Can Endangered Biosimilar Markets be Rescued? The Need to Bridge Competing Interests for Long-Term Gain.

Market signals such as: (1) the limited number of biosimilars in the development pipeline, (2) the focus of biosimilar development on high-profit therapeutic areas only, and (3) the increase in the number of biosimilar discontinuations and withdrawals, are indicative of sustainability threats facing biosimilar markets in Europe. Two prominent factors that undermine sustainability are: competing interests between the various stakeholders and a preferential focus on short-term gains, disregarding future sustainability threats, hence the need for effective policies that create sustainable competition in biologic markets. Thus far, measures implemented to foster biosimilar adoption have not been necessarily complied with and have had mixed success. Further, these policies have not consistently led to improving access to affordable biologics. In this commentary, we aim to raise awareness of vulnerabilities of biosimilar markets and of difficulties relating to reaching an agreement on policy solutions with a long-term vision. We propose to build on knowledge from collective action theory to advance in reconciling stakeholder interests. This first-of-its-kind approach can inform long-term solutions for biosimilar markets.

Leveraging the holistic benefits of biosimilars in Europe - part 2: how payers can safeguard the future of a healthy biosimilar market environment.

INTRODUCTION: Biosimilars have improved access to biologic medicines; however, historical thinking may jeopardize the viability of future markets. AREAS COVERED: An expert panel of eight diverse European stakeholders provided insights about rethinking biosimilars and cost-savings, reducing patient access inequalities, increasing inter-market equity, and improving education. The insights reported here (Part 2) follow a study that provides perspectives on leveraging the holistic benefits of biosimilars for market sustainability based on independent survey results and telephone interviews of stakeholders from diverse biosimilar markets (Part 1). Directional recommendations are provided for payers. EXPERT OPINION: The panel's market maturity framework for biosimilars has three stages: 'Invest,' 'Expand' and 'Harvest.' Across market stages, re-thinking the benefits of biosimilars beyond cost-savings, considering earlier or expanded access/new indications, product innovations, and re-investment of biosimilar-generated cost-savings should be communicated to stakeholders to promote further engagement. During 'Expand' and 'Harvest' stages, development of efficient, forward-looking procurement systems and mechanisms that drive uptake and stabilize competition between manufacturers are key. Future biosimilars will target various therapy areas beyond those targeted by existing biosimilars. To ensure a healthy, accessible future market, stakeholders must align their objectives, communicate, collaborate, and coordinate via education, incentivization, and procurement, to maximize the totality of benefits.

Lentiviral gene therapy with IGF2-tagged GAA normalizes the skeletal muscle proteome in murine Pompe disease.

Pompe disease is a lysosomal storage disorder caused by deficiency of acid alpha-glucosidase (GAA), resulting in glycogen accumulation with profound pathology in skeletal muscle. We recently developed an optimized form of lentiviral gene therapy for Pompe disease in which a codon-optimized version of the GAA transgene (LV-GAAco) was fused to an insulin-like growth factor 2 (IGF2) peptide (LV-IGF2.GAAco), to promote cellular uptake via the cation-independent mannose-6-phosphate/IGF2 receptor. Lentiviral gene therapy with LV-IGF2.GAAco showed superior efficacy in heart, skeletal muscle, and brain of Gaa -/- mice compared to gene therapy with untagged LV-GAAco. Here, we used quantitative mass spectrometry using TMT labeling to analyze the muscle proteome and the response to gene therapy in Gaa -/- mice. We found that muscle of Gaa -/- mice displayed altered levels of proteins including those with functions in the CLEAR signaling pathway, autophagy, cytoplasmic glycogen metabolism, calcium homeostasis, redox signaling, mitochondrial function, fatty acid transport, muscle contraction, cytoskeletal organization, phagosome maturation, and inflammation. Gene therapy with LV-GAAco resulted in partial correction of the muscle proteome, while gene therapy with LV-IGF2.GAAco resulted in a near-complete restoration to wild type levels without inducing extra proteomic changes, supporting clinical development of lentiviral gene therapy for Pompe disease. SIGNIFICANCE: Lysosomal glycogen accumulation is the primary cause of Pompe disease, and leads to a cascade of pathological events in cardiac and skeletal muscle and in the central nervous system. In this study, we identified the proteomic changes that are caused by Pompe disease in skeletal muscle of a mouse model. We showed that lentiviral gene therapy with LV-IGF2.GAAco nearly completely corrects disease-associated proteomic changes. This study supports the future clinical development of lentiviral gene therapy with LV-IGF2.GAAco as a new treatment option for Pompe disease.

