Navigating large-volume subcutaneous injections of biopharmaceuticals: a systematic review of clinical pipelines and approved products

ABSTRACT

Subcutaneous (SC) administration is transforming the delivery of biopharmaceuticals, facilitating care in a variety of healthcare settings, including home self-treatment. Large-volume single SC doses have gained attention for their potential to expand therapeutic applications and improve long-term, patient-centric dosing regimens, often at a reduced SC injection frequency. However, a systematic understanding of dose volumes and frequencies for large-volume (>2.0 mL) SC biopharmaceuticals (LVSCs) is lacking. Accordingly, this study systematically reviewed clinical-stage and approved intravenous (IV) and SC biopharmaceuticals, identifying 182 LVSCs – predominantly monoclonal or bispecific antibodies – which correspond to approximately 15% of all IV and SC biopharmaceuticals. These LVSCs are designed to target cancer and a range of non-cancer chronic disease states, including autoimmune, neurological, and cardiovascular diseases. Results show that anti-cancer LVSCs (n = 75) typically require 5.0 to 20.0 mL doses every three weeks and are administered by healthcare professionals. In contrast, non-cancer LVSCs (n = 107), which are typically self-administered monthly, show more significant dosing variability, with < 5.0 mL being the predominant volume range. Furthermore, the study identified a substantial clinical pipeline of potential LVSCs, many of which are being injected at increasingly lower dosing frequencies, suggesting significant future growth in this area. Most non-cancer LVSCs are currently undergoing clinical trials via the SC route, whereas the majority of the cancer LVSCs are being administered IV and require transition to the SC route. These findings highlight the importance of developing large-volume drug delivery systems and novel formulations to reduce injection volumes. The analysis provides valuable guidance for new product development, as well as for marketing and commercialization strategies in the rapidly evolving LVSC landscape.

Introduction

Biopharmaceuticals are transforming healthcare by offering new and effective treatment options across a range of therapeutic areas.¹ Monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), antibody-drug conjugates (ADCs), oligonucleotides, and other protein-based drugs offer enhanced specificity and increased therapeutic efficacy, addressing previously unmet medical needs.^2–6 The sustained high approval rate of antibody-based drug approvals in recent years,^7,8 coupled with their unprecedented commercial success,⁹ underscores the growing interest in expanding access to this emerging class of therapeutics.

Biopharmaceuticals are predominantly administered parenterally, either intravenously (IV) or subcutaneously (SC).^10,11 Healthcare professionals use IV infusion typically in acute care settings, as an initial loading dose¹² or when additional IV agents are administered concurrently. This route is also often chosen for initial exposure to drugs with potentially serious side effects and for doses that exceed the capacity for SC administration.^13,14

To optimize the use of healthcare resources and reduce the burden of IV infusions, researchers have developed SC dosing alternatives that shift care from hospitals to outpatient settings, including community centers, referral hospitals, and homes.^15,16 SC drug delivery is increasingly preferred over IV infusion due to its shorter administration time and is recognized as a safe, cost-effective, and non-inferior alternative to the complex and lengthy processes associated with IV drug administration in infusion centers.^17–21 A notable example of a successful transition from IV to SC is daratumumab (Darzalex Faspro®). Initially approved as an IV formulation requiring 3-to-7-hour infusions, daratumumab was later approved in 2020 as an SC formulation, which can be injected in less than 5 minutes. Currently, the SC version accounts for approximately 93% of daratumumab usage in the US.²² Furthermore, a recent study highlighted an unexpected efficacy advantage of SC administration over IV infusion for the anti-cancer immunotherapy agent amivantamab; this enhanced efficacy could be due to SC absorption via the lymphatic system, potentially increasing immune-mediated activity.²³ If similar efficacy advantages can be demonstrated for other cancer drugs, it could significantly drive the adoption of SC administration in immuno-oncology. SC administration of biopharmaceuticals is not only gaining traction in oncology. It is also being used in various chronic disease areas, enabling patient-centered care and, in many cases, facilitating self-care.^24–26

The pharmaceutical industry has recently prioritized the development of large-volume SC dosing options that minimize disruption to patients’ lives using easier-to-use devices and formulation strategies that allow for more convenient injection regimens.^27–32 Several SC biopharmaceuticals are now approved for injection up to 2.0 mL using hand-held autoinjectors, administered in less than 15 seconds.^30,33,34 Research into the upper feasible volume limits of single-dose SC injections has received substantial attention, with drug developers exploring the feasibility of SC administration well beyond 2.0 mL.^13–30–38 This interest has led to the advancement of new delivery device concepts and formulation strategies.^13,39 For instance, prolonged large-volume injections facilitated by permeation enhancers, such as hyaluronidase, are being studied in clinical trials and commercialized across various therapy areas.^40–42 Research is also underway to explore the use of high drug concentration suspensions to allow for the SC delivery of large doses in smaller injection volumes.^13,43 Moreover, several on-body injectors (OBDs) with SC volumes ranging from 2.4 to 20.0 mL have been approved as combination products by the US Food and Drug Administration (FDA),⁴⁴ and numerous devices are being developed and tested in clinical studies.^31,32,45 In certain cases, tethered SC syringe pump drivers have also been used to allow patients to self-administer large single doses.⁴⁶

Despite extensive research and development in large-volume SC dosing,^13,30,38,39 a comprehensive understanding of the expected large-volume doses and injection frequencies for clinical-stage biopharmaceutical drug candidates and approved IV products with potential for SC delivery is lacking. This gap in the literature is critical, as accurate prediction of large-volume doses and injection frequencies is essential for developing appropriate delivery systems and drug formulations and understanding the competitive landscape of large-volume SC biopharmaceuticals. We aimed to fill this gap by systematically evaluating publicly available dosing information for approved products and clinical-stage biopharmaceutical drug candidates with the potential for large-volume SC drug delivery.Our analysis provides insights into the distribution of large-volume SC biopharmaceuticals across dose-volume ranges, stages of clinical testing, modality types, biological targets, therapeutic areas, and dosing intervals. The analysis concludes by discussing the implications for device and formulation development.

Review methodology and data analysis

The authors conducted a four-step review process to identify approved and clinical-stage biopharmaceuticals that require, or may require, large-volume (>2.0 mL) SC maintenance doses (LVSCs) and to determine the expected dosing interval. Figure 1 shows a summary of this stepwise process.

Figure 1.

Four-step review process to identify potential large-volume (>2.0 mL) SC biopharmaceuticals (LVSCs) and to estimate dose-volume ranges and dosing intervals, detailing the number of agents included at each step.

Abbreviations used: ADC, antibody-drug conjugate; SC, subcutaneous injections; IV, intravenous infusions; Q6mo, dosing every 6 months.

Step 1: Identification of clinical-stage and approved SC and IV biopharmaceuticals

The systematic review includes clinical-stage and approved IV and SC proprietary biopharmaceuticals. For this review, biopharmaceuticals are defined as biologic therapeutic (non-vaccine) agents, that exclude small molecules, anti-infectives, and polysaccharide drugs (such as low molecular weight heparins). IV biopharmaceuticals were included in the analysis, and each assessed for their potential to transition to the SC delivery route.

