Medical Policy

This document addresses gene therapy for glycogen storage disease type Ia (also known as GSD-Ia, Von Gierke disease, glycogenosis type 1, glucose-6-phosphate deficiency, and hepatorenal glycogenosis). GSD-Ia is a rare, life-threatening, inherited carbohydrate metabolism disorder caused by glucose-6-phosphatase (G6Pase) deficiency), which is essential for gluconeogenesis and glycogenolysis. GSD-Ia management involves adherence to a strict, medically prescribed diet that typically includes daily doses of uncooked cornstarch, often administered overnight, to maintain euglycemia.

Gene therapy is being proposed as a one-time treatment to significantly lessen the severity of GSD-Ia. At this time, one gene therapy has been approved by the Food and Drug Administration (FDA) to treat GSD-Ia: pariglasgene brecaparvovec-opnr (GENGLYCOS), an adeno-associated virus vector-based gene therapy.

Note: For a high-level overview of this document, please see “Summary for Members and Families” below.

Investigational and Not Medically Necessary:

Gene therapy for glycogen storage disease type Ia (GSD-Ia) using pariglasgene brecaparvovec-opnr (GENGLYCOS) is considered investigational and not medically necessary for all indications.

This document describes clinical studies and expert recommendations, and explains whether gene therapy for glycogen storage disease type Ia (GSD-Ia) is clinically appropriate. The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Key Information

GSD-Ia is a rare inherited condition that affects how the body keeps blood sugar levels safe. People with this condition cannot properly break down stored sugar because they lack an enzyme called glucose-6-phosphatase (G6PC1). This can lead to very low blood sugar, enlarged liver and kidneys, and other health problems. Standard treatment focuses on strict diets and frequent doses of uncooked cornstarch to keep blood sugar stable.

Pariglasgene brecaparvovec-opnr (DTX401, GENGLYCOS) is a one-time gene therapy designed to treat the root cause of GSD-Ia by delivering a working copy of the G6PC1 gene to liver cells. The goal is to help the body make the missing enzyme so blood sugar stays stable without constant dietary treatment. The FDA approved this treatment for people ages 8 and older to reduce the amount of daily cornstarch they need. However, studies have not shown that it improves blood sugar control, prevents episodes of very low blood sugar, helps people live longer, or prevents long-term health problems from GSD-Ia..

What the Studies Show

Pariglasgene brecaparvovec-opnr (GENGLYCOS) uses a changed virus to carry a working gene into liver cells. The goal is to help the liver make an enzyme that people with GSD-Ia lack. In an early study of 12 adults, people needed much less cornstarch after treatment. They were also able to go longer without food before their blood sugar became too low. No one had a serious treatment-related side effect in that study. However, the study included few people, and longer follow-up is needed.

A larger study compared the gene therapy with placebo, which did not contain the gene therapy. After 48 weeks, people who received the gene therapy used about 31% less cornstarch and about one fewer cornstarch dose each day. However, they had more blood sugar readings below 70 mg/dL. Side effects were common. About 71% had higher liver enzyme levels, which can be a sign of liver injury. Other side effects included nausea, headache, constipation, high blood fats, high blood sugar, effects from steroid treatment, and severe allergic reactions. Serious health problems were also reported. There may also be a long-term risk that the treatment could affect DNA in a way that may raise cancer risk, but this risk is not yet known. The FDA approval was based on reduced cornstarch use, not proof of better blood sugar control or better long-term health. Better studies are needed to know if pariglasgene brecaparvovec-opnr improves health over time.

Is this clinically appropriate?

Pariglasgene brecaparvovec-opnr gene therapy for GSD-Ia is not considered clinically appropriate at this time because it has not been proven to improve health.

Studies show that the treatment can reduce the need for cornstarch. However, the larger study did not show better blood sugar control. Some people had more low blood sugar readings, and side effects included liver problems and severe allergic reactions. Long-term benefits and harms are also not yet clear. Better studies are needed to know if this treatment improves health.

Unnecessary or unproven treatments can lead to needless worry, to treatment that does not help, and risks such as immune reactions. Long term risks are still being studied.

(Return to Description/Scope)

Summary

GSD-Ia is a rare inherited condition that prevents an individual from releasing glucose from the liver into the blood, which can lead to life threatening hypoglycemic episodes from birth. Individuals with GSD-Ia usually require strict diets with frequent meals and uncooked cornstarch to avoid hypoglycemia. Pariglasgene brecaparvovec-opnr (DTX401, GENGLYCOS) gene therapy is designed to be administered in a single therapeutic dose to deliver a working copy of the G6PC1 gene to liver cells so the body can produce the missing enzyme needed to control blood sugar. This gene therapy presents an opportunity for individuals with GSD-Ia to diverge from the current strict dietary regimens that require constant monitoring, and are disruptive to daily life and sleep routines, especially in infants.

