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Pomen zdravil za subkutano aplikacijo je čedalje večji, predvsem zaradi številnih prednosti, ki jih ta način apliciranja zdravil ponuja, tako za bolnika kot zdravstveni sistem. S pomočjo elektronskih podatkovnih baz PubMed in ScienceDirect smo proučevali področje subkutane aplikacije z vidika vgrajenih zdravilnih učinkovin in tehnoloških specifik pri oblikovanju formulacij za subkutano dostavo. Pregled smo naredili po različnih časovnih obdobjih, in sicer od 2013 do 2017 in od 2018 do 01/2023. Razvidno je bilo povečevanje števila objav v zadnjem obdobju, prednjačijo pa raziskovalni članki, skupno 153, napram 45 preglednim člankom. Na področju subkutane aplikacije je glavnina raziskovanja vezana na zdravilne učinkovine, ki so ali bi bile primerne za subkutani način apliciranja, predvsem učinkovine biološkega izvora za zdravljenje avtoimunih bolezni (npr. luskavica, revmatoidni artritis). Aktualno je tudi področje različnih tehnologij izdelave in uporabe novih inovativnih pomožnih snovi (npr. rekombinantna humana hialuronidaza) v formulacijah. S pomočjo Centralne baze zdravil smo naredili izbor vseh zdravil za subkutano aplikacijo, ki imajo trenutno veljavno dovoljenje za promet z zdravilom, ne glede na to ali so na voljo na trgu ali imajo priglašeno motnjo v oskrbi ali potekajoče začasno prenehanje (trenutno jih je na voljo 221). Ugotovili smo, da je večina zdravil za subkutano aplikacijo v Sloveniji v obliki raztopine za injiciranje. Na trgu izstopa skupina insulinov, sledijo ji različne učinkovine biološkega izvora. V Sloveniji trenutno prevladujejo originatorji, vendar je razlika v primerjavi z generiki skoraj zanemarljiva. S pomočjo povzetka glavnih značilnosti zdravil, ki se nahaja na Centralni bazi zdravil smo naredili povzetek vseh pomožnih snovi, ki se uporabljajo v zdravilih za subkutano aplikacijo, ki so trenutno na voljo na slovenskem trgu. Ugotovili smo, da lahko uporabljene pomožne snovi razdelimo v več skupin po njihovi vlogi v formulaciji (npr. pufri, adjuvansi, solubilizatorji, snovi za uravnavanje osmolarnosti). Je pa uporaba posameznih skupin pomožnih snovi v tesni povezavi s farmacevtsko obliko, v kateri se nahaja zdravilo za subkutano aplikacijo. The importance of subcutaneous administration is growing, for the most part due to many advantages this route of drug administration offers both for the patient and the healthcare system in general. Using the online databases PubMed and ScienceDirect, we investigated the field of subcutaneous administration with regard to active ingredients and technological approaches in the design of formulations for subcutaneous delivery, over different time periods, namely from 2013 to 2017 and from 2018 to 01/2023. The number of articles increased with each period, with research articles being the most prominent, with a total of 153 articles compared to 45 review articles. In the field of subcutaneous administration, the main focus of research is on active substances that are or could be suitable for subcutaneous administration, in particular active substances of biological origin for the treatment of autoimmune diseases (e.g. psoriasis, rheumatoid arthritis). Researchers are also focusing on the investigation of different technologies for the production and use of new innovative excipients (e.g. recombinant human hyaluronidase) in formulations. Using the Central Medicines Database, we have made a selection of all subcutaneous medicinal products with a currently valid marketing authorisation, whether they are available on the market or have a notified supply disruption or an ongoing suspension (currently 221). We have found that the majority of subcutaneous medicinal products in Slovenia are in the form of an injectable solution. The insulin group stands out on the market, followed by various active substances of biological origin. Originators currently dominate in Slovenia, but the difference is almost negligible compared to generics. Using the summary of the main characteristics of medicinal products available on the Central Medicines Database, we have summarised all excipients used in subcutaneous injectable medicinal products currently available on the Slovenian market. We found that the excipients used can be divided into several groups according to their role in the formulation (e.g. buffers, adjuvants, solubilisers, osmolarity adjusters). However, the use of each group of excipients is closely related to the pharmaceutical form of medicinal product for subcutaneous delivery.

The glycosaminoglycan hyaluronan forms a gel-like substance, which presents a barrier to bulk fluid flow in the subcutaneous (SC) space, limiting SC drug delivery volume and administration rates. Recombinant human hyaluronidase PH20 (rHuPH20) acts locally to temporarily remove this barrier, facilitating rapid SC delivery of large volumes and/or high doses of sequentially or co-administered therapeutics.An extensive clinical and post-marketing dataset of safety and immunogenicity of rHuPH20 in its current applications with approved therapeutics demonstrates that rHuPH20 acts locally, without measurable systemic absorption at the SC doses used in the approved products, and is well tolerated in combination with several co-administered therapeutic agents across diverse patient groups. The immunogenicity profile demonstrates no adverse effects associated with treatment-emergent rHuPH20 antibody responses. Immunogenicity to monoclonal antibodies co-formulated with rHuPH20 shows no clinical difference between SC and intravenous administration. Safety assessments of patient subsets for special populations, including children, elderly patients, and pregnant women, raise no additional safety concerns.The benefits of SC administration for patients and healthcare systems often outweigh those of intravenous administration, driving future initiation of SC-only drug development programs. Injection devices allowing large-volume SC administration could be facilitated by incorporating co-formulated biologics containing rHuPH20.

Compared with intravenous formulations, subcutaneous (s.c.) formulations of therapeutic monoclonal antibodies may provide increased patient access and more convenient administration options, although historically high-volume s.c. administration (> 10-15 mL) has been challenging. We report results from two phase I studies in healthy participants (GP29523 and GP40201) that evaluated s.c. crenezumab, an anti-Aβ monoclonal antibody in development for individuals at risk for autosomal-dominant Alzheimer's disease. GP29523 assessed safety, tolerability, and pharmacokinetics (PK) in 68 participants (aged 50-80 years) who received single ascending doses (600-7,200 mg) of crenezumab or placebo (4-40 mL). GP40201 assessed safety, tolerability, and PK in 72 participants (aged 18-80 years) who received different combinations of dose (1,700-6,800 mg), infusion volume (10-40 mL), and flow rate (2-4 mL/minute), with/without recombinant human hyaluronidase (rHuPH20). There were no serious or dose-limiting adverse events in either study. There were no meaningful differences in pain scores among reference placebo (4 mL), test placebo (4-40 mL), or crenezumab (600-7,200 mg) in GP29523, or across treatments with varying infusion volume, flow rate, dose, or rHuPH20 co-administration or concentration in GP40201. Transient erythema was the most common infusion site reaction in both studies. In GP40201 at volumes of ≥ 20 mL, rHuPH20 co-administration appeared to reduce infusion site swelling incidence, but, in some cases, was associated with larger areas of infusion site erythema. Crenezumab exhibited approximately dose-proportional PK, and s.c. bioavailability was 66% and independent of dose or rHuPH20 co-administration. High-dose, high-concentration, high-volume s.c. crenezumab formulated with/without rHuPH20 was well-tolerated in healthy participants, with an acceptable safety profile.