Clinical-stage biopharmaceuticals were identified through a comprehensive assessment of clinical studies published in databases between January 1, 2020 and June 27, 2024. This period was selected to identify agents actively developed in ongoing clinical studies, reflecting the typical maximum duration of Phase 3 clinical trials, as outlined by the FDA.⁴⁷ The initial search was conducted using ClinicalTrials.gov from the US National Library of Medicine (NLM) database,⁴⁸ according to predefined search criteria (Table 1). Subsequently, additional SC and IV agents were identified through supplementary searches in public clinical trials registries, including the EU Clinical Trials Registry,⁴⁹ the Japan Registry of Clinical Trials,⁵⁰ the Australian New Zealand Clinical Trials Registry (ANZCTR),⁵¹ and the AdisInsight database.⁵² Consistent search criteria, as outlined in Table 1, were applied across all databases to ensure coverage and accuracy in identifying relevant clinical-stage agents.

Table 1.

Search criteria for identifying clinical-stage SC and IV agents from ClinicalTrials.gov.

“Advanced Search” Criteria	Detailed Search Terms
Recruitment:	Active, Recruiting AND Not Yet Recruiting AND Completed
Clinical Phase:	Interventional studies at: Phase I AND Phase II AND Phase III AND Phase IV
Funder Type:	Industry Funded
Boolean search keywords of clinicaltrials.gov:	Subcutaneous OR subcutaneously OR SC OR S.C. OR Intravenous OR intravenously OR IV OR I.V.
Date First Posted:	January 1, 2020 to June 27, 2024

Approved currently marketed products were identified through an analysis of product approvals from December 31, 2002 to June 27, 2024. This starting date was selected to mark the approval of the first SC mAb Humira (adalimumab) by the FDA.⁵³ Approved SC and IV antibody agents were identified using The Antibody Society’s Database of Approved mAbs.⁵³ Dosing information on approved mAbs, bsAbs, oligonucleotides, fusion proteins, peptides, immunoglobulins, enzymes and other protein-based biopharmaceuticals was obtained from the FDA database,⁵⁴ published FDA-approved prescribing information, and UK and EU medicine agencies databases.^55,56

All IV and SC agents identified in Step 1 were cross-referenced with published pipeline information from drug company websites and company research and development (R&D) updates to ensure that each agent was actively being pursued. At the end of Step 1, 1,338 SC and IV biopharmaceutical agents were identified and further analyzed.

Step 2: Exclusion of IV biopharmaceuticals with low potential for SC delivery

Step 2 involved a detailed analysis of each IV agent to evaluate its suitability for transitioning to SC delivery. During this step, the authors excluded IV agents deemed unlikely to be delivered via the SC route. The final selection of IV agents with the highest potential for SC switching was determined through repeated discussion among the authors and consultations with drug delivery and formulation development experts from the pharmaceutical industry.

Early-stage IV agents in Phase I clinical trials were excluded from consideration for IV to SC switching. This exclusion was based on the rationale that the final dosing regimens are typically not established during Phase I. The authors also excluded agents with a high risk of severe injection site reactions following SC injection, such as cytotoxic drugs and ADCs containing cytotoxic moieties as payloads. Additionally, agents requiring acute emergency or critical care dosing, close monitoring, or those with severe potential side effects that could preclude SC use were excluded from the analysis. Specialty IV drugs with limited shelf life and requiring special preparation including therapies that involve CAR-T cells, stem cells, CRISPR therapy, viral gene transfer, and radiopharmaceuticals, were also excluded. These agents are likely to be prepared and administered intravenously by healthcare professionals (HCPs) in a hospital setting. Other agents excluded were IV enzyme replacement therapies which generally require variable dosing, reconstitution, and have been associated with low SC bioavailability and an increased potential for immunogenicity.⁵⁷ However, a few recently approved and clinical-stage SC enzyme replacement agents were included and analyzed further.

IV biosimilar agents were included as potential SC switch candidates only if clinical studies exploring the SC route were under investigation. Furthermore, IV agents requiring dosing intervals greater than 6 months or involving three or fewer doses were excluded, as such regimens are usually manageable by IV administration and do not necessitate SC delivery.

At the conclusion of Step 2, a total number of 925 agents were identified as either currently being delivered via the SC route or being delivered IV with the potential to switch to SC delivery. These agents were subjected to further analysis in Step 3.

Step 3 – Exclusion of SC and IV biopharmaceuticals without definitive dosing data

Clinical agents without publicly available dosing data or those undergoing dose-ranging studies without disclosed final dose were excluded. SC agents in dose-ranging trials were included if the lower dose range exceeded 300 mg for mAbs and bsAbs and 380 mg for oligonucleotides, corresponding to an expected SC injection volume greater than 2.0 mL at the assumed concentrations described below. SC agents in Phase 1 were only included if they had publicly available Recommended Phase 2 dosing (RP2D) data or if there was dosing information available for an IV formulation at a more advanced clinical stage. After Step 3, 751 agents remained for further analysis.

Step 4 – Estimation of dose volumes for SC agents and IV-to-SC switch candidates

SC agents

For approved SC agents, the injection volume(s) from prescribing information^54–56 were assigned to each specific drug entry in the database. SC agents with maintenance dose injection volumes lower than 2.0 mL were excluded from further consideration. For pipeline SC agents, the injection volume was calculated by dividing published SC dosing data (mg) by the drug concentration (mg/mL). This data was obtained from clinical protocol summaries in various clinical database,^48–52 as well as peer reviewed journals, conference publications, posters and abstracts, pharmaceutical company investor presentations, and patient community websites.^58,59

In the absence of SC drug concentration data for antibody agents, a value of 150.0 mg/mL was assigned, a threshold where many mAbs may start exhibiting higher solution viscosity properties posing delivery and manufacturing challenges.^60,61 For SC oligonucleotides, a concentration of 189 mg/mL was assigned based upon the concentration of 5 recently launched large-dose (>200.0 mg) oligonucleotide drugs.^54,56 For pipeline SC agents dosed by body weight, we assumed future SC agents would be developed as flat fixed-dose products, as observed in many recent approvals.^62,63 An average body weight of 80 kg was used as a conversion factor for dosing standardization.^62–64 Different doses or dosing intervals for various therapeutic areas or body weights were considered separately. For instance, if an agent had two dosing regimens, 350.0 mg Q3W for one type of cancer and 700.0 mg Q6W for another, both dosing regimens were analyzed as separate products.

Agents requiring initial large IV or SC loading doses followed by chronic maintenance SC doses were excluded if the SC maintenance dosing was lower than 2.0 mL. This exclusion assumed the large loading dose would likely be administered by an HCP as a single IV infusion or multiple SC injections. Agents delivered as co-formulations with another agent had the total administered dose (mg) calculated as the sum of both agents’ dosages.