The pivotal trial for pariglasgene brecaparvovec-opnr was a 48-week, randomized, double-blind, placebo-controlled Phase III study evaluating the gene therapy in 49 participants aged 8 years and older with GSD-Ia. The trial demonstrated a statistically significant 31% reduction in daily cornstarch use at 48 weeks and about one fewer daily cornstarch dose. However, participants also had a 3% increase in glucose readings below 70 mg/dL, indicating that reduced cornstarch use did not necessarily translate into better glycemic control. Adverse effects were common, including elevated liver enzymes in 71% of treated participants, nausea, hypertriglyceridemia, headache, steroid-related effects, and anaphylaxis; several serious adverse events were also reported.

The FDA granted accelerated approval on August 19, 2026, for pariglasgene brecaparvovec-opnr as an adjunct to nutritional management in individuals 8 years and older with GSD-Ia, specifically based on its ability to reduce daily cornstarch intake. Importantly, approval was not based on evidence of improved blood glucose control, fewer hypoglycemic episodes, improved survival, or prevention of long-term GSD-Ia complications. Postmarketing studies are required to further evaluate safety and clinical benefits.

Despite FDA approval, pariglasgene brecaparvovec-opnr is considered investigational and not medically necessary for all indications. The main concerns are limited evidence of durable clinical benefit, uncertainty about long-term gene expression and the ability to re-dose, immune-mediated liver toxicity, steroid-related effects, variable patient response, and theoretical risks of insertional mutagenesis and tumorigenicity. While pariglasgene brecaparvovec-opnr can substantially reduce the burden of cornstarch treatment in GSD-Ia and has received accelerated FDA approval, the available evidence does not yet establish durable improvement in glycemic control or long-term health outcomes. Because important safety and effectiveness questions remain, the use of Pariglasgene brecaparvovec-opnr to treat GSD-Ia is considered investigational and not medically necessary at this time.

Discussion

GSD-Ia is a rare, life-threatening, inherited, autosomal recessive deficiency of glucose -6-phosphatase (G6Pase-α) that results in impaired glycogenolysis and gluconeogenesis. G6Pase-α is expressed in a tissue-restricted manner, primarily in the gluconeogenic organs, namely, the liver, intestine and kidney cortex. Without intervention to stabilize blood glucose levels, GSD-Ia can be fatal if not treated immediately. The worldwide incidence of GSD-Ia is approximately 1 in 100,000 live births.

GSD-Ia is characterized by the accumulation of glycogen and fat in the liver and kidneys resulting in hepatomegaly and nephromegaly. Due to fasting intolerance, individuals with GSD-Ia typically exhibit symptoms related to hypoglycemia in infancy when the interval between feedings is extended to 3-4 hours. Other signs of the disease vary in age of onset, rate of disease progression, and severity. Commonly, at the age of 3 to 4 months, untreated infants present with hepatomegaly, severe hypoglycemia (with or without seizures), lactic acidosis, hyperuricemia, and hypertriglyceridemia. Affected children often have doll-like facial features with full cheeks, along with relatively thin extremities, short stature, and a distended abdomen due to pronounced hepatomegaly and nephromegaly. Diarrhea and xanthoma may be present. Development of reduced or dysfunctional von Willebrand factor and impaired platelet function may cause a bleeding tendency with frequent epistaxis and menorrhagia in females. Long-term complications of untreated GSD-Ia include short stature, delayed puberty, systemic hypertension, pulmonary hypertension, osteoporosis, renal disease (including proximal and distal renal tubular acidosis, kidney stones, and renal failure), gout, pancreatitis, and polycystic ovaries. In most individuals with GSD-Ia, hepatomegaly declines with age; however, development of liver adenomas is common with increasing age, and some individuals develop hepatocellular carcinoma (HCC). Seizures and cognitive impairment due to prolonged periods of hypoglycemia may also occur. Most individuals with GSD-Ia live into adulthood (Bali, 2021; Jauze, 2019; Kishnani, 2014).

GSD-Ia might be suspected in individuals with hypoglycemia, hypertriglyceridemia, hyperuricemia, lactic acidemia, and hepatomegaly, with or without neutropenia. DNA testing is conducted to confirm the diagnosis of GSD-Ia. Commercial sequencing of G6PC (G6Pase gene) is generally available. Prior to the use of DNA sequencing, diagnostic testing included liver biopsies for histologic studies and enzyme analysis, but these are done less frequently now. Liver histology demonstrates prominent storage of glycogen and substantial steatosis with minimal fibrosis.

