Galactosemia Disease

“Life Beyond Lactose: Navigating the Journey with Galactosemia”

Galactosemia, a rare metabolic disorder affecting the processing of sugar galactose, manifests worldwide and significantly impact individuals and healthcare systems.

The Galactosemia Foundation, a non-profit charitable organization that advocates for people with galactosemia and their families, urges the U.S Food and Drug Administration (FDA) to incorporate the experiences and perspectives of people living with galactosemia and their caregivers in the agency's review of overstate (AT-007), the potential first-ever treatment for this rare genetic disease that might be life-threatening for Galactosemia newborns symptoms cause severe lifelong complications. The Galactosemia Foundation has shared qualitative data on the patient journey and burden of disease with the FDA on several occasions including an externally led patient-focused drug development meeting held in September 2022, patient and caregiver focus groups, and direct outreach to the agency.

The results of the ACTION-Galactosemia Kids registrational clinical study evaluating overstate in children with galactosemia were recently announced. The study sponsor, Applied Therapeutics, also announced its plans to request a meeting with the FDA as soon as possible to discuss a potential New Drug Application (NDA) submission in the second half of 2023, as well as its intention to submit a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) in mid-2023.

The rare genetic condition known as galactosemia impairs the body's capacity to metabolize carbohydrates by preventing it from converting galactose to glucose. Milk, which includes the Galactosemia milk of humans and other dairy products, contains a sugar called galactose. We refer to this as endogenous galactose because it is also created by the human body. It is not the same sugar as glucose. Galactose-1-phosphate uridylyl transferase (GALT) deficiency, an enzyme that is essential to this activity, is deficient in the condition.

In newborns, classic galactosemia symptoms begin to appear after a few days of feeding. Symptoms are mild Galactosemia or severe and it include loss of appetite, vomiting, diarrhoea, weakness, and lethargy. These symptoms require immediate medical attention. After a healthcare provider diagnoses galactosemia and you remove galactose from your baby’s diet, these symptoms should improve.

Early diagnosis and treatment with a lactose-restricted (dairy-free) diet as soon as possible to prevent severe intellectual impairment, liver failure, and Galactosemia neonatal mortality.

Depending on the diagnostic standards employed by the program, newborn screening programs worldwide diagnose cases of classic galactosemia between 1/16,000 and 1/48,000 newborns. Every ethnic group has reported experiencing the disorder. There is a higher incidence of galactosemia among those with Irish heritage. Due to a particular gene mutation, African Americans and native Africans living in South Africa are most affected by clinical variant galactosemia.

International organizations like the Galactosemia Foundation and the International Society for Pediatric and Adolescent Diabetes provide support and resources for individuals and families affected by the disease.

Three types of galactosemia have been identified -

Galactosemia Type I: Classic Galactosemia

The most severe variety of galactosemia is called type I, or classic. Early treatment with a galactose-free diet is able to prevent life-threatening problems in newborns with typical galactosemia.

For a kid to have typical galactosemia, both parents must carry a faulty copy of the GALT gene. All 50 states have newborn screening programs that check for this kind of galactosemia.

Galactosemia Type II: Galactokinase Deficiency Galactosemia

A mutation in the GALK1 gene causes galactokinase deficiency galactosemia, which prevents the afflicted kid from completely breaking down galactose. A normal result might be deceiving since this kind of the deficit is not covered by all galactosemia in newborn screening tests.

Galactosemia Type III: Epimerase-Deficiency Galactosemia

Hereditary mutations in GALE genes lead to a partial lack of activity in the GALE enzyme, which is the cause of galactosemia type III. Epimerase deficiency comes in three Flavors: peripheral, intermediate, and generalized. The severity of generalized epimerase deficiency is like that of typical galactosemia. As with galactosemia type II, several newborn screening tests do not screen for epimerase deficiency.

Duarte Galactosemia:

GALT gene mutations, which also cause typical galactosemia, are the cause of Duarte galactosemia. It's a milder mutation. The vital enzyme activity in charge of breaking down galactose is diminished but not eliminated. Although they don't experience the same medical consequences, those with Duarte galactosemia should experience some digestive issues from meals containing galactose. Galactose doesn't have to be completely avoided in their diet.