Primary immunodeficiency disorder (PID) refers to a heterogeneous cluster of over 350 syndromes that upshot from defects in the immune system development or function. PIDs are broadly classified as disorders of adaptive immunity or innate immunity. The enhanced efficacy of human immune serum globulin 10% with recombinant human Hyaluronidase with comparison to blood vessel human gamma globulin is a very prospective open-label study for PID. Treatment of primary immunological disorder diseases (PIDD) with Subcutaneous(SC) infusions of immune gamma globulin headed by an injection of hyazyme to extend SC tissue porousness was evaluated in two consecutive, prospective, non-controlled, multi-center studies. HYQVIA could be a subcutaneously mediated medication to treat the primary immunological disorder in adults. ENHANZE® drug delivery technology relies on the proprietary rHuPH20 macromolecule that facilitates the SC delivery of co administered medical specialty. Recombinant Human Hyaluronidase works by degrading the glycosaminoglycan hyaluronan, which plays a role in resistance to excessive flow of fluid within the Subcutaneous matrix, limiting massive volume SC drug delivery, dispersion, and absorption. Co-administration of recombinant Hyazyme with partner therapies can overcome administration time and volume barriers associated with existing SC therapeutic formulations.

Summary Purpose Hyaluronic acid (HA) fillers can be reversed with hyaluronidase, but their dose responses are not well-characterized. We evaluated 12 fillers’ in vitro responses to varying doses of recombinant human hyaluronidase (RHH). Methods For the 12 HA gels, 0.2 mL aliquots were placed on six slides. Samples received no injection, saline injection, or RHH (2.5, 5, 10, or 20 units). The most resistant gels received 40 units of RHH on a seventh slide. Photos of gels were taken from bird's-eye and lateral views with a ruler at multiple time points. Results Restylane-L and Restylane Lyft were the most easily dissolvable HA fillers. Both demonstrated a significant response to 2.5 units RHH/0.2 mL. Juvederm Ultra, Belotero, Restylane Silk, and Restylane Defyne had moderate resistance to RHH. Restylane Refyne, Juvederm Ultra Plus, Vollure, Versa, and Voluma were most resistant, requiring more than 20 units RHH/0.2 mL for complete dissolution. Volbella was moderately resistant up to 20 units RHH but demonstrated pronounced dissolution with 40 units RHH. Conclusions This study visually and objectively demonstrates the in vitro response of HA to dissolution by hyaluronidase. Fillers were categorized into least, moderate, and most resistant to RHH. Interesting findings include markedly different degrees of liquefaction for products used for similar indications (such as Restylane Lyft being more liquefied than Voluma), and Belotero easily flattening but retaining texture. Combined with in vivo data, this may help calculate hyaluronidase doses needed for controlled, partial reversal of commercially available HA gels.

Objectives Drug–drug interaction studies for hyaluronidase safety assessments have evaluated only animal-derived enzyme preparations. We therefore set out to evaluate whether high-dose administration of two antihistamines, a potent corticosteroid, steroid hormone, adrenocorticotropic hormone (ACTH), or salicylic acid would alter the dispersive activity of recombinant human hyaluronidase PH20 (rHuPH20). Methods NCr nu/nu mice were pretreated with diphenhydramine, cetirizine, dexamethasone, estrogen, ACTH, salicylic acid, and/or neutral-buffered saline (NBS). An hour following final pretreatment, dosed mice were anesthetized with ketamine/xylazine and placed in an imaging chamber. A 120 mg/mL immunoglobulin G (IgG) solution with 0.3 μg/mL IgGDL755 (labeled IgG) was injected intradermally, with/without 2,000 U/mL rHuPH20. Fluorescent images of labeled IgG dispersion were acquired ≤20 min post injection. Results Dispersion of high-concentration labeled IgG combined with rHuPH20 was greater at all time points vs. antibody alone. At 20 min post injection (last time point), the antibody dispersion area was significantly increased with rHuPH20 vs. without rHuPH20 (p≤0.005). The relative percent increase in antibody dispersion with rHuPH20 ranged from 22.8‒106.6% over the 20-min time course, compared with the corresponding non-rHuPH20 treated groups. The area of labeled IgG dispersion was statistically similar between rHuPH20 groups pretreated with an active compound and their paired NBS pretreated controls. Conclusions The addition of 2,000 U/mL rHuPH20 to a high-concentration antibody solution reproducibly incre-ased local antibody dispersion. Systemic pretreatment with diphenhydramine, cetirizine, dexamethasone, estrogen, ACTH, or salicylic acid did not affect the enzymatic spreading activity of rHuPH20, as measured by intradermal dispersion of labeled IgG in mice.

Humoral immunodeficiency diseases represent a heterogeneous group of disorders that require long-term therapies. Thus, the treatment provided must not only be effective but also safe and well tolerated. In this paper, we report our data on the efficacy, safety, and tolerability of recombinant human hyaluronidase-facilitated subcutaneous infusion of immunoglobulin (Ig) (fSCIG; HyQvia(®)) in immunodeficiency patients. We collected retrospective data from 30 patients with primary and secondary immunodeficiency diseases in therapy with fSCIG from September 2014 to December 2019. We evaluated the efficacy of the therapy, taking into account serum IgG values during follow-up and the number of annual infectious events and serious bacterial infections reported by patients. Safety was assessed on the basis of the number and intensity of adverse events (AEs) and local reactions reported. Our real-life data suggest that long-term repeated self-administration of recombinant human hyaluronidase-facilitated subcutaneous infusion of immunoglobulins results in a reduced rate of infectious events if compared to the pre-treatment rate. Both AEs and local reactions are mild to moderate and were never reasons for treatment discontinuation. Therapy with HyQvia shows prolonged efficacy and good tolerability; these aspects, together with the possibility of self-administration at home, minimize the impact the illness has on patients.

Introduction There is currently no consensus in the literature concerning the impact of aging on the properties of hyaluronan (HA) in the subcutaneous (SC) space. Recombinant human hyaluronidase PH20 (rHuPH20) facilitates SC administration of injected therapeutics by depolymerizing SC HA, facilitating bulk fluid flow, dispersion and absorption. This study assessed the impact of intrinsic aging on HA in the SC space and thus the ability of rHuPH20 to enhance delivery of co-administered therapeutics. Methods Histologic evaluations of HA levels and degradation were performed on human skin samples from six age groups, aged from 20 to 100 years. HA levels were evaluated by HA staining and degradation by staining samples for HA following incubation with rHuPH20. HA was extracted from samples and HA size determined by gel electrophoresis. Dermal reconstitution was assessed in young (aged 1.5 months) and elderly (aged > 16 months) mice. Baseline dye dispersion was measured at 5 and 20 min post-intradermal dye injection. Following treatment with rHuPH20, dye dispersion was measured again at 2, 24, 48, 72 and 96 h. Results Distribution of HA was confined to the interstitial space between adipocytes, with similar pericellular presence and levels of HA found across all age groups. Substantial levels of high-molecular-weight HA were observed in all age groups at baseline. Incubation with a clinically relevant dose of rHuPH20 resulted in degradation of all SC HA and similar degradation profiles independent of age. No difference in dye dispersion time was observed between young and elderly mice across the range of time points assessed, with dye dispersion returning to baseline levels by 24 h after rHuPH20 treatment. Conclusions Subcutaneous delivery of approved therapeutics facilitated by co-administration with rHuPH20 should not be impacted by intrinsic aging, with this study providing no evidence for an effect of aging on HA distribution, structure or a loss of rHuPH20 efficacy.