Current treatments for GSD-Ia focus solely on controlling symptomatic hypoglycemia. Other clinical and biochemical parameters, (for example somatic growth, lactic acidosis, and hypertriglyceridemia), improve in parallel with improved glucose control. Individuals are placed on a strict medically prescribed diet that typically includes daily uncooked cornstarch doses. Individuals receive frequent feedings by mouth, and in some cases, continuous nighttime nasogastric feeding to maintain euglycemia. Dietary treatment has improved the prognosis for individuals with GSD-Ia; however, the disease itself, its management and monitoring impose significant physical, psychological, and psychosocial burden on individuals, parents, and caregivers. The risk of hypoglycemia persists if a single dose of uncooked cornstarch is delayed/omitted or in cases of gastrointestinal intolerance. Anxiety regarding hypoglycemia continues to be a significant burden for affected individuals. Treated children typically experience normal growth and puberty (Derks, 2021; Lei, 1993)

Gene Therapy

Gene therapy has revolutionized the approach to medicine aimed at treating diseases by repressing, replacing, or editing faulty genes. This treatment has been utilized to address a wide range of diseases, including but not limited to cancer, neurological disorders, viral infections, cardiovascular disease, and metabolic disorders. Gene therapy can be employed through two primary applications: ex vivo and in vivo. In the ex vivo approach, cells are taken from the individual, modified to incorporate the therapeutic gene, and then reintroduced to the individual. For in vivo gene therapy, a recombinant vector is directly delivered to the target tissue inside the individual's body. Both ex vivo and in vivo therapies have strengths and limitations, depending on various factors such as the specific disease to be treated, the target cells, and the overall treatment plan. Whereas ex vivo gene therapy methods are typically utilized for indications such as CAR-T cell therapies and hematopoietic stem cell-based treatments for sickle cell disease, in vivo gene therapies are generally used for delivery of genetic material to post-mitotic or difficult-to-access tissues, including neurons, liver, muscle, and retina (Agbogbo, 2026; Roy 2025).

The introduction of therapeutic genes into target cells can be accomplished by two delivery mechanisms: non-viral and viral methods. Examples of non-viral delivery approaches include naked plasmid delivery by electroporation, microinjection, or ultrasound, lipid nanoparticles, extracellular vesicles, and cationic polymers. Non-viral gene delivery methods offer advantages compared to viral delivery, such as lower immunogenicity and the potential for repeat dosing with reduced neutralizing antibody responses. However, non-viral delivery methods generally demonstrate lower transduction efficiency and limited ability to achieve precise tissue or cell-type targeting in vivo. Viral methods take advantage of the natural ability of viruses to infect host cells to deliver genetic material. While both viral and non-viral delivery methods have advantages and challenges, viral delivery methods are generally considered best in terms of efficiency, specificity, and ability to provide stable and long-term gene expression (Agbogbo, 2026; Roy, 2025).

Recombinant Adeno-Associated Virus (rAAV)-Mediated Liver-Directed Gene Therapy

The use of rAAV vectors in gene therapy is a substantial advancement in the treatment of genetic disorders and other diseases. Some of the distinct features of rAAV are its non-pathogenic nature, relative stability, durable episomal transgene expression, low likelihood of replication competence, and modifiable capsids. Following cellular entry, the rAAV single-stranded DNA transgenes undergo second-strand synthesis and form stable, non-integrating, circular DNA structures (episomes) inside the nucleus. The episomes are not lost during cell division and can aid long-lasting therapeutic gene expression but are diluted in actively dividing cells. Therefore, rAAV treatments are usually applied to static tissues, like liver, muscle, or the central nervous system. It minimizes the risk associated with random integration into the host genome, thereby reducing the potential for insertional mutagenesis and the activation of oncogenes. While rare, preclinical studies have demonstrated insertional mutagenesis after treatment with rAAV (Agbogbo, 2026; Batty, 2026).

While early studies on the use of gene therapy to treat GSD-Ia are promising, concerns have been raised regarding the duration of transgene expression, the potential for hepatotoxicity and the activation of oncogenes following gene therapy.

Durability of Hepatic Transgene Expression

Variation in the durability of transgene expression may be influenced by several biological mechanisms which influence how well expression persists. Although AAV gene therapy for genetic conditions can produce transgene expression, the durability of expression varies and is difficult to predict. Most rAAV genomes remain predominately episomal and are diluted as hepatocytes divide. A lesser proportion of AAV genomes (approximately 0.1-3%) integrate into host DNA and may contribute disproportionately to long-term expression. Persistent episomes in slowly dividing or inactive hepatocytes may also support the stable phase. The current consensus is that expression follows two phases: an initial high but transient phase from episomal genomes, followed by a lower but stable steady state, likely sustained by the small fraction of integrated genomes and by quiescent (non-dividing) hepatocytes. The durability of therapeutic response is key to long-term treatment success, especially since immune responses to rAAV vectors may prevent re-dosing with the same therapy (Muhuri, 2022). Chou and colleagues (2023) concluded that "The rAAV vectors rarely integrate into the host genome, remaining predominantly as circular episomal elements, that can establish long-term transgene expression” and “durable gene therapy depends upon minimizing loss of both the episomal transgene and its expression.”