Diagnosis of Galactosemia –

The diagnosis of galactosemia is mostly made up of a physical examination, certain biochemical testing, and a detailed evaluation of medical and family history. They also work with the New England Newborn Screening Program, one of the best newborn screening programs in the world. Every baby in New England is receiving a galactosemia screening on their second day of life.

Moreover, every newborn in New England gets screened for over 30 genetic, endocrine, and metabolic diseases as part of the Newborn Screening Program.

Laboratory Tests

Newborn screening evaluation –

The NIH states that because the physical symptoms of metabolic diseases like galactosemia aren't always evident at birth, diagnosing them are sometimes difficult. To detect these types of disorders in babies, a diagnostic protocol called newborn screening was created. Because a child's chances of developing long-term issues or irreversible difficulties are reduced the sooner these diseases are detected, the screening test is crucial. Sadly, in cases with galactosemia, this is not necessarily the case.

• Babies in New England might be sent to the Metabolism Program at Boston Children's Hospital if their fat tests come back positive. To confirm the diagnosis, physicians gather fresh blood and urine samples and send them to our metabolic laboratory. As untreated neonates could pass away in the first two weeks of life, physicians should start feeding treatment even before a positive diagnosis is obtained.
• Although screening tests are required in every state, not all states screen for the same disorders. The National Newborn and Genetics Resource Center has a comprehensive list of the disorders that your state screens for.

Blood Tests –

Galactose-1-phosphate uridyltransferase test is a blood test that is given to newborns to check for a rare genetic disorder called galactosemia, which is a disorder that prevents the body from breaking down a simple sugar called galactose, which is found in many foods and all dairy products, including breast milk and milk-based baby formulas.

Urine Tests –

Urine tests are able to be done to detect the presence of galactose and galactitol galactosemia in the urine.

Confirmatory Tests

Quantitative GALT enzyme assay -

This test directly measures the amount of Galactosemia GALT-related activity in red blood cells. It is used to confirm a diagnosis of galactosemia, and it also helps determine the severity of the condition.

Genetic testing -

A sample of amniotic fluid or CVS is used for genetic testing for galactosemia. This test assesses the likelihood that a fetus has the disease. When a newborn has a verified GALT enzyme deficit, genetic testing is used postnatal to identify the precise kind of GALT gene mutation.

Imaging tests

X-rays, CT scans, Ultrasound, or MRIs is used to look for signs of damage to the bones or brain in severe cases of galactosemia.

MRI –

As per DLI analysis, a report is provided on the brain findings during magnetic resonance imaging in 67 patients with transferase deficiency who are galactosemic (36 females, 31 males; median age, 10 years). On T2-weighted scans, 11 patients had several small hyperintense lesions in the cerebral white matter, 8 had cerebellar atrophy, and 22 had mild cerebral atrophy. On intermediate and T2-weighted images, the classic galactosemic patients (those without detectable transferase activity) older than 1 year of age did not exhibit the typical decline in peripheral white matter signal strength. The authors suggest that this anomalous signal intensity is related to impaired myelin development after the failure to synthesize adequate and/or normal galactocerebroside.

X-rays –

X-rays is used to look for signs of bone fractures, which is occur in people with galactosemia due to the buildup of galactose in the bones.

Ultrasound -

Ultrasound is a safe and painless imaging test that uses sound waves to create pictures of the inside of the body. In galactosemia, ultrasound is used to look for Galactosemia signs of liver and kidney damage, such as enlargement or inflammation.

Governments and healthcare organizations are moving quickly to expand testing, which is speeding up the market's growth. Market participants might use new technology to offer a range of diagnostic kits. In addition, it's critical to offer rapid, affordable diagnostic tools in the field of galactosemia diagnosis.

By offering information on the market dynamics of diagnostic kits, diagnostic processes, current stakeholders, and their growth trajectories, DiseaseLandscape Insights helps important participants. Through the utilization of DLI data, stakeholders make business decisions and execute market expansion plans.

The following table lists the names of the market leaders who are redefining healthcare with their forefront diagnostic innovations:

Diagnostic Key Players

Diagnostic Product

Treatment Analysis –

According to DLI analysis, the main Galactosemia treatment is strict dietary management, focusing on eliminating galactose and lactose from the diet. This is because individuals lack the galactosemia enzymes needed to break down these sugars, leading to various health complications if consumed.

• Here are some specific dietary treatments for Galactosemia recommendations:

Infants: Newborns with galactosemia should be fed a soy-based formula or another lactose-free formula. Breastfeeding is not recommended.