Introduction HyQvia (Immune Globulin Infusion 10% [Human] with Recombinant Human Hyaluronidase) was developed to combine the advantages of intravenous and subcutaneous immune globulin (SCIG), allowing administration of larger volumes at a single subcutaneous site with less frequent dosing when compared to other SCIG products. Current US prescribing guidelines for HyQvia are limited to adults and do not encompass the flexibility required to achieve success in all patients with primary immunodeficiency (PID). Methods This retrospective study was designed to evaluate the clinical experience of treating patients with PID with HyQvia regimens outside of package insert recommendations as well as in pediatric patients. Data were abstracted from 38 patient records (317 HyQvia infusions), including five patients less than 16 years of age, from seven US immunology clinics. Results Among 37 patients receiving HyQvia regimens differing from prescribing guidelines, the most notable variations included shorter ramp-up periods, use of two rather than one infusion site, and slower than maximal infusion rates to mitigate local adverse events (AEs). The medication volume infused for single site doses ranged from 75 to 200 mL and doses split between two sites ranged from 100 to 750 mL. The most common type of regimen variation was a condensed ramp-up phase (shorter schedule, higher doses), and 96% (24/25) of patients managed in this way completed ramp-up. The most common ramp-up schedule was three infusions (one at 25–45%, another at 50–75%, and the final at 100% of target dose) spread over 2–4 weeks. Conclusions A shorter ramp-up schedule did not appear to increase the number of AEs compared to standard ramp-up schedules. For patients with AEs, slower infusion rates and the use of two sites may improve medication tolerability. Four of five pediatric patients reported no AEs, and only one discontinued, stating a fear of needles. HyQvia may be tailored to adults requiring alternative rates, ramp-up, and/or dosing regimens and may be especially well-suited to children. Electronic supplementary material The online version of this article (10.1007/s12325-020-01264-7) contains supplementary material, which is available to authorized users.

Aim: Data on the real-world use of hyaluronidase-facilitated subcutaneous 10% immunoglobulin (fSCIG; HyQvia (R)) in elderly patients with primary or secondary immunodeficiencies (PID or SID) are unreported. This study determined real-world patterns from one administration of fSCIG. Materials & methods: In this retrospective, multicenter study, medical records of patients aged >= 65 years with PID or SID were reviewed. Results: The majority of patients (mean age: 69.9 years) with PID (n = 10) or SID (n = 6) self-administered fSCIG (200-350 ml) at home every 3-4 weeks using a single infusion site by infusion pump at rates up to 300 ml/h. Conclusion: This study provides initial real-world evidence supporting home-based, self-administration of large volumes of fSCIG in elderly patients with PID or SID.Lay abstract: Elderly patients may have physical difficulties and medical conditions that could challenge or limit the use of immunoglobulin therapy. Recombinant human hyaluronidase-facilitated subcutaneous 10% immunoglobulin (fSCIG) is a treatment that can reduce infections in people who have immunodeficiencies. fSCIG allows for self-administration of a large quantity of IgG, every 3-4 weeks, in the comfort of the patient's home. We report on 16 elderly patients with impaired immune systems who have received at least one treatment of fSCIG. We found that, similar to younger patients, older patients with impaired immune systems could be safely treated with fSCIG at home.Graphical abstract:[GRAPHICS].

Background Scarce drug penetration in solid tumours is one of the possible causes of the limited efficacy of chemotherapy and is related to the altered tumour microenvironment. The abnormal tumour extracellular matrix (ECM) together with abnormal blood and lymphatic vessels, reactive stroma and inflammation all affect the uptake, distribution and efficacy of anticancer drugs. Methods We investigated the effect of PEGylated recombinant human hyaluronidase PH20 (PEGPH20) pre-treatment in degrading hyaluronan (hyaluronic acid; HA), one of the main components of the ECM, to improve the delivery of antitumor drugs and increase their therapeutic efficacy. The antitumor activity of paclitaxel (PTX) in HA synthase 3-overexpressing and wild-type SKOV3 ovarian cancer model and in the BxPC3 pancreas xenograft tumour model, was evaluated by monitoring tumour growth with or without PEGPH20 pre-treatment. Pharmacokinetics and tumour penetration of PTX were assessed by HPLC and mass spectrometry imaging analysis in the same tumour models. Tumour tissue architecture and HA deposition were analysed by histochemistry. Results Pre-treatment with PEGPH20 modified tumour tissue architecture and improved the antitumor activity of paclitaxel in the SKOV3/HAS3 tumour model, favouring its accumulation and more homogeneous intra-tumour distribution, as assessed by quantitative and qualitative analysis. PEGPH20 also reduced HA content influencing, though less markedly, PTX distribution and antitumor activity in the BxPC3 tumour model. Conclusion Remodelling the stroma of HA-rich tumours by depletion of HA with PEGPH20 pre-treatment, is a potentially successful strategy to improve the intra-tumour distribution of anticancer drugs, increasing their therapeutic efficacy, without increasing toxicity.

Interstitial, e.g. subcutaneous (SC) or intradermal (ID), administration of monoclonal antibodies (mAb) is less invasive than intravenous administration and leads to mAb uptake into both lymphatic and blood capillaries draining the injection site. Interstitial administration, however, is hindered by the presence of hyaluronan (HA), a glycosaminoglycan that is a major fluid barrier in the interstitial space. The transient removal of HA with recombinant human hyaluronidase (rHuPH20) helps facilitate the interstitial administration of often high therapeutic doses of mAb in the clinic. rHuPH20's impact on the systemic pharmacokinetics of several mAbs has been previously described, however effects on route of absorption (lymph vs blood) are unknown. The current study has therefore explored the lymphatic transport and bioavailability of cetuximab and trastuzumab after SC and ID coadministration in the presence and absence of rHuPH20 in rats. After SC administration cetuximab absolute bioavailability increased from 67 % to 80 % in the presence of rHuPH20. Cetuximab recovery in the lymphatics also increased after SC (35.8 % to 49.4 %) and ID (26.7 % to 58.8 %) administration in the presence of rHuPH20. When the injection volume (and therefore dose) was increased 10-fold in the presence of rHuPH20 cetuximab plasma exposure increased approximately linearly (12- and 8.9-fold respectively after SC and ID administration), although the proportional contribution of cetuximab lymphatic transport reduced slightly (6.2-fold increase for both administration routes). In contrast, co-administration with rHuPH20 did not lead to increases in plasma exposure for trastuzumab after SC or ID administration, most likely reflecting the fact that the reported absolute bioavailability of trastuzumab (in the absence of rHuPH20) is high (∼77-99 %). However, lymphatic transport of trastuzumab did increase when coadministered ID with rHuPH20 in spite of the lack of change to overall bioavailability. The data suggest that co-administration with rHuPH20 is able to increase the volume of mAb that can be administered interstitially, and in some instances can increase the amount absorbed into both the blood and the lymph. In the current studies the ability of rHuPH20 to enhance interstitial bioavailability was higher for cetuximab where intrinsic interstitial bioavailability was low, when compared to trastuzumab where interstitial bioavailability was high.