Immune-Mediated Hepatotoxicity

Elevated liver enzymes (such as ALT, AST, and occasionally bilirubin) following AAV gene therapy are most often due to immune-mediated hepatotoxicity, though other mechanisms can also contribute to elevated liver enzyme levels. AAV vectors may cause dose-dependent immune activation in the liver. In these instances, the immune system recognizes the vector capsid or transgene product as foreign, leading to antibody-mediated or T-cell-mediated injury. A mild increase in aminotransferases is the most frequent hepatic manifestation, occurring variably in 20%-80% of individuals undergoing gene therapy which uses viral vectors, although there have been rare cases where this immune response progresses to acute liver failure. Hepatotoxicity is unpredictable and varies depending on patient comorbidities, vector dose, vector type, and degree of immune activation. Pretreatment screening for underlying chronic liver disease and exclusion of advanced fibrosis or cirrhosis using noninvasive tests is crucial (Reiss, 2025; Roy, 2025; Simini, 2025; Whiteley, 2023).

Pre-existing anti-capsid neutralizing antibodies prevent some individuals from receiving AAV therapy and generally block re-dosing with the same serotype. Because high-titer anti-AAV8 neutralizing antibodies can persist for a decade or longer after the initial treatment, AAV therapy remains a one-time opportunity for most individuals. Additionally, recipients of AAV therapy may experience asymptomatic elevations in transaminase levels, which can lead to a loss of the therapeutic expression (Reiss, 2025; Simini, 2025).

Combination of Disease and Targeted Cells

Researchers have also investigated whether the combination of disease and targeted cell might have an impact on the duration of expression. As an example, researchers reported sustained and undiminished factor IX expression in individuals with hemophilia B for up to 8 - 13 years (HOPE-B study). This contrasts with the progressive decrease or full loss of factor VIII expression observed in several trials of gene therapy for hemophilia A. Possible factors contributing to dissimilarities in expression have been attributed to the larger, more immunogenic transgene expressed in a heterologous cell type (Herzog, 2025; Pierce, 2024; Pipe, 2026).

Gene Therapy for GSD-Ia

Pariglasgene brecaparvovec-opnr (DTX401), manufactured by Ultragenyx Pharmaceutical Inc. (Novato, CA), is an adeno-associated virus serotype 8 vector expressing the human G6PC1 gene that encodes G6Pase. Weinstein and colleagues (2025) reported the results an open-label, phase 1/2, dose-escalation, 52-week gene therapy trial (NCT03517085) to evaluate the safety of single doses of pariglasgene brecaparvovec-opnr and the incidence of dose-limiting toxicities (DLTs) at each dose level. The 12 participants in the trial were each at least 18 years of age with molecularly confirmed GSD-Ia with biallelic pathogenic G6PC1 variants, had a history of at least one hypoglycemic event with glucose < 60mg/dL (< 3.33mmol/L), and stable GSD Ia disease (as evidenced by no hospitalization for severe hypoglycemia during the 4-week period preceding the screening visit). Of the 12 participants, 3 in Cohort 1 received pariglasgene brecaparvovec-opnr 2.0 × 10¹² genome copies (GC)/kg while 3 participants each in Cohorts 2, 3, and 4 received 6.0 × 10¹² GC/kg.

The primary endpoint was the evaluation of safety based on the incidence of adverse events (AEs), including dose-limiting toxicities (DLTs) at each dose level, treatment-emergent AEs (TEAEs), and serious AEs (SAEs) for each cohort, assessed by severity and relationship to pariglasgene brecaparvovec-opnr. DLTs were defined as any AE/SAE ≥ Grade 3 that was considered by the sponsor and/or investigator to be associated with pariglasgene brecaparvovec-opnr. Any abnormal laboratory test results (clinical chemistry [including liver function tests], hematology, urinalysis, coagulation panel, or other laboratory parameters), including those that worsened from baseline or were felt to be clinically significant in the medical/scientific judgment of the investigator, were documented as AEs or SAEs. Any clinically significant safety findings associated with GSD-Ia were not reported as AEs unless the study investigator considered it to be more severe than expected for the condition of the participant.