• Children and adults: Galactosemia in adults should avoid all dairy products and foods that contain lactose or galactose. This includes processed foods, such as some breads, crackers, candies, and salad dressings.
• Fruits and vegetables: Some fruits and vegetables, such as apples, pears, melons, potatoes, and green beans, contain small amounts of galactose. People with galactosemia usually eat these foods in moderation. However, it is important to talk to a registered dietitian to determine how much is safe to eat.
• Legumes: Legumes, such as beans, lentils, and peas, also contain small amounts of galactose. People with galactosemia usually eat these foods in moderation as well.

In addition to dietary restrictions, people with galactosemia also need to take vitamins and mineral supplements, such as calcium, vitamin D, and vitamin K. These nutrients are often found in dairy products, so people with galactosemia is not getting enough of them from their diet alone.

With proper treatment, most people with galactosemia live healthy and normal lives. However, it is important to follow the dietary restrictions carefully to avoid complications, such as Galactosemia liver damage, cataracts, and developmental delays.

1. Gene-Based Therapies

Gene-based treatments include gene therapy and mRNA therapy and aim at restoring GALT function up to 10–15%, therefore avoiding clinical illness. In GALT null rat pups, GALT gene therapy using several Aden-associated virus (AAV) vectors boosted GALT levels in the liver (64–595%) and brain (3–42%) without causing substantial Galactosemia side effects. There was also an improvement in cataracts and a decrease in the amounts of galactose, galactic, and galactose 1-P in the liver, blood, and brain.

Biochemical and clinical improvement was reported up to 2 months in treated rats, showing the effectiveness of gene substitution until early adulthood. Fibroblasts from CG patients transduced with AAV2-CMG-h GALT also showed decreased oxidative stress and restored GALT activity and protein levels. Even though gene therapy can be advantageous, further research is necessary before it can be used in clinical settings due to the documented differences in GALT activity between the liver and brain, the immune system's reaction to AAV vectors, and genomic instability.

2. Small Molecules

Three types of small compounds are being studied to treat CG: (1) endoplasmic reticulum (ER) stress-reducing drugs, (2) enzyme inhibitors, and (3) pharmacological chaperones.

Low molecular weight substances known as pharmacological chaperones selectively attach to and stabilize proteins as their target. As a result, they could prevent premature degradation and/or facilitate protein folding and intracellular trafficking.

Pharmacological chaperones have several benefits, including the capacity to penetrate the blood-brain barrier and oral availability, but not all patients benefit from their usage. They work well for saving missense variants that are not active site variations, but they are ineffective for deletion, stop gain, splicing, or active site variants.

Although initial studies suggested a potential benefit of arginine on specific GALT variants, subsequent research failed to confirm the effect of arginine on GALT stability. Since the GALT contains at least two binding sites (the active site and the binding site for allosteric modulators), it is anticipated that future drug candidates can be discovered by a mix of in silico screening of predicted ligands, screening of chemical libraries, and logical screening of substrate. The defining of the safety profile, the right (age-dependent) dosage, and particular indications (i.e., GALT variations) are still significant obstacles to overcome.

Galactokinase 1 (GALK1) inhibitors and aldose reductase (AR) inhibitors are examples of enzyme inhibitors. Reducing galactose 1-P accumulation is the goal of GALK1 inhibitors, as this is a crucial step in the pathophysiology of CG. Through high-throughput screening, several potential compounds have been found. Among these, it has been demonstrated that phenylsulfamides reduce the levels of galactose 1-P in fibroblasts from CG patients. More recently, it has been determined that non-competitive GALK1 inhibitors possibly benefit from more research and clinical trials. Further investigation beyond cellular models is necessary since the in vivo effect of these inhibitors is yet unknown.

3. Other Therapies

Therapies (aimed at) treating the enzyme deficiency have been developed in addition to strategies addressing the clinical effects of Galactosemia. Patients still run the risk of long-term problems even with a diet low in galactose.

CG is frequently characterized by emotional instability, mobility abnormalities, verbal delay, and intellectual incapacity. Besides current approaches used to treat patients who develop such complications, transcranial alternating current stimulation (tACS), and Babble Boot Camp (BBC) is a non-invasive brain stimulation technique that induces long-term neural plasticity, and it is being studied in CG. This method has worked well for both dyslexia and Parkinson's illness. A speech therapist leads the proactive parental participation in the speech intervention program BBC, which aims to avoid speech problems. Four CG children who received BBC showed a trend in speech outcomes compared to one CG kid who did not get BBC, suggesting that this technique is beneficial.