Capturing the holistic value of biosimilars in Europe - part 1: a historical perspective.

INTRODUCTION: Approved biosimilars exhibit comparable efficacy, safety, and immunogenicity to reference products. This report provides perspectives on the societal value of biosimilars within Europe and potential factors that have influenced market dynamics. METHODS: An independent, self-administered survey or one-on-one in-depth interview was used to collect viewpoints about the impact of biosimilar medicines within European markets. Key insights were also sought from an expert panel of European stakeholders. RESULTS: Survey respondents were clinicians, pharmacists, and payers from Europe (N = 103). Perceived benefits of biosimilars included increased access to innovative medicines (73% of respondents) or biologic treatments (66%). Biosimilar competition was thought to expand access to biologics (~50% of respondents) or drug combinations (~36%) and reduce biologic access time (34%). Key drivers of biologic access after biosimilar competition included increased biologic awareness (51%) and changes to prescribing guidelines (37%) and/or treatment paradigms (28%). The expert panel developed a market maturity framework of biosimilar adoption/opportunities comprising three stages: 'Invest,' 'Expand,' and 'Harvest.' Findings were supported by published literature. CONCLUSIONS: In Europe, the perceptions of well-informed survey/interview respondents are that biosimilars have improved patient outcomes via increased access to biologics and innovative biologic products, contributing to earlier and longer treatment of a broader population.

The impact of policy interventions to promote the uptake of biosimilar medicines in Belgium: a nationwide interrupted time series analysis.

BACKGROUND: The Belgian government has taken several measures to increase the uptake of biosimilars in past years. However, no formal evaluation of the impact of these measures has been made yet. This study aimed to investigate the impact of the implemented measures on biosimilar uptake. METHODS: An interrupted time series analysis was performed using an autoregressive integrated moving average (ARIMA) model with the Box-Jenkins method. All data were expressed as defined daily doses (DDD) per month/quarter and obtained from the Belgian National Institute for Health and Disability Insurance (NIHDI). Three molecules were included in the analysis: etanercept (ambulatory), filgrastim (hospital), and epoetin (hospital). A significance level of 5% was used for all analyses. RESULTS: In the ambulatory care, the effect of a financial prescriber incentive of 2019 was investigated. After this intervention, 44.504 (95% CI -61.61 to -14.812; P < 0.001) fewer etanercept biosimilar DDDs were dispensed monthly than expected in the absence of the intervention. Two interventions were modelled for biosimilars in the hospital setting. The first intervention of 2016 includes prescription targets for biosimilars and monitoring of hospitals on adequate tendering. The second intervention involves an information campaign on biosimilars. After the first intervention, a small decrease in quarterly epoetin biosimilar uptake of 449.820 DDD (95% CI -880.113 to -19.527; P = 0.05) was observed. The second intervention led to a larger increase in quarterly epoetin biosimilar uptake of 2733.692 DDD (95% CI 1648.648-3818.736; P < 0.001). For filgrastim, 1809.833 DDD (95% CI 1354.797-2264.869; P < 0.001) more biosimilars were dispensed immediately after the first intervention and 151.639 DDD (95% CI -203.128 to -100.150; P < 0.001) fewer biosimilars each quarter after the first intervention. An immediate and sustained increase of 700.932 DDD (95% CI 180.536-1221.328; P = 0.016) in quarterly biosimilar volume was observed after the second intervention. All other parameter estimates were not statistically significant. CONCLUSIONS: The results of this study suggest that the impact of past policy interventions to increase the uptake of biosimilars has been variable and limited. A holistic policy framework is required to develop a competitive and sustainable off-patent biologicals market in Belgium.

Biosimilar competition in European markets of TNF-alpha inhibitors: a comparative analysis of pricing, market share and utilization trends.