IV-to-SC switching candidates

For IV-to-SC switching candidates, Equation [1] was used to estimate the SC Injection volume for the IV to SC switch. It was assumed that the SC injection would maintain the same dosing interval and equivalent systemic dose as the approved or clinical-stage IV dosage form.

$$\mathit{SC}\mathit{injection}\mathit{volume}\left(\mathit{IV}\mathit{to}\mathit{SC}\mathit{switching}\right)=\frac{\mathit{IV}\mathit{dose}/\mathit{SC}\mathit{bioavailibility}}{\mathit{SC}\mathit{drug}\mathit{concentration}}$$ (1)

The IV dose (mg) and SC bioavailability data were sourced from various publicly available sources. When SC bioavailability was not available, an average value of 69% was used to convert the IV dose to an equivalent SC dose, as reported by recent reviews on SC bioavailability of approved antibody-based biotherapeutics.^8,9

At the end of Step 4, the final sample of 182 LVSCs was categorized into the following volume ranges: a) >2.0–5.0 mL, b) >5.0 – 10.0 mL, c) >10.0 – 20.0 mL, d) >20.0 – 30.0 mL and e) >30.0 mL. These specific volume ranges were selected because each range likely requires a different type of SC injection device and primary drug container to accommodate the necessary dosage volume.

The list of potential LVSCs was validated with additional clinical data from sources such as conference abstracts, peer-reviewed articles, and company press releases. Additionally, we consulted with selected industry experts, including senior executives in pharmaceutical R&D, to validate assumptions and ensure we included all relevant agents.

Estimation of LVSC dosing intervals

In a separate analysis of Step 4, the final group of LVSCs was evaluated for their respective dosing intervals. This data represents the frequency of SC dosing administered during the long-term maintenance period of therapy. When multiple dosing intervals were associated with a LVSC, each interval was recorded. Dosing interval data for approved agents was obtained from prescribing information, while for clinical stage agents, it was sourced from publicly available clinical study protocols. Commonly used abbreviations for dosing are used here: Qw for weekly dosing, Q2w for biweekly dosing, Q3W for dosing every 3 weeks, Q4w for monthly dosing, Q6w for dosing every 6 weeks, Q8w for dosing every 8 weeks and Q6mo for dosing every 6 months. For IV-to-SC switch candidates, we assumed that the SC dosing intervals would match those of the approved IV product or the IV form in a later stage of clinical development. Where available, the frequency of dosing intervals and trends toward different dosing schedules were also assessed.

Results

Initial dataset composition by route of administration

1,338 approved and clinical-stage SC and IV biopharmaceuticals were analyzed in the search for LVSC agents. The distribution between IV-only and SC-only agents was approximately equal, with a slightly higher number of IV agents identified. Approximately 8% (n = 113) of all agents were either approved or undergoing clinical testing using both SC and IV routes (Figure 2).

Figure 2.

Route of administration and total number of approved and clinical-stage agents (n=1,338) that comprise the initial sample at the outset of the search for large-volume subcutaneous biopharmaceuticals (LVSCs).

Abbreviations used: SC, subcutaneous injections; IV, intravenous infusions.

Distribution of LVSC dose-volume ranges by therapeutic categories

A total of 182 LVSCs were identified, corresponding to approximately 15% of all the IV and SC biopharmaceutical agents. Figure 3 shows the distribution of these LVSCs by dose volume range and therapeutic category (anti-cancer vs. non-cancer). The categories of anti-cancer and non-cancer were chosen based on the many commonalities between agents and treatments within each category. LVSCs were found across all the volume tiers, with the largest number of LVSCs (n = 81) between 2.0 mL and 5.0 mL, predominantly comprising non-cancer agents (n = 59). Thirty-seven and 43 LVSCs were allocated to the dose volume ranges of 5.0 mL to 10.0 mL and 10.0 mL to 20.0 mL, respectively. The 5.0 mL to 20.0 mL volume tiers were mainly populated by anti-cancer agents, which accounted for 60% of all LVSCs within this range. Relatively few LVSCs were in the >20.0 mL range (n = 21), with most of these non-cancer LVSCs (n = 16).

Figure 3.

Distribution of LVSCs (N = 182) by dose volume range and therapeutic category (anti-cancer vs. non-cancer).

Abbreviations used: SC, subcutaneous injections.

A total of 75 anti-cancer agents were identified as potential LVSCs. As illustrated in Figure 3, the majority of these anti-cancer agents were distributed roughly equally between the volume tiers of >2.0 mL to 5.0 mL (n = 22), >5.0 mL to 10.0 mL (n = 23) and >10.0 mL to 20.0 mL (n = 25). A smaller number of LVSCs were found at >20.0 mL (n = 5).

The 107 non-cancer LVSCs were distributed across all volume tiers. Most of these non-cancer LVSCs fell in the volume range of 2.0 mL to 5.0 mL (n = 59). Non-cancer LVSC were also found in the >5.0 mL volume tiers (n = 48), including 16 LVSCs with dose volumes greater than 20.0 mL. This volume tier included four approved SC immunoglobulins (SCIGs) and 12 additional clinical-stage agents for various indications.

Distribution of LVSC dose-volume ranges by clinical development stage

When analyzing the dose-volume ranges of all LVSCs by clinical development stage, a significant clinical pipeline of LVSCs becomes apparent (Figure 4). A substantial proportion of all identified LVSCs (n = 151; 83%) either are in SC clinical studies (n = 83; 46%) or have the potential to switch from IV to SC dosing (n = 68; 37%).

Figure 4.

Dose volume ranges for all IV-to-SC switching candidates, SC clinical-stage assets, and approved LVSCs (N = 182) for non-cancer and anti-cancer indications across various stages of clinical testing. The number of LVSCs in each volume range is indicated on the bar chart.

Abbreviations used: SC, subcutaneous injections; IV, intravenous infusions; PR, pre-registration phase.

The clinical pipelines reveal a trend toward lower dose volumes, with a more significant proportion of LVSCs actively being tested between 2.0 mL and 5.0 mL (n = 51; 63% of all clinical-stage agents) compared to those that have been approved (n = 15; 48% of all approved drugs). However, for agents with the potential to switch from IV to SC, these predominantly need to be delivered at dose volumes greater than 5.0 mL (n = 52; 76% of all IV-to-SC switch candidates).

Figure 4 compares the dose-volume ranges for approved and clinical stage LVSCs for both non-cancer and anti-cancer agents. Of the 107 identified non-cancer LVSCs, 25 are already approved as LVSCs, with just over half of these approved agents falling in the >2.0 mL − 5.0 mL volume range (n = 13; 56%). In the clinical phases, a greater proportion of non-cancer agents were found at the lowest >2.0 mL to 5.0 mL volume tier (n = 45; 69%). A smaller number of non-cancer potential IV-to-SC switching agents were identified (n = 17), with the majority requiring larger (>10.0 mL) SC volumes (n = 14).

For anti-cancer LVSC agents, the majority of both approved and clinical stage agents fall in the >5.0 mL to 20.0 mL volume range (n = 48; 64%) with the potential IV-to-SC switch candidates representing a significant area of interest (n = 51; 68% of all anti-cancer LVSCs), whereas only 17 agents (16%) of non-cancer drugs required IV-to-SC switching.