The secondary endpoint was defined as a change from baseline in time to first hypoglycemic event (glucose < 54 mg/dL [< 3.0 mmol/L]) during the controlled fasting challenge (CFC) at 12, 24, and 52 weeks after pariglasgene brecaparvovec-opnr administration. The CFC was performed at night during a 24-hour hospital stay, and evaluated fasting tolerance after a standardized dinner and a small cornstarch dose to minimize the post-prandial insulin response. Blood samples were obtained at established glucose concentration-dependent intervals to measure analytes, (glucose, insulin, and lactate concentrations). Stopping criteria for the CFC were (a) glucose < 54 mg/dL (changed from < 60 mg/dL with a protocol amendment), (b) duration of 15 hours, or (c) symptoms of hypoglycemia or hyperlactatemia at the discretion of the physician or participant. Corticosteroids were administered to minimize vector‑induced inflammatory response.

All participants experienced a treatment-emergent adverse event (TEAE) in addition to a related TEAE. However, none of the participants experienced a dose-limiting toxicity, TEAE leading to study discontinuation, TEAE leading to death, or serious treatment-related TEAE. Mean (SD) time to hypoglycemia in minutes/gram of carbohydrate during a CFC was 5.0 (1.6) at baseline and 6.9 (2.7) at week 52, (mean [SD] increase of 46% [72%]). At baseline, the mean total daily cornstarch intake was 284 g and 85 g at week 52 in the 10 participants with available values at both time points, a mean (SD) total daily cornstarch intake reduction of 68% (20%) p<0.001. The researchers concluded that pariglasgene brecaparvovec-opnr demonstrated an acceptable safety profile, with no dose-limiting toxicities or serious treatment-related adverse events. Participants demonstrated clinically significant reductions in cornstarch intake while maintaining stable glucose levels. The ability to reduce reliance on cornstarch suggests improved endogenous glucose production, which is critical in minimizing the risk of severe hypoglycemic episodes. While the results of this study suggest that over 52 weeks the gene therapy is safe and efficacious, additional data with longer-term progress is needed. Also, data on the outcomes of individuals with GSD-Ia treated with the gene therapy who are less than 18 years of age is also needed.

Turner-Bowker and colleagues (2026) reported the results of participant experience interviews conducted as part of an open-label, phase 1/2 dose-escalation trial (NCT03517085) evaluating the safety and efficacy of pariglasgene brecaparvovec-opnr in adults at least 18 years of age with GSD-Ia. A semistructured interview guide was used to conduct telephone interviews at weeks 24, 52, and 104. Qualitative interview information was audio recorded, transcribed, coded, and analyzed. The majority of participants (86%; n=6/7) reported overall symptom improvement and reduced burden following treatment with pariglasgene brecaparvovec-opnr. Three (43%) participants reported no negative outcomes following gene therapy; 4 (57%) reported at least one negative change attributed to instances of blood sugar instability, lifestyle, or diet adjustments. Satisfaction fluctuated across timepoints; however, most were somewhat satisfied/very satisfied with the gene therapy at weeks 24 (80%), 52 (86%), and 104 (86%). None of the participants reported being very dissatisfied. The researchers concluded that overall, most of the participants described positive experiences, including substantial reduction in burden and improved health-related quality of life following treatment throughout the trial. The researchers recommended that in order to optimize patient outcomes and experience with gene therapy, guidance on and close monitoring of dietary changes during implementation should be provided.

In a pivotal, Phase 3, randomized, double-blind, placebo-controlled trial (NCT05139316), researchers assessed the safety and efficacy of pariglasgene brecaparvovec-opnr to reduce or eliminate dependence on exogenous glucose replacement therapy to maintain euglycemia and to maintain or improve the quality of glucose control. At the time of this review, although results of this clinical trial were not available on clinicaltrials.gov., results were available as part of the FDA prescribing information (FDA Prescribing Information, GENGLYCOS, 2026).

A total of 49 participants were included in the study, however three participants discontinued prior to receiving any treatment and the remaining 46 participants received the assigned treatment and were included in the efficacy analysis. Individuals with detectable baseline anti-AAV8 total antibodies were excluded. All participants were at least 8 years of age with confirmed GSD-Ia (by molecular testing or enzymatic activity on liver biopsy) and currently receiving a therapeutic regimen of cornstarch (or equivalent), following international guidance/recommendations with stable nutrition, glycemic, and clinical status. Prior to randomization, all subjects underwent a 16-week nutritional optimization and stabilization period during which cornstarch dosing and dietary intake were adjusted. Participants were randomized 1:1 to pariglasgene brecaparvovec-opnr or placebo group and followed for 48 weeks. At week 48, eligible participants crossed over and received pariglasgene brecaparvovec-opnr if they had previously received placebo or placebo if they had previously received pariglasgene brecaparvovec-opnr and were followed for an additional 48 weeks. After completion of week 144 or early withdrawal, participants were offered enrollment into a Disease Monitoring Program (DMP) where they would be followed for at least 12 years post pariglasgene brecaparvovec-opnr infusion. The primary outcome measure was the percent change from baseline to week 48 in total daily cornstarch ingestion (based on blinded weekly assessments of continuous glucose monitoring data). Secondary outcomes included the change from baseline in the number of daily cornstarch doses and the percent of glucose values in the hypoglycemic range (<70 mg/dL), averaged over a 4-week period (FDA Prescribing Information, GENGLYCOS, 2026).