The deposition of aggrecan/hyaluronan (HA)-rich matrix within the tendon body and surrounding peritenon impede tendon healing and result in compromised biomechanical properties. Hence, the development of novel strategies to achieve targeted removal of the aggrecan-HA pericellular matrix may be effective in treating tendinopathy. The current study examined the therapeutic potential of a recombinant human hyaluronidase, rHuPH20 (FDA approved for reducing HA accumulation in tumors) for treating murine Achilles tendinopathy. The 12-week-old C57Bl/6 male mice were injected with two doses of rHuTGF-β1 into the retrocalcaneal bursa (RCB) to induce a combined bursitis and tendinopathy. Twenty-four hours following induction of injury, treatment groups were administered rHuPH20 Hyaluronidase (rHuPH20; Halozyme Therapeutics) into the RCB. At either 6 h (acute), 9 days, or 25 days following hyaluronidase treatment, Achilles tendons were analyzed for gene expression, histology and immunohistochemistry, fluorophore-assisted carbohydrate electrophoresis, and biomechanical properties. The rHuPH20 treatment was effective, particularly at the acute and 9-day time points, in (a) removing HA deposits from the Achilles tendon and surrounding tissues, (b) improving biomechanical properties of the healing tendon, and (c) eliciting targeted increases in expression of specific cell fate, extracellular matrix metabolism, and inflammatory genes. The potential of rHuPH20 to effectively clear the pro-inflammatory, HA-rich matrix within the RCB and tendon strongly supports the future refinement of injectable glycosidase preparations as potential treatments to protect or regenerate tendon tissue by reducing inflammation and scarring in the presence of bursitis or other inducers of damage such as mechanical overuse. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:59-69, 2020.

Objective The primary aim was to determine the safety of treatment with human immune globulin 10% with recombinant human hyaluronidase (fSCIg) compared to intravenous immunoglobulin (IVIg) in a prospective open-label study in patients with multifocal motor neuropathy (MMN). Methods Our study consisted of two phases: the IVIg phase (visits 1–3; 12 weeks), in which patients remained on IVIg treatment, and the fSCIg phase (visits 4–7; 36 weeks), in which patients received fSCIg treatment. After visit 3, IVIg was switched to an equivalent dose and frequency of fSCIg. Outcome measures were safety, muscle strength, disability and treatment satisfaction. Results Eighteen patients were enrolled in this study. Switching to fSCIg reduced the number of systemic adverse events (IVIg 11.6 vs. fSCIg 5.0 adverse events/per person-year, p

PURPOSE Pegylated recombinant human hyaluronidase (PEGPH20) degrades hyaluronan (HA) and, in combination with chemotherapy, prolongs survival in preclinical models. The activity of PEGPH20 with modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) was evaluated in patients with metastatic pancreatic cancer (mPC). MATERIALS AND METHODS Patients had untreated mPC, a performance status of 0 to 1, and adequate organ function. Tumor HA status was not required for eligibility. After a phase Ib dose-finding study of mFOLFIRINOX plus PEGPH20, the phase II open-label study randomly assigned patients (1:1) to the combination arm or to mFOLFIRINOX alone (n = 138). The primary end point was overall survival (OS). RESULTS PEGPH20 dosages of 3 µg/kg every 2 weeks were more tolerable than twice-weekly dosages used in the phase I study, so 3 µg/kg every 2 weeks was the phase II dosage. An amendment instituted enoxaparin prophylaxis in the PEGPH20 combination arm as a result of increased thromboembolic (TE) events. The planned interim futility analysis when 35 deaths (of 103 analyzable patients) occurred resulted in an OS hazard ratio (HR) of 2.07 that favored the control arm, and the study was closed to accrual. The treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination arm relative to control (odds ratio, 2.7; 95% CI, 1.1 to 7.1). The median OS in the mFOLFIRINOX arm was 14.4 months (95% CI, 10.1 to 15.7 months) versus 7.7 months (95% CI, 4.6 to 9.3 months) in the PEGPH20 combination arm. CONCLUSION Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly GI and TE events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median OS in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good PS.

ENHANZE® drug delivery technology is based on the proprietary recombinant human hyaluronidase PH20 enzyme (rHuPH20; Halozyme Therapeutics, Inc.) that facilitates the subcutaneous (SC) delivery of co-administered therapeutics. rHuPH20 works by degrading the glycosaminoglycan hyaluronan (HA), which plays a role in resistance to bulk fluid flow in the SC space, limiting large volume SC drug delivery, dispersion, and absorption. Co-administration of rHuPH20 with partner therapies can overcome administration time and volume barriers associated with existing SC therapeutic formulations, and has been shown to reduce the burden on patients and healthcare providers compared with intravenous formulations. rHuPH20 (as HYLENEX® recombinant) is currently FDA-approved for subcutaneous fluid administration for achieving hydration, to increase the dispersion and absorption of other injected drugs, and in subcutaneous urography for improving resorption of radiopaque agents. rHuPH20 is also co-formulated with two anticancer therapies, trastuzumab (i.e. Herceptin® SC) and rituximab (i.e. RITUXAN HYCELA®/RITUXAN® SC/MabThera® SC) and dosed sequentially with human immunoglobin to treat primary immunodeficiency (i.e. HyQvia®/HYQVIA®). This article reviews pharmaceutical properties of rHuPH20, its current applications with approved therapeutics, and the potential for future developments.