Figure 5 shows trends in approval numbers and dose volumes of the 31 approved LVSCs. Over the past eight years, there has been a significant increase in approvals and a trend toward larger SC injection volumes. Table 2 provides additional details for each of the approved LVSCs in Figure 5. Eight LVCSs are co-formulated with recombinant hyaluronidase (PH20) for manual injection over several minutes. Four are approved for use in large-volume OBDs. Many assets transitioned from variable body mass dosed IV formulations (e.g., mg/kg) to fixed-dosed SC formulations. Some are approved in multiple volume formulations to accommodate different body weights. SCIGs, often exceeding 30.0 mL, are typically self-administered with SC syringe pumps.⁴⁶ Eleven of the 15 approved LVSC agents with injection volumes >2.0 to 5.0 mL are administered by multiple, up to 2 mL, injections.

Figure 5.

First approval dates and injection volumes for LVSCs (N = 31).^53–56.

Each product is shown at approved maintenance dose volume(s). Circles indicate the first approval date, color-coded by biopharmaceutical modality type or if co-formulated with hyaluronidase. Circles marked with an asterisk (*) denote approval for use with an on-body injection device (OBD). Abbreviations used: SCIG, subcutaneous immunoglobulin G, Q4W, dosed every 4 weeks

Table 2.

Overview and key features of approved LVSCs. All LVSC products are approved in US except where indicated (* for China only; ** for Europe only). Data obtained as of June 27, 2024.

Brand Name	INN Name	First Year of approval	Molecule Class	Injected Drug Concentration	Co-formulated ?	SC Injection Maintenance Dose Volume	Injection Time	Injection Method and primary container	Approved for Self-Injection	Main Therapeutic Area
Xolair®	Omalizumab	2003	mAb	150 mg/mL	No	up to 4 mL	Rapid multiple boli, each up to 2 mL	Syringe/Vial, prefilled syringe and autoinjector	Yes	Autoimmune
Firmagon®	Degarelix	2008	Peptide	20 mg/mL	No	4 mL	30 secs	Syringe/Vial, reconstituted and delivered by slow bolus injection	No	Oncology
Hizentra®	Immune globulin SC human	2010	IgG	200 mg/mL	No	Variable. Typically >30 mL	Highly variable	Vial and prefilled syringe for delivery using a SC syringe pump	Yes	Immunodeficiency
Herceptin Hylecta®	Trastuzumab/hyaluronidase	2013	mAb	120 mg/mL	Yes co-formulated with hyaluronidase	5 mL	2-5 mins	Syringe/Vial delivered by slow bolus injection	No	Oncology
Hyqvia®	Immune globulin SC human with hyaluronidase	2013	IgG	100 mg/mL	No but hyaluronidase is injected prior to administration	Variable. Typically >30 mL	1-2 ml/min up to 3 hours	Vials of drug and hyaluronidase for sequential delivery using a manual push syringe or syringe pump	Yes	Immunodeficiency
Cuvitru®	Immune globulin SC human	2016	IgG	200 mg/mL	No	Variable. Typically >30 mL	≤60 ml/hr/site	Vial for delivery using a syringe pump	Yes	Immunodeficiency
Repatha®	Evolocumab	2016	mAb	120 mg/mL	No	3.5 mL (monthly dosing)	~5 mins	OBD with a separate prefilled cartridge	Yes	Cardiovascular
Haegarda®	C1 esterase inhibitor SC	2017	Plasma derived Protein	500 iU/mL	No	Depends on body weight. 9.6 mL for 80 kg patient	Variable depending on volume	Syringe/Vial, reconstituted and delivered by slow SC infusion	Yes	Rare Disease
Nucala®	Mepolizumab	2017	mAb	100 mg/mL	No	3 mL (HES and EGPA indications)	Rapid multiple boli, each 1 mL	Syringe/Vial, prefilled syringe or autoinjector	Yes	Autoimmune
Ajovy®	Fremanezumab	2018	mAb	150 mg/mL	No	4.5 mL (Q12w dosing)	Rapid multiple boli, each 1.5 mL	Prefilled syringe or autoinjector	Yes	Central Nervous System
Crysvita®	Burosumab	2018	mAb	30 mg/mL	No	up to 6 mL	Rapid multiple boli, each up to 1.5 mL	Syringe/Vial	No	Supportive Oncology
Hemlibra®	Emicizumab	2018	mAb	150 mg/mL	No	Depends on body weight and dosing interval. 3.2 mL for 80 kg patient (Q4w dosing)	Rapid multiple boli, each up to 2 mL	Syringe/Vial	Yes	Rare Disease
Emgality®	Galcanezumab	2018	mAb	100 mg/mL	No	3 mL (Cluster headache indication)	Rapid multiple boli, each 1 mL	Prefilled syringe	Yes	Central Nervous System
Evenity®	Romosozumab	2019	mAb	90 mg/mL	No	2.3 mL	Rapid multiple boli, each 1.17 mL	Prefilled syringe	No	Bone
Xembify®	Immune globulin SC human	2019	IgG	200 mg/mL	No	Variable. Typically >30 mL	≤2.5 ml/hr/site	Vial for delivery using a syringe pump	Yes	Immunodeficiency
Darzalex Faspro®	Daratumumab/hyaluronidase	2020	mAb	120 mg/mL	Yes co-formulated with hyaluronidase	15 mL	3-5 mins	Syringe/Vial delivered by slow bolus injection	No	Oncology
Phesgo®	Pertuzumab/Trastuzumab/hyaluronidase	2020	mAbs	120 mg/mL	Yes both mAbs are co-formulated with hyaluronidase	10 mL	5 mins	Syringe/Vial delivered by slow bolus injection	No	Oncology
Empaveli®	Pegcetacoplan	2021	Peptide pegylated	54 mg/mL	No	20 mL	20 mins	Syringe/Vial for delivery using a syringe pump or OBD	Yes	Autoimmune
Skyrizi®	Risankizumab	2022	mAb	150 mg/mL	No	2.4 mL (Crohn’s and Ulcerative colitis indications)	~5 mins	OBD with a separate prefilled cartridge	Yes	Autoimmune
Ultomiris®	Ravulizumab	2022	mAb	70 mg/mL	No	7 mL	10 mins	OBD with a separate prefilled cartridge	Yes	Autoimmune
Rituxan Hycela®	Rituximab/hyaluronidase	2023	mAb	120 mg/mL	Yes co-formulated with hyaluronidase	13.3 mL and 11.7 mL depending on indication	5 to 7 mins depending on indication	Syringe/Vial delivered by slow bolus injection	No	Oncology
Rystiggo®	Rozanolixizumab	2023	mAb	140 mg/mL	No	3 to 6 mL depending on body weight	9 to 18 mins	Syringe/Vial delivered in a SC syringe pump	Yes	Autoimmune
* Sintbilo®	Tafolecimab	2023	mAb	150 mg/mL	No	up to 4 mL (Q6w dosing)	Rapid multiple boli, each 1 mL	Autoinjector	Yes	Cardiovascular
** Tecentriq® SC	Atezolizumab/hyaluronidase	2023	mAb Checkpoint inhibitor	125 mg/mL	Yes co-formulated with hyaluronidase	15 mL	~7 mins	Syringe/Vial delivered by slow bolus injection	No	Oncology
Veopoz®	Pozelimab	2023	mAb	200 mg/mL	No	up to 4 mL	Rapid multiple boli, each 2 mL	Syringe/Vial	No	Autoimmune
Vyvgart Hytrulo®	Efgartigimod/hyaluronidase	2023	Immunoglobublin G1 Fc fragment	180 mg/mL	Yes co-formulated with hyaluronidase	5.6 mL	1.5 mins	Syringe/Vial delivered by slow bolus injection	No	Autoimmune
** Loargys®	Pegzilarginase	2024	Enzyme	5 mg/mL	No	up to 3.2 mL	Rapid multiple boli, each up to 2 mL	Syringe/Vial	Yes	Rare
** Ocrevus® SC	Ocrelizumab/hyaluronidase	2024	mAb	40 mg/mL	Yes co-formulated with hyaluronidase	23 mL	~10 mins	Syringe/Vial delivered by slow bolus injection	No	Central Nervous System
Piasky®	Crovalimab	2024	mAb	170 mg/mL	No	4 to 6 mL (Q4w dosing) depending on body weight	Rapid multiple boli, each 2 mL	Syringe/Vial	No	Autoimmune