Study eligibility criteria for NCT05139316 were as follows (FDA Prescribing Information, GENGLYCOS, 2026).

Inclusion Criteria

• Documented GSD-Ia with confirmation by molecular testing or enzymatic activity on liver biopsy
• Currently receiving a therapeutic regimen of cornstarch (or equivalent), following international guidance/recommendations with stable nutrition, glycemic, and clinical status
• Willing and able to complete the informed consent process and to comply with study procedures and visit schedule
• Females of childbearing potential and fertile males must consent to use highly effective contraception from the period following informed consent through the duration of the 144-week study and in cases of early withdrawal at least 48 weeks after the last dose of investigational product (IP). Female subjects must agree not to become pregnant. Male subjects must agree not to father a child or donate sperm.

Exclusion Criteria

• Detectable pre-existing antibodies to the AAV8 capsid
• History of liver transplant, including hepatocyte cell therapy / transplant
• History of liver disease
• Presence of liver adenoma > 5 cm in size
• Presence of liver adenoma > 3 cm and ≤ 5 cm in size that has a documented annual growth rate of ≥ 0.5 cm per year
• Significant hepatic inflammation or cirrhosis as evidenced by imaging or any of the following laboratory abnormalities: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > upper limit of normal (ULN), total bilirubin > 1.5 × ULN, alkaline phosphatase > 2.5 × ULN
• Non-fasting triglycerides ≥ 1000 mg/dL
• Pregnant, breastfeeding, or planning to become pregnant (self or partner) at any time during the study
• Current or previous participation in another gene transfer study
• History of illicit drug use within 60 days prior to screening or positive results from an 8-panel urine drug screen during the Screening Period completed at 2 time points at least 4 weeks apart.

Note: additional inclusion/exclusion criteria may apply, per protocol.

Participants followed over 48 weeks after dosing demonstrated a statistically significant mean reduction from baseline in daily cornstarch intake of 31% compared with placebo (primary endpoint). Evaluation of the secondary endpoint revealed a mean reduction of one cornstarch dose per day versus placebo. The study results also revealed a mean 3% increase in the percentage of glucose values in the hypoglycemic range (< 70 mg/dL) versus placebo. During the 48-week primary efficacy analysis period, 71% of participants experienced elevated liver enzymes (ALT or AST). Additional adverse reactions occurring in at least 10 percent of treated participants included: nausea (38%), hypertriglyceridemia (29%), headache (24%), constipation (19%), acne or dermatitis (19%), hyperglycemia (14%), Cushingoid features from steroid exposure (14%), and anaphylaxis (10%). Seven serious adverse events were reported during the primary analysis period, including two cases of anaphylaxis or infusion reactions, two cases of adrenal insufficiency, two elevated lactate episodes, and one hypoglycemia event (FDA Prescribing Information, GENGLYCOS, 2026).

In 15 of the 21 participants treated with GENGLYCOS with available data at 96 weeks, the mean (SD) percent change from baseline (pre-dosing) at week 96 in daily cornstarch intake was -60.8% (19.7%) and the observed mean (SD) change from pre-dosing (baseline) in the number of daily cornstarch doses was -2.0 (1.3). In 19 of the 21 participants treated with GENGLYCOS with available data at week 96, the observed mean (SD) change from pre-dosing (baseline) at week 96 in percentage of glucose values in the hypoglycemic range (glucose < 70 mg/dL) was 5.2% (6.3%) (FDA Prescribing Information, GENGLYCOS, 2026).

It is worth noting that the FDA approval was based on the reduction in daily cornstarch consumed by the participants. It was not approved based on proof that participants experienced improved blood glucose levels, fewer hypoglycemic episodes, lived longer, or avoided the long-term complications of GSD-Ia.

Food and Drug Administration (FDA)

On August 19, 2026, the FDA granted accelerated approval of pariglasgene brecaparvovec-opnr (GENGLYCOS) to reduce daily cornstarch intake as an adjunct to nutritional management in individuals 8 years of age and older with GSD-Ia. Under accelerated approval statutory provisions and regulations, the FDA granted marketing approval of GENGLYCOS based on reduction in daily cornstarch intake (FDA Prescribing Information, GENGLYCOS, 2026).

