Genglycos

Genglycos is a gene therapy used to treat glycogen storage disease type Ia (GSDIa) in adults and children aged 8 years and older to reduce the amount of cornstarch a person needs each day, alongside ongoing nutritional management. It is given once, as a single infusion into a vein.

GSDIa is an ultra-rare inherited disorder of carbohydrate metabolism, caused by changes in the G6PC gene. It affects an estimated 1,500 to 2,500 people in the US. People with GSDIa lack working glucose-6-phosphatase (G6Pase), the liver enzyme that releases stored glucose into the bloodstream, so blood sugar falls dangerously low during fasting and overnight. Severe hypoglycemia can cause seizures and can be life-threatening, and the condition also leads to a build-up of glycogen in the liver and other metabolic complications. Management centers on a demanding, around-the-clock regimen of raw cornstarch as a slow-release source of glucose. Genglycos works by giving the liver a working copy of the gene for the missing enzyme, so less cornstarch is needed.

Genglycos's (pariglasgene brecaparvovec-opnr) mechanism of action involves delivering a copy of the human G6PC gene to liver cells. The gene is carried inside a modified, non-replicating adeno-associated virus type 8 (AAV8) vector, which acts as a delivery vehicle and cannot make copies of itself or cause infection. Once inside liver cells, the delivered gene, together with its native promoter and enhancer, directs the cells to produce normally functioning G6Pase. A single infusion is intended to provide lasting enzyme production, so Genglycos is not repeated.

Genglycos received FDA accelerated approval on August 19, 2026, making it the first gene therapy approved for GSDIa. Accelerated approval was granted based on the reduction in daily cornstarch intake seen in trials, and continued approval may depend on confirmatory trials verifying clinical benefit. Genglycos is also known in the research literature as DTX401.

Serious side effects

Genglycos can cause the following serious side effects:

• Hypersensitivity and infusion reactions. Hypersensitivity reactions, including anaphylaxis and infusion reactions, have occurred with Genglycos, and some have been severe. Signs include hives, flushing, rash, low or high blood pressure, wheezing, breathlessness, chest tightness, nausea, vomiting, headache, abdominal pain, lightheadedness, shivering, and flu-like symptoms. Everyone is given acetaminophen and a non-sedating antihistamine 30 to 60 minutes beforehand, the infusion is started slowly, and treatment centers keep resuscitation equipment and medicines for anaphylaxis on hand. If a reaction occurs, the infusion is paused and, once symptoms settle, restarted at half the previous rate.
• Liver injury. Genglycos can trigger an immune reaction against the liver, raising the liver enzymes ALT and AST. This is common and is the reason everyone receives a course of corticosteroids after treatment. Liver enzymes are checked before the infusion and regularly for at least the first 6 months afterwards. Tell your healthcare provider straight away about tiredness, yellowing of the skin or eyes, dark urine, nausea, vomiting, or pain in the upper right side of the abdomen. Do not take any medicine, herbal product, or supplement after treatment without checking first that it is not harmful to the liver, and discuss alcohol with your care team.
• Adrenal insufficiency. Adrenal insufficiency, sometimes serious, has occurred during and after the course of corticosteroids given with Genglycos. It happens when the body's own cortisol production has not recovered as steroids are reduced. Symptoms include tiredness, weakness, loss of appetite, nausea, vomiting, low blood pressure, low sodium, and low blood sugar; an adrenal crisis can cause severe low blood pressure, sudden abdominal pain, or loss of consciousness. Adrenal function is tested before steroids begin and monitored afterwards, and the steroid dose is tapered gradually. Corticosteroids must never be stopped abruptly.
• Risk of tumors. There is a theoretical risk of cancer because AAV gene therapy DNA can insert itself into a person's own DNA at random. With Genglycos, the vector DNA stays mostly outside the chromosomes, and the significance of individual insertion events is unknown, but the possibility cannot be ruled out. Anyone who develops a tumor after treatment should have it reported to Ultragenyx Pharmaceutical Inc. at 1-888-756-8657.

Do not receive Genglycos if you have:

• severe liver scarring (severe hepatic fibrosis) or cirrhosis
• existing liver impairment or an acute viral liver infection.

Genglycos is only given to people who have no detectable antibodies to AAV8, the viral vector used to carry the gene. Pre-existing antibodies can stop the therapy from working. Everyone is tested before treatment; an FDA-authorized test is not currently available, and available tests vary in accuracy and design.

Before receiving Genglycos tell your healthcare provider about all your medical conditions, including if you:

• have any liver condition, including scarring, cirrhosis, hepatitis or raised liver enzymes. Genglycos must not be given if you have severe fibrosis or cirrhosis, and is avoided in existing liver impairment or acute viral hepatitis
• are due to have any vaccinations. Vaccines should be avoided in the month before Genglycos, and your vaccination schedule may need to be adjusted around the corticosteroid course afterwards.
• are pregnant or plan to become pregnant. Genglycos should not be used during pregnancy, and there are no data on its use in pregnant women. Women who could become pregnant should use effective contraception for at least 12 months after treatment.
• are breastfeeding or plan to breastfeed. It is not known whether Genglycos passes into breast milk or how it might affect a breastfed baby or milk supply. Your care team will weigh the benefits of breastfeeding against your need for treatment.
• are a man of reproductive potential. For 6 months after treatment, men must not donate semen, and men and their female partners must use effective contraception to prevent or postpone pregnancy.