Background: Factors like the number of biosimilar competitors and competitive pricing strategies from originator companies may influence price competition and biosimilar uptake. Objective: The aim of this study was to analyze multiple facets of biosimilar competition of TNF-alpha inhibitors in Europe by exploring the existence of a biosimilar first-mover advantage, pricing strategies of originator companies, and the evolution in patient access. Methods: Sales and volume data on biosimilar and originator infliximab, etanercept, and adalimumab between 2008 and 2020 were provided by IQVIA. Countries included 24 European Union Member States, Norway, Switzerland, United Kingdom, Serbia, and Bosnia and Herzegovina. Sales value was expressed as ex-manufacturer price per defined daily dose (DDD), and volume data were transformed into the number of DDDs per 1,000 inhabitants per day. Descriptive analyses were conducted based on the evolution in price per DDD, trends in biosimilar and originator market shares and utilization trends. Results: Market entry of the first biosimilars of infliximab and adalimumab resulted in a decrease of the volume-weighted average price (VWAP) per DDD by 13.6% and 0.9% on average, whilst the second biosimilars resulted in a decrease by 26.4% and 27.3%, respectively. The first and second etanercept biosimilars generated a similar decrease in the VWAP per DDD by 9.3% and 9.1% on average, respectively. Average market share captured by the first biosimilars was at least twice as large as the second biosimilars for all molecules. In addition, sharp reductions in price per DDD of Humira® in most countries indicated a pricing strategy resulting in low uptake of adalimumab biosimilars. Lastly, utilization of infliximab, etanercept, and adalimumab following biosimilar entry increased by an average of 88.9%, 14.6%, and 22.4%, respectively. However, introduction of (multiple) biosimilar competitors did not necessarily translate into increase in treatment access for all three molecules across some European countries indicating a shift in utilization from one molecule towards the other(s). Conclusion: Overall, this study revealed that biosimilar entry results in increased utilization and price reduction, although at a heterogenous rate among TNF-alpha inhibitors. Observed trends in market shares indicate a biosimilar first-mover advantage whereas pricing strategies considered to be anti-competitive can limit market uptake.

Entangling microwaves with light.

Quantum entanglement is a key resource in currently developed quantum technologies. Sharing this fragile property between superconducting microwave circuits and optical or atomic systems would enable new functionalities, but this has been hindered by an energy scale mismatch of >104 and the resulting mutually imposed loss and noise. In this work, we created and verified entanglement between microwave and optical fields in a millikelvin environment. Using an optically pulsed superconducting electro-optical device, we show entanglement between propagating microwave and optical fields in the continuous variable domain. This achievement not only paves the way for entanglement between superconducting circuits and telecom wavelength light, but also has wide-ranging implications for hybrid quantum networks in the context of modularization, scaling, sensing, and cross-platform verification.

Points to consider for cost-effective use of biological and targeted synthetic DMARDs in inflammatory rheumatic diseases: results from an umbrella review and international Delphi study.

OBJECTIVES: To develop evidence-based points to consider for cost-effective use of biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in the treatment of inflammatory rheumatic diseases, specifically rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis. METHODS: Following EULAR procedures, an international task force was formed, consisting of 13 experts in rheumatology, epidemiology and pharmacology from seven European countries. Twelve strategies for cost-effective use of b/tsDMARDs were identified through individual and group discussion. For each strategy, PubMed and Embase were systematically searched for relevant English-language systematic reviews and, for six strategies, additionally for randomised controlled trials (RCTs). Thirty systematic reviews and 21 RCTs were included. Based on the evidence, a set of overarching principles and points to consider was formulated by the task force using a Delphi procedure. Level of evidence (1a-5) and grade (A-D) were determined for each point to consider. Individual voting on the level of agreement (LoA; between 0 (completely disagree) and 10 (completely agree)) was performed anonymously. RESULTS: The task force agreed on five overarching principles. For 10 of 12 strategies, the evidence was sufficient to formulate one or more points to consider, leading to 20 in total, regarding response prediction, drug formulary use, biosimilars, loading doses, low-dose initial therapy, concomitant conventional synthetic DMARD use, route of administration, medication adherence, disease activity-guided dose optimisation and non-medical drug switching. Ten points to consider (50%) were supported by level 1 or 2 evidence. The mean LoA (SD) varied between 7.9 (1.2) and 9.8 (0.4). CONCLUSION: These points to consider can be used in rheumatology practices and complement inflammatory rheumatic disease treatment guidelines to incorporate cost-effectiveness in b/tsDMARD treatment.

GLORIA - A globally representative hyperspectral in situ dataset for optical sensing of water quality.