The removal of cumulus cells in a process called oocyte denudation is required in order to visualise, grade and manipulate the oocytes before injection. The objective of this study was to appraise critically the published randomised controlled trials (RCTs) comparing recombinant hyaluronidase with bovine hyaluronidase for oocyte denudation before intracytoplasmic sperm injection (ICSI). We performed a comprehensive literature search of the standard medical databases in order to identify the RCTs comparing oocyte denudation with recombinant hyaluronidase or bovine hyaluronidase before ICSI. Three RCTs involving 2445 oocytes collected from 200 women were analysed. There was substantial heterogeneity among the included RCTs. A meta-analysis from the available moderate to high quality trials found no statistical difference in terms of fertilisation rate, embryo quality and live birth rate between the use of recombinant or bovine hyaluronidase for oocyte denudation before ICSI.IMPACT STATEMENTWhat is already known on this subject? The removal of cumulus cells in a process called oocyte denudation is required in order to visualise, grade and manipulate the oocytes before injection. The long-established source of hyaluronidase has been represented by bovine testes, but concern has been raised regarding the possible negative effects over the fragile oocytes by mechanisms involving low enzyme purity, variable concentrations, trauma, prolonged exposure and integration of external DNA in the oocyte. Recombinant human hyaluronidase has been proposed as an alternative in order to counteract the possible negative effects of using animal derived products.What do the results of this study add? A meta-analysis from the available moderate to high quality trials found no statistical difference in fertilisation rate, embryo quality and live birth rate between the use of recombinant or bovine hyaluronidase for oocyte denudation before ICSI.What are the implications of these findings or clinical practice and/or further research? Future trials should be powered adequately in order to be able to identify the possible small differences between the study groups and they should be conducted according to the CONSORT guidelines as the absence of blinding for outcome assessors can induce detection bias.

Background Recombinant human hyaluronidase PH20 (rHuPH20) facilitates the dispersion and absorption of subcutaneously administered therapeutic agents. This study aimed to characterize the transient, local action of rHuPH20 in the subcutaneous (SC) space using focused biodistribution and dye dispersion studies conducted in mice. Materials and methods To evaluate the biodistribution of rHuPH20, mice were intradermally administered rHuPH20 (80 U). The enzymatic activity of rHuPH20 was analyzed in the skin, lymph nodes, and plasma. Animal model sensitivity was determined by intravenous administration of rHuPH20 (80 U) to the tail vein. To evaluate local dispersion, mice received an intradermal injection of rHuPH20 followed by an intradermal injection of Trypan Blue dye at a contralateral site 45 minutes later. Dye dispersion was measured using a digital caliper. Results After intradermal rHuPH20 injection, enzymatic activity was detected within the skin near the injection site with levels decreasing rapidly after 15 minutes. There was no clear evidence of systemic exposure after administration of rHuPH20, and no discernible rHuPH20 activity was observed in lymph or plasma as a function of time after dosing. In the dye dispersion study, delivery of rHuPH20 at one site did not impact dye dispersion at a distal skin site. Conclusion These observations support the classification of rHuPH20 as a transiently active and locally acting permeation enhancer.

Recombinant human hyaluronidase PH20 (rHuPH20) facilitates subcutaneous (SC) delivery of co-administered therapeutic agents by locally and transiently degrading hyaluronan in the SC space, and can be administered with therapeutics using a variety of devices. Two SC delivery studies were carried out to assess auto-injector (AI) performance, each in 18 Yucatan miniature pigs. Abdominal injections were administered using three auto-injectors of 1 mL (AI1) and 2 mL (AI2 and sAI2) with different injection speeds and depths (5.5–7.5 mm) and two pre-filled syringe (PFS) devices of 1 and 2 mL. The injection included a placebo buffer with and without rHuPH20 to evaluate the effect of rHuPH20 on SC injection performance. The feasibility of using similar devices to deliver a placebo buffer in humans was investigated. rHuPH20 was not studied in humans. In miniature pigs, postinjection swelling was evident for most PFS/AI injections, particularly 2 mL. Swelling heights and back leakage were typically lower with rHuPH20 co-administration versus placebo for most device configurations (1 or 2 mL PFS or AI). Auto-injections with versus without rHuPH20 also resulted in reduced swelling firmness and faster swelling resolution over time. Slow injections with rHuPH20 had shorter and more consistent injection time versus placebo. In humans, minimal injection site swelling and negligible back leakage were observed for 2-mL injections of placebo, while more erythema was observed in humans versus miniature pigs. Even at high delivery rates with PFS or AI, the addition of rHuPH20 resulted in improved SC injection performance versus placebo in miniature pigs.

8537 Background: Intravenous DARA (DARA IV) is approved for the treatment of MM. In Part 2 of PAVO, DARA SC, a concentrated, pre-mixed SC co-formulation of DARA and recombinant human hyaluronidase PH20 (rHuPH20), was well tolerated, with a low infusion-related reaction (IRR) rate, and showed consistent serum concentrations and similar efficacy to DARA IV in RRMM pts. In PAVO Part 3, we evaluated the safety of pre- and post-dose corticosteroid tapering during DARA SC administration. Methods: RRMM pts with ≥2 prior lines of treatment, including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), received DARA SC (DARA 1,800 mg + rHuPH20 30,000 U in 15 mL) by manual SC injection per approved IV monotherapy dosing schedule. Pts received a 3-week (wk) tapering schedule (corticosteroid-free by Cycle [C] 1 Day [D] 22), with methylprednisolone (MP) given PO/IV pre-dose (C1D1, 100 mg; C1D8, 60 mg; C1D15, 30 mg) and PO post-dose (C1D1, 20 mg for 2 days; C1D8, 20 mg for 1 day; C1D15, 20 mg for 1 day), or a 2-wk tapering schedule (corticosteroid-free by C1D15), with MP given PO/IV pre-dose (C1D1, 100 mg; C1D8, 60 mg) and PO post-dose (C1D1, 20 mg for 2 days; C1D8, 20 mg for 1 day). Results: Pts (3-wk group, n = 15; 2-wk group, n = 15) received a median of 2 (range: 2-7) prior lines of therapy, with 37% refractory to a PI and an IMiD. The 3-wk and 2-wk groups received a median (range) of 14 (2-19+) and 8 (2-16+) DARA SC doses without corticosteroids, respectively. No IRRs were reported in the 3-wk group. 3 pts (20%) in the 2-wk group experienced IRRs on C1D1 (grade 3 hypertension, grade 2 chills, grade 1 pyrexia, grade 1 oropharyngeal pain, and grade 1 tachycardia). IRRs occurred within 2 h of the first DARA SC administration; no IRRs were reported at later administrations. Most common (≥25%) treatment emergent adverse events (TEAEs) were upper respiratory tract infection (40%) and fatigue and nausea (27% each). Most common (≥5%) grade 3/4 TEAEs were anaemia, lymphopenia, neutropenia, and hypertension (7% each). At median follow-up of 6.8 mo (3-wk group) and 2.4 mo (2-wk group), the overall response rates were 40% (95% CI, 16-68%) and 27% (95% CI, 8-55%) and ≥very good partial response rates were 13% (95% CI, 2-40%) and 7% (95% CI, 0-32%), respectively. Conclusions: Rapid corticosteroid tapering over 2 wks is safe in RRMM pts receiving DARA SC. These data help guide future DARA SC combinations (ie, T-cell redirectors, CAR-T, or checkpoint inhibitors), where limiting concurrent corticosteroids may be preferred. Clinical trial information: NCT02519452 .