As part of accelerated approval, Ultragenyx agreed to provide 2 years of safety and efficacy clinical data from open-label commercial treatment of 50 individuals and 20 control participants through the GSD-Ia Disease Monitoring Program (DMP). The control group will consist of participants who pursued commercial treatment but could not be treated with GENGLYCOS due to the presence of anti-AAV8 antibodies. The study will furnish additional data to support the reduction in cornstarch clinical burden, fasting tolerance, and other measures in a post-marketing setting where participants can know their immediate glucose levels, and their cornstarch and diet can be managed more promptly by their physician. The DMP will also evaluate previously treated clinical trial participants as well as the new commercial participants for a total of 10 years (FDA Accelerated Approval, 2026; FDA Prescribing Information, GENGLYCOS, 2026).

Regarding the risk of tumorigenicity, the prescribing information provided by the FDA states the following:

There is a theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome. GENGLYCOS is composed of a recombinant, non-replicating AAV8 vector whose DNA persists largely in episomal form. Random integration of recombinant AAV-vector DNA into human DNA has been reported with AAV gene therapies. The clinical relevance of individual integration events is unknown, but it is acknowledged that individual integration events could potentially contribute to a risk of tumorigenicity (FDA Prescribing Information, GENGLYCOS, 2026).

GSD-Ia is an inherited autosomal recessive disorder caused by mutations in the G6PC gene, leading to deficiency of the glucose-6-phosphatase enzyme. This causes glycogen to accumulate in organs such as the liver, kidneys, and small intestine, impairing their function. The disease commonly appears in infancy with symptoms like enlarged liver, hypoglycemia, lactic acidosis, hyperlipidemia, hyperuricemia, and growth delay. Other possible features include diarrhea, xanthomas, hypoglycemic seizures, and bleeding problems due to impaired platelet function.

GSD-Ia is usually diagnosed through genetic testing to detect mutations in the G6PC gene. Testing results help confirm the diagnosis and guide proper treatment and management of the disease.

Adeno-associated virus (AAV) wild-type: An AAV that contains its natural genes, including rep (replication) and cap (capsid), which enables it to make copies of itself.

Cellular degeneration: The ongoing loss or dysfunction of cells in affected tissues (such as heart, liver, and skeletal muscle) due to the underlying disease pathology, and potentially to complications from the therapy itself.

Episomal: Relating to an episome.

Episome: A portion of genetic material that exists inside a cell, outside of the main chromosomal genome and is able to copy itself independently.

Gene therapy: A treatment which involves introducing genetic materials to alter gene or protein expression at a level sufficient to improve or cure disease symptoms with minimal adverse events.

Hepatomegaly: Enlarged liver.

Heterologous expression: The result of the introduction of gene encoding for a protein of interest from one species into the cell of another species, which allows the host cells to express the foreign protein.

Hyperlipidemia: Elevated levels of fats in the blood.

Hyperuricemia: Elevated levels of uric acid in the blood.

Hypoglycemia: Low blood sugar levels.

Immunogenicity: The ability of a foreign substance (such as an antigen) to cause the body to make an immune response against that substance.

Lactic acidemia: Elevated levels of lactic acid in the blood.

Recombinant adeno-associated virus (rAAV): An AAV in which the rep and cap genes have been removed and replaced with a custom gene of interest (a transgene) flanked by inverted terminal repeats (ITRs).

