dosing was lower on a g/kg/month basis compared with prior IVIG dosing, mean steady-state serum IgG levels during SCIG administration were about 100-200 mg/dl higher than IVIG trough values. On average, much more rapid infusion was achieved with the SC rapid push method, with 49% of patients reporting infusion times of 9 min or less; median duration of infusion pump administration was 45 min. The use of 20% SCIG increased dosing efficiency compared with 16% SCIG, allowing for a smaller weekly mean SCIG volume and fewer dosing days per week. Adverse event (AE) rates were lower in the pediatric subgroup compared with adults (15.8% vs. 18.8% of visits), and the majority of AEs were local. SC rapid push was reported most frequently for patients under age 2; its use decreased between ages 2 and <10 yr and then increased in adolescence and into adulthood. Only one of the pediatric patients returned to IVIG use. CONCLUSIONS: Administration of replacement Ig via SC rapid push is a safe and viable option in pediatric patients with PIDD.

Why I use subcutaneous immunoglobulin (SCIG).

Immunoglobulin (IgG) replacement is a life-saving treatment for individuals with primary immunodeficiency disease (PIDD). Today, there are many options for IgG replacement, and the choice is an individual one based on many factors. My preference for most patients is the subcutaneous (SCIG) route. It offers many advantages not offered by the intravenous (IVIG) route. These include: 1) independence from hospital-based infusion settings; 2) an alternative for patients with poor venous access; 3) better tolerability in those patients who are not able to tolerate IVIG; 4) flexibility of dosing; 5) ease of administration; 6) a very low side-effect profile; 7) a comparatively more even, almost physiological, IgG level; 8) less cost to administer than IVIG; and 9) improved quality of life in patients treated with SCIG compared with those treated with IVIG. For most patients with PIDD who require IgG replacement, SCIG offers advantages not available with IVIG.

Clinical ambiguities--ongoing questions.

Many factors need to be considered when choosing the mode of delivery of immunoglobulin (IgG) replacement therapy for a given patient with primary immunodeficiency disease (PIDD). Despite some general guidance as provided in the previous discussions, a number of ongoing questions remain. This article attempts to provide some answers and clarification for clinical situations in which the choice of intravenous IgG (IVIG) or subcutaneous IgG (SCIG) may be ambiguous.

Improved IgG3 levels and reduced infection rate in a woman with CVID switched from intravenous to subcutaneous immunoglobulin therapy.

AIM: To report the interesting case of a patient with common variable immune deficiency disease who demonstrated varied responses to intravenous (IV) and subcutaneous (SC) immunoglobulin (Ig) therapy with regard to both infection frequencies and IgG3 subclass determinations. PATIENT & METHODS: As part of routine medical care, the author monitored total and IgG subclass levels, along with infection frequencies in a 35-year-old woman, with recurrent sinopulmonary infections diagnosed with common variable immune deficiency disease. RESULTS: During treatment with IVIg, the patient's annual rate of infections decreased, although she experienced severe headaches. After being switched to daily SCIg therapy, the headaches stopped, and her annual infection rate declined further. Her IgG3 levels, which were undetectable during IVIg therapy, increased substantially during SCIg treatment. CONCLUSION: The reason for the observed correlation between IgG3 level restoration and a decline in infection rate after being switched to SCIg therapy is not entirely clear. At the minimum, it may suggest that IgG3 levels may be a simple and useful surrogate marker to monitor Ig replacement sufficiency in certain patients.

Payor issues: barriers to optimal management of patients with primary immunodeficiency.

Since 2005, when changes in Medicare reimbursement for IgG replacement therapy went into effect, physicians and patients with primary immunodeficiency disease (PIDD) have encountered a number of challenges to administering and receiving appropriate immunoglobulin therapy. A 2006 membership survey conducted by the American Academy of Allergy, Asthma & Immunology found that 95 % of responders thought that the health of their patients was at risk due to Medicare changes; many patient surveys also found a significant number adversely affected by these changes. Decisions critical for optimal care being made by third-party payors are often in conflict with guidelines on recommended standard of care. Many payors, for example, are dictating where infusions can occur despite evidence clearly demonstrating that choice of the site of care needs to be determined by the particular patient's circumstance and experience. Another critical issue is the lack of product availability due to the determination by payors of which IgG products appear on formularies. Patients, physicians, and payors all bring their own perspective to these issues, and finding a solution to these challenges requires balancing the needs of all three groups.

Local and national advocacy support.

Decisions by third-party payors that are restricting delivery of appropriate IgG treatment for primary immunodeficiency disease (PIDD) are summoning action from patients, physicians, and their organizations to ensure that high quality treatment remains accessible. Some of the strongest advocacy to date is from patient organizations, such as the Immune Deficiency Foundation (IDF), which strive to educate stakeholders on key issues that determine patient access to appropriate IgG treatment. These issues include the ability to choose the appropriate site of care based on a patient's experience and circumstance and greater awareness of product choice. Advocacy by physicians on these issues at the local level is needed, as are national efforts by organizations such as the American Academy of Allergy, Asthma & Immunology and their regional societies.