Abbreviations used: EGPA, Eosinophilic granulomatosis with polyangiitis; HES, Hypereosinophilic syndrome; IgG, Immunoglobulin G; mAb, Monoclonal antibody; OBD, on-body injection device; Q4w dosing every 4 weeks; Q6w dosing every 6 weeks; Q12w dosing every 12 weeks; SC, subcutaneous.

LVSC modality types, biological targets, and therapeutic areas

LVSC modality types

The majority of the LVSCs are antibody-based agents (88%), including mAbs and bsAbs (see Figure 6). For the anti-cancer agents, 95% are antibodies, with several already approved, including rituximab (Rituxan Hycela®/MabThera®), trastuzumab (Herceptin Hylecta®), pertuzumab/trastuzumab (Phesgo®), daratumumab (Darzalex Faspro®), and atezolizumab (Tecentriq® SC). These approved mAbs are injected SC in volumes of 5.0 to 15.0 mL over several minutes, using PH20 to facilitate large volume delivery.⁶¹ Future anti-cancer LVSCs are expected to include mAbs, bsAbs, and fusion proteins transitioning from IV to SC formulations. Most recently approved and pipeline SC bsAbs known as T-cell redirecting bsAbs, e.g., epcoritamab (Epkinly®), teclistamab (Tecvayli®), elranatamab (Elrexfio®) and talquetamab (Talvey®) are administered at low doses in injection volumes below 2 mL.

Figure 6.

Number of LVSCs by molecule class (N = 182).

In the anti-cancer area, several fixed dose combination products, comprising two different co-formulated mAbs (e.g., checkpoint and non-checkpoint inhibitors), were identified as LVSCs (n = 8; 11%). These combinations require larger SC injection volumes due to the increased total dose. Notable examples include the approved product Phesgo® (pertuzumab/trastuzumab)⁶⁵ and the clinical stage SC agents nivolumab/relatimab.⁶⁶ Additionally, several co-formulated mAbs currently in IV form may switch to SC delivery in future (n = 6).

For non-cancer LVSCs, 84% are mAbs with the remainder consisting of bsAbs (n = 4), fusion proteins (n = 5), immunoglobulins (n = 4), enzymes (n = 4) and pegylated proteins/peptide/oligonucleotides (n = 4). Notably, many recently approved or clinical stage SC GLP-1 peptides and oligonucleotide (e.g., RNA based) therapeutics generally require dose volumes at or below 2.0 mL.

Biological targets of LVSCs

Several recurring receptor targets were identified for both anti-cancer and non-cancer LVSCs (Figure 7). For anti-cancer LVSCs, the most frequent targets are the IV checkpoint inhibitor mAbs and bsAbs targeting programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), lymphocyte-activation gene-3 (LAG3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) (n = 34). Additionally, a non-checkpoint inhibitor mAb, targeting CD38 is also prominent among LVSCs (n = 5).

Figure 7.

Most common biological targets of anti-cancer and non-cancer LVSCs.

Abbreviations used: PD1(-), Programmed Cell Death Protein 1; PD-L1(-), Programmed Cell Death Ligand 1; CTLA-4 (-), Cytotoxic T-Lymphocyte Associated Protein 4; TIGIT (-), T cell immunoreceptor with Ig and ITIM domains; LAG3 (-), Lymphocyte activation gene 3, FcRn (-), Neonatal fragment crystallizable receptor; TSLP (-), Thymic stromal lymphopoietin and SCIG subcutaneous immunoglobulin G.

For non-cancer LVSCs, key recurrent biological targets include inhibitors of the complement system (n = 13) and FcRn (n = 8) for various autoimmune diseases and amyloid/Tau protein for Alzheimer’s disease (n = 8). Other important targets in early clinical stages include CD40 inhibitors for diseases such as lupus, Sjogren’s and rheumatoid arthritis (RA) (n = 4). Additionally, four LVSCs for SCIG replacement therapy and four TSLP inhibitors, under clinical investigation for asthma, atopic dermatitis and nasal polyps, were identified. These latter agents typically have SC injection doses of less than 5.0 mL.

Therapeutic areas of LVSCs

LVSCs cover a wide range of therapeutic areas with cancer (n = 75), autoimmune (n = 49), neurological disease (CNS) (n = 15), and cardiovascular (CV) diseases (n = 10) being the most prominent (Figure 8).

Figure 8.

Therapeutic areas for approved and clinical-stage anti-cancer and non-cancer LVSCs (N = 182).

Abbreviations used: CNS, Central Nervous System/Neurological disease; CV, Cardiovascular Disease.

Recent approvals for LVSCs in cancer treatment are mentioned above. For autoimmune diseases, a number of LVSCs have also been approved, including efgartigimod (Vyvgart Hytrulo®)⁶⁷ and rozanolixizumab (Rystiggo®)⁶⁸ for generalized myasthenia gravis (gMG), pegcetacoplan (Empaveli® and Aspaveli®),⁶⁹ crovalimab (PiaSky®),⁷⁰ and ravulizumab (Ultomiris®)⁵⁴ for paroxysmal nocturnal hemoglobinuria (PNH), pozelimab (Veopoz®) for CHAPLE disease,⁷¹ risankizumab (Skyrizi®) for Crohn’s disease,⁷² and ocrelizumab (Ocrevus® SC) for multiple sclerosis (MS).⁷³ Several SCIGs have also been approved for many years, often at injection volumes greater than 30 mL, for treating conditions such as primary or secondary immunodeficiency and chronic inflammatory demyelinating polyneuropathy (CIDP).^74,75 In clinical pipelines, numerous LVSCs are being developed for similar indications to those currently approved such as gMG, PNH, thyroid eye disease, CIDP, MS, dyslipidemia, hidradenitis suppurativa (HS), Crohn’s and ulcerative colitis. Additionally, new LVSC indications are being pursued, notably in Alzheimer’s disease, asthma/atopic dermatitis, lupus, Sjogren’s disease, IgA nephropathy, and various chronic cardiovascular indications. If successful, several novel LVSCs are expected to enter the market in new therapeutic areas over the next decade.