The development of algorithms for remote sensing of water quality (RSWQ) requires a large amount of in situ data to account for the bio-geo-optical diversity of inland and coastal waters. The GLObal Reflectance community dataset for Imaging and optical sensing of Aquatic environments (GLORIA) includes 7,572 curated hyperspectral remote sensing reflectance measurements at 1 nm intervals within the 350 to 900 nm wavelength range. In addition, at least one co-located water quality measurement of chlorophyll a, total suspended solids, absorption by dissolved substances, and Secchi depth, is provided. The data were contributed by researchers affiliated with 59 institutions worldwide and come from 450 different water bodies, making GLORIA the de-facto state of knowledge of in situ coastal and inland aquatic optical diversity. Each measurement is documented with comprehensive methodological details, allowing users to evaluate fitness-for-purpose, and providing a reference for practitioners planning similar measurements. We provide open and free access to this dataset with the goal of enabling scientific and technological advancement towards operational regional and global RSWQ monitoring.

Niacin supplementation impairs exercise performance.

Several pre-workout supplements contain niacin, although the exercise performance effects of niacin are poorly understood. The purpose of the present study was to examine the performance effects of niacin versus caffeine as a pre-workout supplement. Twenty-five untrained males were recruited to complete three identical ramped aerobic cycling exercise trials. Participants were administered caffeine (CA) at 5 mg/kg body weight, 1000 mg niacin (NI), or a methylcelluloce placebo (PL) supplement prior to each trial. NI treatment induced significantly higher respiratory exchange ratio (RER) during exercise compared to the CA treatment, but not the PL treatment (PL=0.87±0.08, NI=0.91±0.08, CA=0.87±0.08; p=0.02). Similarly, exercise time to exhaustion (in minutes) was significantly different between the NI treatment and the CA treatment, but not the PL treatment (PL=27.45±4.47, NI=26.30±4.91, CA=28.76±4.86; p<0.01). Habitual caffeine use (p=0.16), habitual aerobic exercise (p=0.60), and habitual resistance exercise (p=0.10) did not significantly affect RER. Similarly, habitual caffeine use (p=0.72), habitual aerobic exercise (p=0.08), and habitual resistance exercise (p=0.39) did not significantly affect total work performed. The elevated RER and decreased time to exhaustion in the NI treatment suggests limited lipid availability during exercise and impaired exercise performance.

IGF2-tagging of GAA promotes full correction of murine Pompe disease at a clinically relevant dosage of lentiviral gene therapy.

Pompe disease is caused by deficiency of acid α-glucosidase (GAA), resulting in glycogen accumulation in various tissues, including cardiac and skeletal muscles and the central nervous system (CNS). Enzyme replacement therapy (ERT) improves cardiac, motor, and respiratory functions but is limited by poor cellular uptake and its inability to cross the blood-brain barrier. Previously, we showed that hematopoietic stem cell (HSPC)-mediated lentiviral gene therapy (LVGT) with codon-optimized GAA (LV-GAAco) caused glycogen reduction in heart, skeletal muscles, and partially in the brain at high vector copy number (VCN). Here, we fused insulin-like growth factor 2 (IGF2) to a codon-optimized version of GAA (LV-IGF2.GAAco) to improve cellular uptake by the cation-independent mannose 6-phosphate/IGF2 (CI-M6P/IGF2) receptor. In contrast to LV-GAAco, LV-IGF2.GAAco was able to completely normalize glycogen levels, pathology, and impaired autophagy at a clinically relevant VCN of 3 in heart and skeletal muscles. LV-IGF2.GAAco was particularly effective in treating the CNS, as normalization of glycogen levels and neuroinflammation was achieved at a VCN between 0.5 and 3, doses at which LV-GAAco was largely ineffective. These results identify IGF2.GAA as a candidate transgene for future clinical development of HSPC-LVGT for Pompe disease.

Determinants of prescribing decisions for off-patent biological medicines in Belgium: a qualitative study.