Hyaluronan (or hyaluronic acid, HA) is a nonsulfated, negatively charged, single-chain megadalton glycosaminoglycan distributed through the body, especially in soft connective tissue. In many solid tumors, HA accumulates in the extracellular matrix, can impede access of anticancer agents, and is associated with an aggressive tumor phenotype. Recombinant human hyaluronidase PH20 (rHuPH20) enzymatically degrades hyaluronan and has been approved by the US Food and Drug Administration to enhance dispersion and absorption of subcutaneously delivered therapies. A PEGylated version of rHuPH20, pegvorhyaluronidase alfa (PEGPH20), has been developed to enable prolonged systemic exposure to rHuPH20 and to investigate the potential therapeutic effects of hyaluronan degradation. In animal models, intravenous pegvorhyaluronidase alfa enzymatically degrades tumor hyaluronan, reduces tumor interstitial pressure, and improves vascular perfusion, resulting in increased intratumoral access of anticancer agents and increased tumor immune cell density. Consistent with these effects, pegvorhyaluronidase alfa has demonstrated antitumor efficacy when used alone or in combination with other anticancer therapies in nonclinical models. In the Phase II HALO 109-202 trial, pegvorhyaluronidase alfa plus nab-paclitaxel and gemcitabine demonstrated favorable activity in patients with pancreatic cancer. A global, multicenter, Phase III trial (HALO 109-301) of pegvorhyaluronidase alfa in patients with pancreatic cancer is ongoing, with completion expected in 2020.

Only a limited number of therapeutic strategies are available for patients diagnosed with pancreatic adenocarcinoma, and disease recurrence and mortality are consequently high. For metastatic disease, two combinations are approved in the first line setting: a triplet with 5-fluoruracil, irinotecan, and oxaliplatin, and the combination of gemcitabine and nab-paclitaxel. In patients who have progressed on gemcitabine, a new nanoliposomal formulation of irinotecan has recently been approved. While these treatments have demonstrated some efficacy, there has been little increase in survival rates for metastatic pancreatic cancer patients. Consequently, there is an urgent need for research and development of new treatments. As there is now a deeper understanding of pancreatic cancer biology, new drugs targeting altered pathways are under research, including agents that target TGF-β, IGF, or NOTCH. Furthermore, taking into account the role of the tumor stroma in this disease, some stroma-targeting drugs are being developed, including PEGPH20, a pegylated recombinant human hyaluronidase. In the immunotherapy field, although checkpoint inhibitors have failed to demonstrate benefit as monotherapies, combinations with other drugs are being investigated, with promising preliminary results. Other strategies under research are targeting tumor metabolism or DNA repair deficiency.

BACKGROUND An advantage of hyaluronic acid (HA)-based fillers is reversibility. OBJECTIVE To evaluate the ability of 2 hyaluronidases to degrade 3 HA-based fillers using a novel in vivo model. MATERIALS AND METHODS Rats were injected with 3 HA fillers (HYC-24L+, VYC-20L, and RES-L) to create a projecting bolus. After 4 days, recombinant human hyaluronidase (HX) or ovine hyaluronidase (VIT) was administered at (1) varying doses (5 U, 10 U, or 30 U per 0.1 mL filler) or (2) different dilutions (10 U diluted 3-fold). The impact of tissue integration was assessed by administering 10 U/0.1 mL filler 4 weeks after filler injection. Three-dimensional images quantified projection loss over 72 hours. RESULTS Complete loss of projection was achieved for all fillers with the highest HX and VIT doses; lower doses achieved less degradation. No difference in degradation was observed between HYC-24L+ and VYC-20L using HX or VIT. RES-L was slightly more degraded with 10 U VIT but not with 10 U HX. Enzyme dilution resulted in less degradation. Tissue integration did not impact the degree of degradation. CONCLUSION This model incorporates the biological system while controlling variables including filler depth and volume and location of hyaluronidase delivery. Hyaluronic acid filler degradation by exogenous hyaluronidase was not hindered by differences among fillers.

The anti-CD20 monoclonal antibody rituximab (MabThera®/Rituxan®) has been proven to improve outcomes in a range of B-cell malignancies. Initially developed as a formulation for intravenous infusion, administration times for rituximab can be prolonged and associated with infusion-related reactions, prompting a combined clinical development program investigating subcutaneous delivery in combination with recombinant human hyaluronidase. As this program comes to fruition, this article reviews the evidence demonstrating subcutaneous rituximab to have noninferior pharmacokinetics when delivered at a fixed-dose as well as equivalent clinical outcomes in the treatment of follicular lymphoma, chronic lymphocytic leukemia and diffuse large B-cell lymphoma. This mode of delivery is more preferable to patients and healthcare professionals and is associated with time and cost savings.

The absorption and distribution of biological medicinal agents after subcutaneous (sc) and intramuscular injections are influenced by the molecular characteristics of the drug. The large size of the mAbs limits their distribution primarily to the vascular system, their volume of distribution is similar to that of albumin. They are mostly administered by iv injection, however co-administration with recombinant human hyaluronidase derivate (rHuPH20) enables their rapid absorption after subcutaneous administration. Target mediated drug disposition (TMDD) is the main mechanism of the elimination of the biological macromolecules. The plasma half-lives of IgG based mAbs are determined by their binding to the neonatal Fc receptors (FcRn) protecting them from proteolysis in the endosomes. When the endosomes recirculate to the cell surface the mAb will be released back into the circulation. This mechanism is responsible for their unusually long (> 10 days) half-lives. The excretion of the drug proteins proceeds through catabolization to smaller peptides which are then excreted by the kidney (

Introduction Subcutaneous (SC) formulations of therapeutics with recombinant human hyaluronidase PH20 (rHuPH20) are currently approved across various disease indications. The rHuPH20-mediated enzymatic degradation of SC hyaluronan (HA) facilitates bulk fluid flow and dispersion of co-administered therapeutics. However, current methods of quantifying dispersion in the SC space are limited. Here, a novel method is outlined to quantify and follow rapid SC volumetric dispersion of a representative therapeutic fluid in the presence of rHuPH20 using computed tomography (CT). Methods Ten Yucatan miniature swine were randomized to three groups. Animals received simultaneous infusions of contrast agent (CA) alone (left side of the animal) or in combination with rHuPH20 (right side) at infusion rates of 2.5, 5, or 10 mL/min. Spiral CT scans (1.5 mm thickness) were conducted before and after the infusion and at regular time intervals throughout. Scans were used to create three-dimensional (3D) reconstructions of the fluid pockets and analyze surface area, volume, and sphericity. Results 3D reconstruction showed increased dispersion of CA with rHuPH20 compared with CA alone, with fenestration and increased dispersion in the craniocaudal and lateromedial directions. The CA with rHuPH20 fluid pockets showed an average increase of 46% in surface area (p = 0.001), a 35% increase in volume (p = 0.001) and a 17% decrease in sphericity post-infusion compared with CA alone at 30 min post-infusion. Discussion This exploratory study confirms the value of CT imaging as a non-invasive method of assessing real-time spatial and temporal behavior of SC-administered fluids. This technique could help to assess the dispersion pattern of novel rHuPH20 SC co-formulations.