Dosing intervals of LVSCs

Monthly (Q4w) dosing emerged as the most frequently observed interval for the LVSCs (n = 60, see Figure 9). Distinct patterns were noted between anti-cancer and non-cancer LVSCs. Non-cancer LVSCs predominantly used Q4w dosing (n = 45), but also showed occurrences at the extremes: Q6w or less frequently (n = 15) and Qw or more frequently (n = 29). For anti-cancer LVSCs, dosing every third week was predominant (n = 44). Recently, the dosing frequency of several IV anti-cancer checkpoint inhibitors has been extended from Q3w to Q6w⁷⁶ or from Q2w to Q4w.⁷⁷ Extending dosing intervals requires larger dosages compared to more frequent dosing, leading to increased SC injection volumes.

Figure 9.

Distribution of LVSCs (N = 182 LVSCs, with 216 different dosing intervals) by dosing intervals and therapeutic category (anti-cancer vs. non-cancer).

Abbreviations used Qw, weekly dosing; Q2w, dosing every 2 weeks; Q3w, dosing every 3 weeks; Q4w, dosing every 4 weeks and Q6w, dosing every 6 weeks.

Figure 10 illustrates the dosing interval of LVSCs across various stages of development. Among approved LVSCs, Q4w (n = 14) and Qw or more frequent dosing (n = 13) were the most common intervals. In clinical phases, Q4w dosing remained predominant (n = 34, 33% of all dosing intervals in clinical studies), while Qw or more frequent interval declined (n = 18, 17% of all dosing intervals in clinical studies). Clinical candidates (Phases I/II to pre-registration) showed a higher proportion of Q3w dosing or less frequent dose intervals. For IV-to-SC switching LVSC candidates, Q3w dosing is expected to become the most common dosing interval, driven by the large number of Q3w IV anti-cancer LVSCs.

Figure 10.

Dosing frequency for all IV-to-SC switching candidates, SC clinical-stage assets, and approved LVSCs (N = 182) across various stages of clinical testing. The frequency of each specific dosing interval is denoted within the bar chart. Note: a single LVSC asset can have multiple dosing intervals.

Abbreviations used: SC, subcutaneous injections; IV, intravenous infusions; PR, pre-registration phase Qw, weekly dosing; Q2w, dosing every 2 weeks; Q3w, dosing every 3 weeks; Q4w, dosing every 4 weeks and Q6w, dosing every 6 weeks.

Discussion

The recent surge in the development and approvals (Figure 5) of LVSC biopharmaceuticals prompted this systematic analysis of publicly available dosing information for clinical-stage and approved products. The landscape survey has revealed that, of the total of 1,338 IV and SC biopharmaceuticals analyzed,182 LVSCs were identified that treat a variety of diseases, many utilizing diverse device and formulation strategies to facilitate delivery. The insights derived from this analysis will guide development of future delivery systems for both new and existing biopharmaceuticals.

LVSCs span across all SC injection volume tiers (Figure 3), with the majority in the >2.0 – 20.0 mL range. The most prevalent volume tier is the >2.0 - 5.0 mL range. For each volume tier, the appropriate delivery device varies based on whether the administration is by HCPs in a healthcare setting, or by a caregiver, or self-administered by patients. At the lower volume end, within the >2.0 – 5.0 mL range, many LVSCs could potentially be administered by HCPs, caregivers or suitable patients, via two SC injections of 2.0 mL each, considering that the injection of 2.0 mL is generally accepted as feasible and commercially viable.^33,61 Notably, 68 of 81 LVSCs in this range are 4.0 mL or less. However, the sequential administration of multiple injections to achieve the target dose may not represent the optimal long-term commercialization strategy, especially in needle-phobic patients. For instance, with the objective of optimizing patient convenience when administering less than 2.0 mL, considerable efforts are being made to transform the sequential administration of two low-volume injections into a single large-volume injection.^78,79 As large-volume injection systems evolve, it is anticipated that a similar trend will emerge for volumes above 2.0 mL. Therefore, a wearable OBD may be appropriate to deliver volumes in this range, particularly to facilitate self-injection for patients who are unwilling or unable to self-administer multiple injections. Some HCPs, caregivers and patients, however, may still prefer rapid SC injections using handheld devices.³⁶ Research is ongoing to investigate the feasibility of self-administering single-dose volumes in the  2.0 – 10.0 mL range using large-volume handheld autoinjectors.^30,39 For dose volumes between 4.0 and 30.0 mL, delivery options also include manual injections over several minutes using biopharmaceuticals co-formulated with PH20. PH20 is currently used in several marketed drug products to reversibly modify the solid extracellular matrix, thereby increasing volumes of SC injections.^29,61,80 Manual SC injection of these large-volume agents is performed by HCPs over injection times ranging from 1.5 to 10 minutes (Table 2). However, development is currently underway to investigate whether the administration of these large-volume PH20-containing formulations can be shortened and automated in handheld autoinjectors⁸¹ to enable patients to self-inject. Alternatively, OBDs or syringe pumps can facilitate the SC delivery of larger volumes, either for home-based self-injection or by HCPs in settings with limited IV access.^13,17,32,46 At volumes exceeding 30 mL, manual injections may become difficult to administer and large-volume or multiple wearable OBDs may be challenging for prolonged use. In such cases, tethered SC infusion pumps may become a more practical option for HCP and patients, as established for marketed SCIGs.⁴⁶ A subset of LVSCs requires variable SC dosing based on body weight (mg/kg), resulting in the need for more complex delivery options able to deliver a range of different volumes. In these cases, flexible delivery systems such as manual injection from a vial and syringe, variable dosing syringe pumps, or multiple injectors may present viable options.

In addition to the various device and formulation options currently available for facilitating the SC delivery of large volumes (i.e., >2 mL), other potential strategies are being developed with the objective of delivering high doses of biopharmaceutical drugs. One strategy is to formulate the drug at high concentrations (>200 mg/ml) and then administer a lower volume of the solution via the SC route. The resulting high concentrations, however, can increase protein-protein interaction or self-association, leading to the formation of viscous formulations that are difficult to inject due to the high injection forces, as well as leakage and pain at the site of injection.²⁷ Various device approaches have been used to facilitate the delivery of high-viscosity formulations. These include the use of shorter injection needles with large inner diameters, which serve to reduce the injection force,⁸² and the deployment of high-force autoinjectors.¹³ The use of excipients comprising a combination of amino acids, salts, and other small molecular weight compounds has also been used to reduce the viscosity of high concentration mAb formulations.^9,28,83,84 These excipients are added to reduce protein-protein interactions or self-association to increase the overall solubility and colloidal stability. For example, arginine, a well-known basic amino acid, has been used as an excipient in multiple high-concentration marketed antibody products.⁸⁵ Another promising approach, still in the early development stage, is the use of micro- or nano-amorphous particle suspensions of proteins in non-aqueous solvents to facilitate the injection of high-concentration protein formulations into SC space. It has been reported that the use of such particulate suspensions of proteins can result in low-viscosity and high-concentration (400–700 mg/mL), which is suitable for SC administration.^44,86 If this latter approach is successful and clinically validated, it could fundamentally alter the landscape of LVSCs across volume tiers, potentially shifting many to the lower range, including below 2.0 mL. For these lower volumes, there are numerous proven delivery device platforms available for SC self-administration.^33,87,88

83 LVSCs are currently being studied in SC clinical trials. If these pipeline agents receive approval, we anticipate a substantial increase in commercialized LVSCs over the next decade. For non-cancer LVSCs (Figure 4), clinical studies indicate an increasing focus on lower dosing volume ranges (>2.0 – 5.0 mL). Many of these drugs target chronic diseases such as asthma, irritable bowel disorder, atopic dermatitis, and migraine where at-home self-injection has long been established as the standard of care.^26,89–91 Consequently, these agents will likely also be intended for self-administration, highlighting the need for convenient, patient-centered devices for home-use within this volume tier, such as handheld autoinjectors. Clinical stage non-cancer LVSCs are prevalent across all volume tiers >5.0 mL, necessitating unique delivery technologies to facilitate self-injection of these larger volumes, such as OBDs and tethered SC infusion pumps. For chronic diseases with significant unmet needs, such as Alzheimer’s, convenient SC delivery systems for outpatient or home settings with minimal or no IV capacity would be highly desirable to enhance access to innovative therapies.