BACKGROUND: A competitive market for off-patent biologicals leads to more affordable and high-quality healthcare. In recent years, Belgium has been characterized by its low use of biosimilars and by its shifts from off-patent biologicals toward new alternative therapies. Yet, the prescribing decisions involved in these observations are poorly understood. This study aims to better understand prescribing choices among Belgian physicians in the ambulatory care setting. METHODS: This study consisted of two phases. First, a scoping literature review to identify determinants of prescribing choices was conducted. Scientific databases (Embase and PubMed) were searched until 4 November 2021. Second, the nominal group technique (NGT) was employed during focus group discussions with Belgian physicians to consider and validate these determinants for off-patent biologicals in the Belgian context. The qualitative data resulting from the literature review and focus group discussions were analyzed using the thematic framework method. RESULTS: Fifty-three scientific articles that discussed elements that determine prescribing choices were identified. Out of these, 17 determinants of prescribing choices were found. These were divided into five categories: (1) product-related, (2) physicians' personal, (3) healthcare system-related, (4) patient-related, and (5) determinants related to the pharmaceutical company or brand. Nineteen Belgian physicians from different therapeutic areas that regularly prescribe biologicals then participated in focus group discussions. Using the NGT, the group discussions revealed that prescribing choices for off-patent biologicals are determined by a complex set of elements. Clinical data, geographical region, working environment, pharmaceutical marketing, patient profile, clinical guidelines, and preference of key opinion leaders (KOL) were considered most influential. Physicians indicated that the importance of these determinants differs depending on product classes or therapeutic domain. CONCLUSIONS: Multiple elements determine the choice of an off-patent biological or biosimilar product. The importance of each of these determinants varies depending on the context in which the prescribing choice is made. To increase the prescription of best-value biologicals in the Belgian ambulatory care, a set of synergistic measures is required including information for healthcare providers (HCP) and patients, prescribing feedback, prescribing targets, tangible incentives, KOL involvement, guidelines regarding pharmaceutical promotion, and regular revision of reimbursement modalities.

Maximal Respiratory Pressure Reference Values for Hopi Children Ages 4-13.

Anthropometric variables will influence maximal respiratory pressure (MRP) values. Since significant variations exist in pulmonary nomograms amongst different races, it is important that tribe specific tables of normal maximal inspiratory pressures (MIP) and maximal expiratory pressures (MEP) be developed. To date, MRP prediction equations do not exist for Hopi children. PURPOSE: The purpose of this study was to develop MRP reference values and prediction equations for Hopi children in the ages 4-13 years. METHODS: A cross-sectional study was undertaken with 288 healthy children (125 male, 163 female), a 36% representative population of all the Hopi Native children attending Hopi Tribal Elementary Schools in Arizona. MIP and MEP values were measured. RESULTS: Age and the inverse of body mass were consistently significant predictors of the MRPs for both sexes. Predictions using the derived Hopi equations were significantly different (p≤0.001) than those using the equations for Navajo and Caucasian youth across both sexes, making it important for this population to have specific formulae to provide more accurate reference values. CONCLUSIONS: These data were collected from the children of Hopi ancestry resulting in MIP and MEP reference equations which should be used when measuring MIP and MEP in these children ages 4-13 years.

How to select a best-value biological medicine? A practical model to support hospital pharmacists.

PURPOSE: With the growing availability of biosimilars on the global market, clinicians and pharmacists have multiple off-patent biological products to choose from. Besides the competitiveness of the product's price, other criteria should be considered when selecting a best-value biological. This article aims to provide a model to facilitate transparent best-value biological selection in the off-patent biological medicines segment. SUMMARY: The presented model was developed on the basis of established multicriteria decision analysis tools for rational and transparent medicine selection, ie, the System of Objectified Judgement Analysis and InforMatrix. Criteria for the model were informed by earlier research, a literature search, and evaluation by the authors. The developed model includes up-to-date guidance on criteria that can be considered in selection and provides background on the allocation of weights that may aid hospital pharmacists and clinicians with decision-making in practice. Three main categories of criteria besides price were identified and included in the model: (1) product-driven criteria, (2) service-driven criteria, and (3) patient-driven criteria. Product-driven criteria include technical product features and licensed therapeutic indications. Service-driven criteria consist of supply conditions, value-added services, and environment and sustainability criteria. Patient-driven criteria contain product administration elements such as ease of use and service elements such as patient support programs. Relative weighting of the criteria is largely context dependent and should in a given setting be determined at the beginning of the process. CONCLUSION: The practical model described here may support hospital pharmacists and clinicians with transparent and evidence-based best-value biological selection in clinical practice.

Applications of Behavioral Economics to Pharmaceutical Policymaking: A Scoping Review with Implications for Best-Value Biological Medicines.