Subcutaneous rituximab injectables are formulated with recombinant human hyaluronidase as an adjunct to facilitate the absorption of the large volume of rituximab. We review the clinical considerations regarding the potential for systemic hyaluronidase toxicity and increased systemic absorption of subcutaneous or topical drugs administered subsequent to rituximab.

8046 Background: APOLLO (NCT03180736) is a phase 3 trial of pomalidomide and dexamethasone (Pd) ± subcutaneous daratumumab (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) in patients with RRMM and ≥1 prior line of therapy including lenalidomide and a proteasome inhibitor. After 16.9 months (mo) median follow-up, D-Pd significantly reduced the rate of progression or death by 37% relative to Pd. Patients with RRMM have reduced HRQoL compared with age- and sex-matched populations. Here, we present PROs from the APOLLO trial. Methods: Patients were randomized 1:1 to D-Pd or Pd and treated in 28-day cycles until disease progression/unacceptable toxicity. PROs were assessed on Day 1 of each cycle using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30), EORTC QLQ Multiple Myeloma Module 20-item (MY20), and EuroQol 5-dimensional descriptive system. PRO analyses were performed on patients from the intent-to-treat population with a baseline (BL) and ≥1 post-BL assessment. Treatment effect was assessed by a mixed effects model with repeated measures. Time to worsening was estimated using the Kaplan-Meier method. Results: A total of 304 patients were included (151 D-Pd, 153 Pd). Median treatment duration was 11.5 mo with D-Pd vs 6.6 mo with Pd. At Cycle 16 (Cyc 16), 63 and 40 patients remained on treatment in the D-Pd and Pd groups, respectively. Compliance rates for PRO instruments were high and comparable between groups. Patients treated with D-Pd had a reduction in pain (maximum improvement: 6.8 points at Cyc 12) measured with the EORTC QLQ-C30 and no mean change in disease symptoms or the treatment side effects subscales of the EORTC QLQ-MY20. Group mean physical and emotional functioning were unchanged from BL with D-Pd but worsened in the Pd group (maximum worsening: 6.4 at Cyc 4 and 9.1 points at Cyc 14). The proportion of patients with a meaningful improvement from BL was 55.0% vs 49.0% for disease symptoms, 43.0% vs 35.3% for physical functioning, and 41.7% vs 31.4% for emotional functioning with D-Pd vs Pd, respectively. Median time to worsening was ̃4 mo, except for the disease symptoms subscale (̃10 mo); there were no differences between groups. Conclusions: When daratumumab was added to Pd, patients did not experience any decrements in HRQoL while on treatment, but some patients experienced reductions in pain as well as clinically meaningful improvements in symptoms and emotional/physical function. These findings complement the clinical benefits of D-Pd in RRMM patients and further support its use in this RRMM population. Clinical trial information: NCT03180736.

Purpose Treatment of primary immunodeficiency diseases (PIDD) with subcutaneous (SC) infusions of IgG preceded by injection of recombinant human hyaluronidase (rHuPH20) (IGHy) to increase SC tissue permeability was evaluated in two consecutive, prospective, non-controlled, multi-center studies. Methods Subjects >4 years of age received SC IgG replacement at a weekly dose equivalent of 108 % of their previous intravenous (IV) dose, facilitated by prior injection of 75 U/g IgG of rHuPH20. Starting with weekly SC infusions, the interval was increased (ramped-up) to a 3- or 4-week schedule. Results Eighty-three subjects (24

One of the major challenges in applying nanomedicines to cancer therapy is their low interstitial diffusion in solid tumors. Although the modification of nanocarrier surfaces with enzymes that degrade extracellular matrix is a promising strategy to improve nanocarrier diffusion in tumors, it remains challenging to apply this strategy in vivo via systemic administration of nanocarriers due to biological barriers, such as reduced blood circulation time of enzyme-modified nanocarriers, loss of enzyme function in vivo, and life-threatening side effects. Here, we report the conjugation of recombinant human hyaluronidase PH20 (rHuPH20), which degrades hyaluronic acid, on the surfaces of poly(lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG) nanoparticles followed by anchoring a relatively low density layer of PEG, which reduces the exposure of rHuPH20 for circumventing rHuPH20-mediated clearance. Despite the extremely short serum half-life of rHuPH20, our unique design maintains the function of rHuPH20 and avoids its effect on shortening nanocarrier blood circulation. We also show that rHuPH20 conjugated on nanoparticles is more efficient than free rHuPH20 in facilitating nanoparticle diffusion. The facile surface modification quadruples the accumulation of conventional PLGA-PEG nanoparticles in 4T1 syngeneic mouse breast tumors and enable their uniform tumor distribution. The rHuPH20-modified nanoparticles encapsulating doxorubicin efficiently inhibit the growth of aggressive 4T1 tumors under a low drug dose. Thus, our platform technology may be valuable to enhance the clinical efficacy of a broad range of drug nanocarriers. This study also provides a general strategy to modify nanoparticles with enzymes that otherwise may reduce nanoparticle circulation or lose function in the blood.

Recombinant human hyaluronidase (rHuPH20) is widely used as a spreading factor, which enhances the absorption of subcutaneously injected medicines. The anti-inflammatory and anti-edema effects of the enzyme were demonstrated in previous studies. In the present study, the anti-edema effect of rHuPH20 was compared with that of dexamethasone in a traumatic rat paw edema model.Twenty-four Sprague-Dawley rats (weight 200 to 450 g) were divided into 3 groups: control (group 1), rHuPH20 (group 2), and dexamethasone (group 3). Traumatic edema was induced in the right hind paws of the rats using Feeney's weight-drop model. After edema induction, 0.4 mL of rHuPH20 (100 U/kg = 0.88 μg/kg dose) and 0.4 mL of dexamethasone (0.5 mg/kg dose) were injected into the right hind paws of the rats in groups 2 and 3. The paw volumes were measured before edema induction and at 3, 6, 12, 24, 48, and 72 hours after induction using a plethysmometer. The Mann-Whitney U test was used for the statistical analyses. Probabilities .05 were accepted as statistically significant.The between percentage change in the edema mean values of groups 1 and 3 showed no significant difference at all time points; however, group 2 showed significantly less change in the edema mean values at 3, 6, 12, 24, and 48 hours after edema induction (P .05) compared with group 1. The change in the edema mean value for group 2 was significantly less than that for group 3 at 3, 6, 12, 24, and 48 hours after edema induction (P .05).Local rHuPH20 injection more effectively reduced the edema that was induced traumatically in rat paws than did dexamethasone. However, further clinical studies are needed regarding the use of rHuPH20 as a postoperative anti-edema agent in place of dexamethasone.