The majority of LVSC anti-cancer agents fall within the >5.0 to 20.0 mL volume range, a trend that is expected to persist for clinical-stage SC candidates and potential IV-to-SC switches, with the latter being of particular significance. At present, most approved anti-cancer LVSCs are administered in hospital settings by HCPs.^92,93 These SC injections are typically administered over a period of 2 to 7 minutes,⁹⁴ often with co-formulated PH20,⁹⁵ using a syringe and vial; Table 2 includes details on the recommended SC injection times and administration context for the oncology drugs Phesgo®, Darzalex Faspro®, Tecentriq®, Rituxan Hycela® and Herceptin Hylecta®. The approval of the first SC checkpoint inhibitor, atezolizumab (Tecentriq®), in Europe, along with a robust immuno-oncology pipeline, indicates a likely rise in anti-cancer LVSCs. Co-formulated LVSCs, comprising 2 different biopharmaceuticals, will likely require SC injection volumes of >10.0 – 20.0 mL.

It is anticipated that anti-cancer LVSCs could be administered in more convenient healthcare settings, such as community outpatient clinics or potentially in home environments.^14,16 This shift will necessitate more user-friendly delivery technologies, especially in the >5.0 to 20.0 mL volume range. Several barriers to home self-injection of anti-cancer LVSCs exist, most notably for patients receiving combination therapy with IV chemotherapy or radiotherapy, which requires visits to infusion centers and hospitals. In such cases, the value of at-home SC administration may be diminished. However, it may be feasible for certain patients to administer the drug at home, either through self-injection or with the assistance of an HCP or caregiver. Suitable patients may be in the early stages of disease, such as those undergoing adjuvant therapy with SC monotherapy (i.e., not on IV chemotherapy), or in combination with oral anti-cancer therapies. Several clinical studies are currently underway to investigate potential home use of a variety of anti-cancer agents.^15–96–98 In these cases, convenient delivery technologies, such as OBDs, syringe pumps, and large volume handheld autoinjectors, are likely to play a crucial role in facilitating at-home administration.

In recent years there has been a trend toward less frequent, more patient-friendly dosing intervals of SC biopharmaceuticals, as this dosing attribute is regarded as one of the most important predictors of therapy preference and adherence.^36,99,100 The identified LVSCs are administered across various dosing intervals, with Q4w being the most common. For non-cancer LVSCs, Q4w is the most frequently encountered, but many are also dosed at Qw, Q2w, and some at Q8w or beyond. For anti-cancer LVSCs, Q3w is the predominant dosing interval, often selected to align with radiation therapy and IV chemotherapy schedules.^101,102 Recently, several Q2w and Q3w IV immuno-oncology agents have been approved at extended dosing intervals, such as Q4w and Q6w,^76,77 leading to increased clinical testing of new larger volume SC formulation at these extended intervals. The clinical pipelines of anti-cancer and non-cancer LVSCs show a trend toward even less frequent dosing (Q3w and above) (Figure 10). These trends will necessitate the injection of even larger doses and the development of larger volume delivery systems. In addition, delivery systems for less frequent usage must be designed to help users easily remember to re-administer their medication.

There has been a notable increase in recently approved LVSCs (Figure 5), driven by advancements in formulation technologies and innovative large-volume SC delivery devices.^13,30 Several factors contribute to this trend. Anti-cancer mAbs and non-T cell redirecting bsAbs often require large systemic doses (>300 mg), often due to the need to switch from IV to SC injections, resulting in larger doses to offset reduced SC bioavailability.^9,27,103 Additionally, there is usually a need to provide high doses to inhibit widely disseminated and often poorly accessible target sites on tumors or immune cells.¹⁰⁴ Co-formulation of anti-cancer mAbs, such as checkpoint inhibitors, can also lead to high total doses, necessitating larger SC injection volumes.⁶⁵ For non-cancer biopharmaceuticals, different diseases can require different doses/injection volumes. Figure 11 highlights the differences in annual dose requirements for various approved biopharmaceuticals across autoimmune indications. Initially approved for indications such as RA, psoriatic arthritis (PsA), and psoriasis, newer indications such as Crohn’s disease, UC, and HS can require larger doses, often exceeding 2.0 mL. For example, risankizumab (SKYRIZI®) was initially approved in a prefilled syringe and autoinjector for plaque psoriasis and PsA at a maintenance dose of 150.0 mg.¹⁰⁵ It was subsequently approved for Crohn’s disease at larger maintenance doses of 180.0 mg or 360.0 mg every 8 weeks.⁷² A wearable OBD now delivers either 180.0 mg/1.2 mL or 360.0 mg/2.4 mL of SKYRIZI in up to five minutes.¹⁰⁶ In Crohn’s and UC, larger doses may be necessary to compensate for increased drug clearance due to the disease.¹⁰⁷ In neurological diseases such as Alzheimer’s, larger doses may be required due to low bioavailability at the target site, for example, due to very limited penetration of antibodies across the blood-brain barrier.¹⁰⁸ The need for larger doses can also be attributed to the characteristics of several recurring drug targets (Figure 7). Two examples include complement inhibitors and FcRn inhibitors, prevalent in the non-cancer LVSC category. Large SC doses are required due to the substantial endogenous production of these proteins and their high circulating levels and rapid turnover, which requires significant dosing to achieve sustained inhibition.^109,110

Figure 11.

Total highest annual SC dose per patient for selected FDA approved SC mAbs across various autoimmune indications. For purposes of this analysis, IV loading doses are converted to SC doses by dividing by theSC bioavailability. Data from US and EU prescribing information.⁵⁴

Abbreviations used: UC, Ulcerative Colitis; Crohn’s, Crohn’s Disease; RA, rheumatoid arthritis; PsA, Psoriatic Arthritis, PsO, Psoriasis and HS, Hidradenitis suppurativa.

Directions for future research

The results of our study suggest several areas for future research. First, there is a need for continued investigation into the feasibility of delivering SC injection volumes from > 2.0 to 10.0 mL using large-volume bolus handheld injectors. Today, handheld injectors such as prefilled syringes, pens, and autoinjectors are widely accepted for self-injection by patients for volumes up to 2.0 mL in less than 15 seconds. Increasing the injection volume and holding time to explore the upper limits of injection feasibility will require testing to establish if there are significant problems with patient self-injection, such as leakage, pain and incomplete delivery, and how these can be overcome.