BACKGROUND AND OBJECTIVE: Pharmaceutical policies are generally based on the assumption that involved stakeholders make rational decisions. However, behavioral economics has taught us that this is not always the case as people deviate from rational behavior in rather predictable patterns. This scoping review examined to what extent behavioral concepts have already been applied in the pharmaceutical domain and what evidence exists about their effectiveness, with the aim of formulating future applications and research hypotheses on policymaking for best-value biologicals. METHODS: A scoping literature review was conducted on the evidence of behavioral applications to pharmaceuticals. Scientific databases (Embase, MEDLINE, APA PsycArticles, and Scopus) were searched up to 20 October, 2021. RESULTS: Forty-four full-text scientific articles were identified and narratively described in this article. Pharmaceutical domains where behavioral concepts have been investigated relate to influencing prescribing behavior, improving medication adherence, and increasing vaccination uptake. Multiple behavioral concepts were examined in the identified studies, such as social norms, defaults, framing, loss aversion, availability, and present bias. The effectiveness of the applied interventions was generally positive, but depended on the context. Some of the examined interventions can easily be translated into effective policy interventions for best-value biological medicines. However, some applications require further investigation in a research context. CONCLUSIONS: Applications of behavioral economics to pharmaceutical policymaking are promising. However, further research is required to investigate the effect of behavioral applications on policy interventions for a more sustainable market environment for best-value biological medicines.

Biosimilar Use and Switching in Belgium: Avenues for Integrated Policymaking.

Background: By improving the affordability and accessibility of biologicals, biosimilar competition provides important benefits to healthcare systems and patients. In Belgium, biosimilar uptake and competition is limited compared to other European markets. Whereas other countries have initiated structured biosimilar introduction or switching plans, no such framework or guiding principles are yet available in Belgium. Objective: This study aims to develop recommendations that can inform policy action in Belgium on biosimilar use, especially in the context of switch decision-making, and this by drawing from the perspectives of healthcare professionals involved in procuring, prescribing, switching and dispensing biologicals including biosimilars. Methods: This study made use of the consensus-building Nominal Group Technique, consisting of a three-step process 1) individual grading, 2) three structured Focus Group Discussions, 3) final individual grading involving an expert group of Belgian healthcare professionals (physician specialists and hospital pharmacists). Results: Participants (n = 13) voiced challenges with the use of biosimilars and switching in practice, and a lack of incentives to use them. Six concrete areas for policy development to support stakeholders with biosimilar use and switch decision-making were identified: 1) address stakeholder hesitations regarding (multiple) switching, 2) provide meaningful incentives, 3) guide healthcare professionals with product decision-making, 4), align practical product modalities when possible, 5) involve healthcare professionals in policy making, and 6) provide practical switch support and patient information material, particularly in the ambulatory care setting. For each area, specific consensus-based recommendations were developed. Furthermore, a set of switch management and patient communication principles was derived, including amongst others, generating buy-in from involved stakeholders prior to switching and communicating with a one-voice message. Conclusion: Without cohesive actions to reduce hurdles and without tangible benefits or steering mechanisms, changes in biosimilar use are unlikely in Belgium. To overcome this and stimulate market competitiveness, this study advances a set of concrete policy recommendations. At large, policy makers should develop an integrated policy framework, with a pro-active, best-value biological implementation roadmap that provides guidance and compelling measures to incentivize healthcare professionals to use biosimilars. Particular consideration should go to the ambulatory care setting, since drivers for biosimilar use are quasi absent in this context.

Lentiviral gene therapy prevents anti-human acid α-glucosidase antibody formation in murine Pompe disease.

Enzyme replacement therapy (ERT) is the current standard treatment for Pompe disease, a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). ERT has shown to be lifesaving in patients with classic infantile Pompe disease. However, a major drawback is the development of neutralizing antibodies against ERT. Hematopoietic stem and progenitor cell-mediated lentiviral gene therapy (HSPC-LVGT) provides a novel, potential lifelong therapy with a single intervention and may induce immune tolerance. Here, we investigated whether ERT can be safely applied as additional or alternative therapy following HSPC-LVGT in a murine model of Pompe disease. We found that lentiviral expression at subtherapeutic dose was sufficient to induce tolerance to the transgene product, as well as to subsequently administered ERT. Immune tolerance was established within 4-6 weeks after gene therapy. The mice tolerated ERT doses up to 100 mg/kg, allowing ERT to eliminate glycogen accumulation in cardiac and skeletal muscle and normalizing locomotor function. The presence of HSPC-derived cells expressing GAA in the thymus suggested the establishment of central immune tolerance. These findings demonstrate that lentiviral gene therapy in murine Pompe disease induced robust and long-term immune tolerance to GAA either expressed by a transgene or supplied as ERT.