The outlook for patients with advanced pancreatic cancer remains poor, despite significant advances in our understanding of pancreatic tumor biology. One emerging theme highlights the distinct composition of the pancreatic tumor microenvironment. Hyaluronic acid is a hydrophilic glycosaminoglycan whose production within the tumor leads to increased interstitial tumor pressure, thereby limiting the access of potentially effective circulating anticancer drugs via reduced tumor perfusion. PEGylated rHuPH20 is a multiply PEGylated recombinant human hyaluronidase that has shown promising efficacy in preclinical models and early phase clinical trials in pancreatic cancer patients. Here, we discuss these findings, and the rationale for the ongoing randomized Phase III trial (HALO-109–301), which seeks to definitively define the efficacy of PEGylated rHuPH20 alongside gemcitabine and nab-paclitaxel in previously untreated, hyaluronic acid-high, stage IV pancreatic cancer.

Most primary immunodeficiency diseases (PIDDs) resulting in antibody deficiency require intravenous or subcutaneous immunoglobulin G (SCIG) replacement therapy. The flow and distribution of SCIG to the vasculature is impeded by the glycosaminoglycan hyaluronan in the extracellular matrix, which limits the infusion rate and volume per site, necessitating frequent infusions and multiple infusion sites. Hyaluronidase depolymerizes hyaluronan and is a spreading factor for injectable biologics. Recombinant human hyaluronidase (rHuPH20) increases SCIG absorption and dispersion. In patients with PIDD, SCIG facilitated with rHuPH20 (IGHy) has been shown to prevent infections, be well-tolerated and reduce infusion frequency and number of infusion sites as compared with conventional SCIG. This article reviews IGHy clinical studies and real-world practice data in patients with PIDD.

The tumor stroma is increasingly recognized as a key player in tumorigenesis through its effects on cell signaling, immune responses, and access of therapeutic agents. A major component of the extracellular matrix is hyaluronic acid (HA), which raises the interstitial gel fluid pressure within tumors and reduces drug delivery to malignant cells, and has been most extensively studied in pancreatic ductal adenocarcinoma (PDA). Pegylated recombinant human hyaluronidase (PEGPH20) is a novel agent that degrades HA and normalizes IFP to enhance the delivery of cytotoxic agents. It has demonstrated promising preclinical results and early clinical evidence of efficacy in the first-line treatment of metastatic PDA with acceptable tolerability. Moreover, intratumoral HA content appears to be a predictive biomarker of response. Phase 2 and 3 trials of PEGPH20 plus chemotherapy are ongoing in metastatic PDA, and it is also being evaluated in other malignancies and in combination with radiation and immunotherapy.

Subcutaneous administration of immunoglobulin (IGSC) in a home setting, compared with intravenous administration, can improve patient quality of life. During IGSC, however, the subcutaneous extracellular matrix inhibits flow and fluid entry into the vascular compartment, which limits the amount of drug delivered. Recombinant human hyaluronidase (rHuPH20) increases the absorption and dispersion of infused fluids and drugs. Results from a Phase III, prospective, open-label, noncontrolled study of patients with primary immunodeficiencies indicated that IGSC infusion, facilitated by rHuPH20, is well tolerated and delivers infusion volumes at treatment intervals and rates equivalent to intravenous administration. This drug evaluation provides an overview of rHuPH20 and results of clinical studies of IGSC infusion facilitated by rHuPH20 in patients with primary immunodeficiencies.

Treatment with monoclonal antibodies (mabs) has become an established component of oncological therapy. The monoclonal antibodies available for this purpose are mainly administered intravenously in individually adapted doses according to body weight over longer treatment times. For other chronic diseases such as, for example, diabetes mellitus, the subcutaneous administration of drugs is an established therapy option. For the subcutaneous administration of larger volumes as needed for mab solutions the extracellular matrix of the subcutaneous tissue represents a problem. The co-formulation with recombinant human hyaluronidase makes the relatively pain-free administration of larger fluid volumes and thus the subcutaneous administration of monoclonal antibodies possible, as illustrated by the development of a subcutaneous formulation of trastuzumab. This constitutes a less invasive, time-optimised and flexible form of administration for patients with HER2-positive breast cancer that, with its fixed dosing possibilities, contributes to therapeutic safety. The example of trastuzumab shows that the subcutaneous administration of monoclonal antibodies can simplify oncological long-term therapy not only for the patients but also for the medical personnel.Die Behandlung mit monoklonalen Antikörpern (mAK) ist ein fester Bestandteil der onkologischen Therapie geworden. Die dafür zur Verfügung stehenden monoklonalen Antikörper werden überwiegend intravenös, individualisiert gewichtsadaptiert und über längere Behandlungszeiträume verabreicht. Bei anderen chronischen Erkrankungen wie beispielsweise Diabetes mellitus stellt die subkutane Applikation von Medikamenten, eine etablierte Therapieform dar. Für die subkutane Applikation größerer Volumina stellt die Physiologie der extrazellulären Matrix des subkutanen Gewebes ein Hindernis dar, wie sie für die Lösung mAK erforderlich ist. Die Koformulierung mit rekombinanter humaner Hyaluronidase ermöglicht die schmerzarme Gabe größerer Volumina und damit die subkutane Applikation von monoklonalen Antikörpern, wie die Entwicklung einer subkutanen Formulierung für Trastuzumab zeigt. Mit dieser steht Patientinnen mit HER2-positivem Mammakarzinom eine weniger invasive, zeitoptimierte und flexiblere Applikationsform zur Verfügung, die mit einer fixen Dosierungsmöglichkeit zur Therapiesicherheit beiträgt. Das Beispiel Trastuzumab zeigt, dass die subkutane Verabreichung monoklonaler Antikörper die onkologische Langzeittherapie sowohl für Patienten als auch für medizinisches Fachpersonal vereinfachen könnte.

Pancreatic ductal adenocarcinoma (PDA) is characterized by a pronounced fibroinflammatory stromal reaction consisting of inordinate levels of hyaluronan (HA), collagen, immune cells, and activated fibroblasts that work in concert to generate a robust physical barrier to the perfusion and diffusion of small molecule therapeutics. The targeted depletion of hyaluronan with a PEGylated recombinant human hyaluronidase (PEGPH20) lowers interstitial gel&ndash, fluid pressures and re-expands collapsed intratumoral vasculature, improving the delivery of concurrently administered agents. Here we report a non-invasive means of assessing biophysical responses to stromal intervention with quantitative multiparametric magnetic resonance imaging (MRI) at 14 Tesla (T). We found that spin-spin relaxation time T2 values and glycosaminoglycan chemical exchange saturation transfer (GagCEST) values decreased at 24 h, reflecting depletion of intratumoral HA content, and that these parameters recovered at 7 days concurrent with replenishment of intratumoral HA. This was also reflected in an increase in low-b apparent diffusion coefficient (ADC) at 24 h, consistent with improved tumor perfusion that again normalized at 7 days after treatment. Phantom imaging suggests that the GagCEST signal is driven by changes in HA versus other glycosaminoglycans. Thus, multiparametric magnetic resonance imaging (MRI) can be used as a non-invasive tool to assess therapeutic responses to targeted stromal therapy in PDA and likely other stroma-rich solid tumors that have high levels of hyaluronan and collagen.