Future research and development should also continue to explore novel formulation approaches, e.g., ultra-high concentration combined with viscosity-reducing technologies such as novel excipients or micro/nano-amorphous protein particle suspensions. These could be developed to reduce injection volume with the goal of integrating them into user-friendly delivery devices.

The results of our research indicate that the largest therapy area (~40% of the total) for LVSCs was in oncology, with demonstrated advantages of SC over IV in both convenience and, in certain cases, improved safety and efficacy. Moreover, our research highlights the need to explore the most appropriate device strategies to facilitate the shift of cancer care from hospitals to more convenient community outpatient healthcare facilities and possibly the home setting. In addition, investigating the feasibility, including addressing the compatibility issues, of co-formulating mAbs for combination cancer therapies for SC delivery, is also an open question for future work.

Future studies should also examine the potential for SC delivery of drugs not considered to be suitable in this analysis, such as cytotoxic agents, ADCs, and cell and gene therapies. Some of these future IV drugs may require frequently injected doses over extended periods of time, and as such may benefit from more convenient SC delivery. In addition, exploring the feasibility of shifting challenging routes of administration, such as intrathecal delivery, to SC, is also an area of interest for future research. Finally, this survey also calls for a deeper understanding of patient preferences for dose volume, dose interval, administration site, and therapy area to guide device design.

In conclusion, this comprehensive analysis examines the landscape of clinical-stage and approved LVSC biopharmaceuticals. Starting from 1,338 SC and IV biopharmaceutical agents, our research identified 182 LVSCs predominantly composed of mAbs and bsAbs. These agents span a spectrum of therapeutic areas, including cancer (n = 75) and various non-cancer chronic diseases (n = 107), and are typically dosed at 3- to 4-week intervals, with single doses exceeding 300 mg.

The research highlights key differences between cancer-and non-cancer therapy categories. While anti-cancer LVSCs typically require doses ranging from >5.0 to 20.0 mL, non-cancer LVSCs show a distribution across all dose volume tiers, with the >2.0 to 5 mL range prevailing. Differences also exist for injection frequency and administration context. Anti-cancer LVSCs are more likely to be administered every three weeks by HCPs, whereas non-cancer LVSCs are primarily dosed monthly, with a trend toward at-home self-administration.

These insights have important implications for innovation in delivery device and formulation to facilitate the administration of LVSCs. The diverse LVSCs on the market and in clinical pipelines highlights the need for convenient large-volume SC delivery systems, both within healthcare settings and in the home environment. Developing and selecting the optimal drug delivery solution is critical, as it not only facilitates the switch of IV to SC administration, but also may determine the overall adoption of the final biopharmaceutical product.

Study limitations

Several limitations of the study should be acknowledged. Dosing parameters for many IV and SC biopharmaceutical agents, undergoing clinical testing, remain undisclosed or uncertain. Although pharmaceutical companies are required to register non-Phase 1 clinical studies in the US, specific dosing data is not always disclosed in publicly available protocols.¹¹¹ Therefore, a number of clinical-stage biopharmaceuticals were not included in our analysis. In most cases dosing information was available, but assumptions were made regarding drug concentration and bioavailability to estimate SC dosing volumes. It is possible that such assumptions may be incorrect and lead to inaccuracies in SC volume requirements.

As agents expand into new therapy areas, dosing requirements and intervals may change, affecting total SC volumes required. Additionally, while combination anti-cancer agents were assumed to be co-formulated for SC delivery, developers may decide to seek approval of the individual agents and to commercialize sequential injections instead, resulting in lower SC injection volumes.

About one third of the agents identified are currently approved, or in clinical trials, as IV agents only (IV-to-SC switching candidates). These agents may not undergo this transition, while other IV drugs not initially considered for switching, such as IV biosimilars, may adopt large-volume SC formulations in the future. Additionally, several pharmaceutical companies may decide to change the dosing regimens prior to drug approval, and this could impact SC injection volume requirements. For example, SC formulations may be commercialized that are dosed more frequently than the original IV formulation. This could allow for the use of established 2.0 mL delivery device platforms and avoid the need to deliver at SC volumes >2.0 mL.

Finally, there is an inherent risk of clinical or regulatory failure for clinical-stage LVSCs, with some agents potentially not reaching the market.

Abbreviations

ADC

Antibody-Drug Conjugate

ANZCTR

Australian New Zealand clinical trials registry

AS

Ankylosing Spondylitis

bsAbs

Bispecific antibodies

CAR-T

Chimeric Antigen Receptor T-cell

CD

Cluster of differentiation

CHAPLE

Complement hyperactivation angiopathic Protein losing enteropathy.

CIPD

Chronic inflammatory demyelinating polyneuropathy

CV

Cardiovascular disease

CNS

Central Nervous System/neurological disease

CRISPR

Clustered regularly interspaced short palindromic repeats

CTLA-4

Cytotoxic T-lymphocyte associated protein 4

EGPA

Eosinophilic granulomatosis with polyangiitis

FcRn

Neonatal fragment crystallizable receptor

FDA

US Food and Drug Administration

gMG

generalized Myasthenia Gravis

HCPs

Healthcare professionals

HES

Hypereosinophilic syndrome

HPV

Human Papilloma virus

HS

Hidradenitis suppurativa

IBD

Irritable bowel disorder

IgA

Immunoglobulin A

IGF-1 R

Insulin-like growth factor

IgG

Immunoglobulin G

IV

Intravenous

LAG3

Lymphocyte Activation Gene 3

LVSC

Large-volume (>2.0 mL) subcutaneous biopharmaceutical agents

mAb(s)

Monoclonal Antibody(s)

MS

Multiple Sclerosis

NLM

National Library of Medicine

OBD

On-body wearable subcutaneous infusion delivery device

PCSK-9

Proprotein convertase subtilisin/kexin type 9 serine protease

PD-1

Programmed cell death protein 1

PD-L1

Programmed cell death ligand 1

PH20

Recombinant human PH20 hyaluronidase

PI

Primary Immunodeficiency disease

PNH

Paroxysmal Nocturnal Hemoglobinuria

PR

Pre-registration phase

PsA

Psoriatic arthritis

PsO

Psoriasis

Qw

Weekly dosing

Q2w

Dosing once every 2 weeks

Q3w

Dosing once every 3 weeks

Q4w

Dosing once every 4 weeks

Q6w

Dosing once every 6 weeks

Q6mo

Dosing once every 6 months

Q8w

Dosing once every 8 weeks

RA

Rheumatoid Arthritis

RP2D

Recommended Phase II dose

SC

Subcutaneous delivery

SCIG

Subcutaneous Immunoglobulin G

SID

Secondary Immunodeficiency disease

TED

Thyroid Eye Disease

TIGIT

T cell immunoreceptor with Ig and ITIM domains

TIM-3

T cell immunoglobulin and mucin domain containing protein 3

TL1a

Tumor necrosis factor 1a

TSLP

Thymic stromal lymphopoietin

UC

Ulcerative Colitis

Funding Statement

The work was supported by Ypsomed AG and Pfizer Inc.

Disclosure statement

No potential conflict of interest was reported by the author(s).