Xanthoma: A yellowish fatty deposit in the skin or other tissues, often indicating elevated blood lipid levels.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
For the following procedure codes, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Agbogbo F, Dismuke D. Status and future of recombinant adeno-associated virus vector manufacturing. Biotechnol Prog. 2026: e88525.
2. Batty P. Adeno-associated virus gene therapy: Is there a risk of insertional mutagenesis? Toxicol Pathol. 2026; 54(5):355-360.
3. Chou JY, Mansfield BC. Gene therapy and genome editing for type I glycogen storage diseases. Front Mol Med. 2023; 3:1167091.
4. Derks TGJ, Rodriguez-Buritica DF, Ahmad A, et al. Glycogen storage disease type Ia: current management options, burden and unmet needs. Nutrients. 2021; 13(11):3828.
5. Hannah WB, Derks TGJ, Drumm ML, et al. Glycogen storage diseases. Nat Rev Dis Primers. 2023; 9(1):46.
6. Herzog RW, Kaczmarek R, High KA. Gene therapy for hemophilia - from basic science to first approvals of "one-and-done" therapies. Mol Ther. 2025; 33(5):2015-2034.
7. Jauze L, Monteillet L, Mithieux G, et al. Challenges of gene therapy for the treatment of glycogen storage diseases type I and type III. Hum Gene Ther. 2019; 30(10):1263-1273.
8. Lei KJ, Shelly LL, Pan CJ, et al. Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a. Science. 1993; 262(5133):580-583.
9. Muhuri M, Levy DI, Schulz M, et al. Durability of transgene expression after rAAV gene therapy. Mol Ther. 2022; 30(4):1364-1380.
10. Pierce GF, Fong S, Long BR, Kaczmarek R. Deciphering conundrums of adeno-associated virus liver-directed gene therapy: focus on hemophilia. J Thromb Haemost. 2024; 22(5):1263-1289.
11. Pipe SW, Miesbach W, Recht M, et al. Final analysis of a study of etranacogene dezaparvovec for hemophilia B. N Engl J Med. 2026; 394(5):463-474.
12. Reiss UM, Davidoff AM, Tuddenham EGD, et al. Sustained clinical benefit of AAV gene therapy in severe hemophilia B. N Engl J Med. 2025; 392(22):2226-2234.
13. Roy A, Bansal S, Kulkarni A, Reddy KR. Hepatic manifestations following gene therapy. Gastro Hep Adv. 2025; 4(8):100681.
14. Simini G, Batty P. The hepatic odyssey of adeno-associated virus: from gene delivery to long-term outcomes. J Thromb Haemost. 2025; 23(12):3781-3790.
15. Turner-Bowker DM, Butler J, Egan S, et al. Trial interviews to explore glycogen storage disease type Ia patient experiences following gene therapy. J Health Econ Outcomes Res. 2026; 13(1):39-47.
16. Weinstein DA, Derks TG, Rodriguez-Buritica DF, et al. Safety and efficacy of DTX401, an AAV8-mediated liver-directed gene therapy, in adults with glycogen storage disease type I a (GSDIa). J Inherit Metab Dis. 2025; 48(2):e70014.
17. Whiteley LO. An overview of nonclinical and clinical liver toxicity associated with AAV gene therapy. Toxicol Pathol. 2023; 51(7-8):400-404.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Bali DS, El-Gharbawy A, Austin S, et al. Glycogen storage disease type I. Apr 19, 2006 [Updated Oct 14, 2021]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1312/. Accessed on August 28, 2026.
2. Kishnani PS, Austin SL, Abdenur JE, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014; 16(11):e1.
3. Rake JP, Visser G, Labrune P, et al. Guidelines for management of glycogen storage disease type I - European Study on Glycogen Storage Disease Type I (ESGSD I). Eur J Pediatr. 2002; 161(Suppl 1):S112-S119.
4. Ultragenyx Pharmaceutical Inc. A study of adeno-associated virus serotype 8-mediated gene transfer of glucose-6-phosphatase in patients with glycogen storage disease type Ia (GSDIa). NLM Identifier: NCT05139316. Last updated: March 25, 2026. Available at: https://clinicaltrials.gov/study/NCT05139316?term=NCT05139316&viewType=Card&rank=1. Accessed on August 28, 2026.
5. Ultragenyx Pharmaceutical Inc. Safety and dose-finding study of DTX401 (AAV8G6PC) in adults with glycogen storage disease type Ia (GSDIa). NLM Identifier: NCT03517085. Last updated on November 18, 2022. Available at: https://clinicaltrials.gov/study/NCT03517085?cond=Glycogen%20storage%20disease%20type%20I&page=2&rank=17. Accessed on August 28, 2026.
6. U.S. Food and Drug Administration (FDA). Accelerated BLA Approval. BL 125858/0. Rockville, MD: FDA. August 19, 2026. Available at: https://www.fda.gov/media/194371/download. Accessed on August 28, 2026.
7. U.S. Food and Drug Administration. GENGLYCOS prescribing information. August 2026. Available at: Available at: https://www.fda.gov/media/194364/download. Accessed on August 28, 2026.
8. U.S. Food and Drug Administration. FDA News Release. FDA approves first therapy for patients aged 8 years and older with glycogen storage disease type Ia. Published August 19, 2026. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-patients-aged-8-years-and-older-glycogen-storage-disease-type-ia. Accessed on August 28, 2026.

1. National Organization for Rare Disorders (NORD). Glycogen storage disease type I. Last updated: December 23, 2019. Available at: https://rarediseases.org/rare-diseases/glycogen-storage-disease-type-i/. Accessed on August 28, 2026.

GENGLYCOS (Pariglasgene brecaparvovec-opnr [DTX401])
Glucose-6-phosphate deficiency
Glycogenosis type 1
Glycogen storage disease type Ia (GSD-Ia)
Hepatorenal glycogenosis
Von Gierke disease

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member’s contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.

No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan.

© CPT Only – American Medical Association