Genglycos has not been studied in children younger than 8 years of age or in adults aged 65 and older.

Common side effects

The most common side effects, occurring in 10% or more of people treated in trials, are raised liver enzymes and nausea. Reactions reported more often with Genglycos than with placebo were:

• raised liver enzymes, ALT or AST (71%)
• nausea (38%)
• high blood triglycerides (29%)
• headache (24%)
• adrenal insufficiency (24%)
• constipation (19%)
• acne or acne-like rash (19%)
• high blood sugar (14%)
• cushingoid features, such as facial rounding (14%)
• anaphylaxis (10%).

Several of these, including acne, cushingoid features, high blood sugar, and adrenal insufficiency, are recognized effects of the corticosteroids given after the infusion rather than of the gene therapy itself.

Liver enzyme rises peaked between 4 and 12 weeks after treatment and resolved within 15 weeks; all were mild to moderate except one severe but symptomless rise (peak ALT 253 U/L).

These are not all the possible side effects of Genglycos. Call your doctor for medical advice about side effects. You may report side effects to Ultragenyx Pharmaceutical Inc. at 1-888-756-8657, or to the FDA at 1-800-FDA-1088.

Genglycos was approved on the basis of GlucoGene (NCT05139316), a phase 3 randomized, double-blind, placebo-controlled trial in 46 people aged 8 to 37 years with GSDIa, who received a single infusion of Genglycos (21 people) or placebo (25 people). The main measure was the change in total daily cornstarch intake at week 48.

• Daily cornstarch intake fell by 41.1% with Genglycos, against 10.2% with placebo, from a baseline of roughly 290 g a day, a treatment difference of 30.9% (95% CI 20.9% to 40.8%, p<0.001).
• The number of daily cornstarch doses fell by 1.2 with Genglycos and by 0.2 with placebo.
• Among the 15 treated people with data at week 96, intake was 60.8% below pre-treatment levels.
• Time spent with glucose below 70 mg/dL rose in both groups, and more so with Genglycos, by 3.1 percentage points against 0.1.

Approval was accelerated and based on cornstarch reduction rather than long-term health outcomes, so further data are needed. Ultragenyx will collect two years of data on 50 commercially treated patients and 20 untreated controls, with 10 year follow-up.

Genglycos is prepared and given by a healthcare team at a treatment center. It is a one-time treatment, given as a single infusion into a vein, and is not repeated.

• The dose is based on body weight: 1.0 × 1013 genome copies per kilogram. It is supplied as a kit of 3 to 15 vials matched to your weight, and people weighing more than 87 kg are dosed as though they weigh 87 kg.
• You will be given acetaminophen and a non-sedating antihistamine 30 to 60 minutes before the infusion to reduce the risk of a reaction.
• The infusion rate is increased in stages and usually takes about 3 hours, followed by a saline flush. It is never given as a rapid injection. You will be monitored during and after the infusion.
• Two weeks after the infusion, you will start an oral corticosteroid, such as prednisone, to reduce the immune reaction against the liver. This runs for at least 8 weeks in total: 4 weeks at the starting dose (1 mg/kg a day, or 60 mg a day if you weigh 60 kg or more), then a gradual taper over at least another 4 weeks.
• Liver blood tests are done weekly until 2 weeks after the steroid taper finishes, then every 2 to 4 weeks until month 6. Adrenal function is checked before, during, and after the steroid course. Tell your team immediately if you miss a steroid dose or vomit it up.
• Your cornstarch regimen is adjusted by your specialist team based on glucose monitoring. Do not change it on your own.

Where can Genglycos be given, and what support is available?

Genglycos is only given at Qualified Treatment Centers, a national network of centers with specific training and expertise in administering gene therapy.

Ultragenyx runs a support program, UltraCare, which includes Gene Therapy Guides who can help with understanding insurance coverage, arranging treatment support and questions about the treatment process. They are available Monday to Friday, 9 a.m. to 8 p.m. Eastern Time, on 888-756-8657, and more information is at ultracaresupport.com and genglycos.com.

Avoid medicines, herbal products, and supplements that can affect the liver unless your healthcare provider has confirmed they are safe to take, and discuss alcohol with your care team before drinking any.

Do not stop or reduce your corticosteroid course on your own, and do not miss doses. Stopping steroids abruptly can cause adrenal insufficiency.

Small amounts of the vector are shed in urine, stool, and saliva for a period after treatment. Follow the hygiene advice your team gives you when handling body waste for 3 months after the infusion. Men must not donate semen for 6 months.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

No specific drug interaction studies have been done with Genglycos, but two things matter around treatment:

• Vaccines. Vaccines should be avoided for 1 month before Genglycos, and your vaccination schedule may need to be adjusted because the corticosteroids given afterwards suppress the immune system.
• Medicines that can affect the liver. Because Genglycos can raise liver enzymes, check with your healthcare provider before taking anything new, including herbal products and supplements, until your team confirms your liver tests have settled.

Genglycos is handled and stored by the treatment center or specialist pharmacy, not by patients. It is shipped and stored frozen at -60°C (-76°F) or below, protected from light, and thawed and diluted immediately before the infusion.

Active ingredient: pariglasgene brecaparvovec-opnr, at 3.0 × 1013 genome copies per mL

Inactive ingredients: magnesium chloride, poloxamer 188, sodium chloride, and tris. Each vial contains 2 mL of extractable volume.