In female patients with CG, hypogonadotropic hypogonadism and primary ovarian insufficiency are typical characteristics. Pregnancy rates are lower in women with CG, despite the possibility of conception. Currently, two therapy options to address subfertility is to be given to patients with CG: cryopreservation and oocyte donation. Only extremely young prepubertal patients have a good chance of preserving their fertility. Three fertility preservation treatments are available: ovarian tissue, mature oocyte, and/or embryo cryopreservation. Cryopreservation lowers the ovarian reserve, however, overall success and complication rates are increasingly linked to this procedure. One such method for treating subfertility in CG is intrafamilial oocyte donation. The patient's cognitive state, family dynamics, and the potential medical consequences must all be considered while evaluating this choice. Techniques for fertility preservation should only be made available with the proper institutional research ethics permission, as they frequently give rise to ethical dilemmas.

Treatment Key Players -

The below table shows the market leader and their products for the treatment of galactosemia -

Regulatory Framework -

The regulatory framework for galactosemia disease is complex and constantly evolving. However, it is important to have a regulatory framework in place to ensure the safety and efficacy of treatments for this rare disease.

The specific regulations for newborn screening vary from country to country. In the United States, for example, newborn screening is regulated by the Centers for Disease Control and Prevention (CDC) and the Department of Health and Human Services (HHS). In Europe, newborn screening is regulated by the European Commission and the European Union member states.

For instance, in the United States, the Food and Drug Administration (FDA) is responsible for regulating food and drugs. The FDA has a specific guidance document for the labeling of foods for individuals with galactosemia.

In the European Union, the European Commission is responsible for regulating food and drugs. The European Commission has a regulation on the labeling of foodstuffs for persons suffering from intolerance to certain sugars.

Thus, Disease Landscape Insights provides data-driven insights to involved market players that guide in international collaboration, risk assessment, regulation formulation, surveillance, and monitoring of research as well as emergency response preparation.

By utilizing data from DiseaseLandscape Insights, institutions, and market participants effectively control, and respond to cancerous outbreaks while ensuring that the impacted populations are safe and well-cared for.

Competitive Analysis –

Competitive analysis in the galactosemia market involves assessing the strategies, products, and innovations of key market players. The galactosemia market is highly competitive, with pharmaceutical companies, medical device manufacturers, diagnostic laboratories, and research institutions vying for prominence.

Here's an overview of the competitive landscape and notable deals by market players:

• BioMarin Pharmaceutical Inc.: A leading player with the enzyme replacement therapy (ERT) Lumizyme (galactokinase).
• Pfizer Inc.: Offers another ERT option, Naglazyme (galactosidase alpha 2).
• Other companies: Developing novel therapies, including gene therapy approaches, are in the pipeline.

Moreover, research continues to explore new treatments and management strategies for galactosemia. As it is a rare Galactosemia disorder, awareness among healthcare professionals and the public is crucial.

In 2022, Applied Therapeutics, Inc. announced a regulatory update on the AT-007 Galactosemia program. The trial named ACTION-Galactosemia Kids Phase 3 trial compares the effects of AT-007 treatment and placebo for different parameters such as speech, behavior, cognition, and motor skills over time. A closed group assesses clinical outcomes with a gap of six months. The initial evaluation has been conducted in the first quarter of 2022.

In summary, market players in the breast cancer market are key drivers of progress, with their research, innovation, and strategic partnerships shaping the competitive landscape. Their contributions continue to improve early detection, treatment options, and patient care, ultimately benefiting breast cancer patients worldwide.

Market Trends –

Therapies involving Dietary Management and Enzyme Replacement:

Patients with galactosemia must avoid galactose and lactose-containing foods for the rest of their lives as dietary management is vital to their treatment. Failure to adhere to a galactose-free diet get results in severe complications such as liver failure, cataracts, and mental retardation. In addition, enzyme replacement therapy (ERT) appears to be a viable treatment option. ERT attempts to reduce the accumulation of toxic substances in the body by administering an enzyme responsible for breaking down galactose. However, additional research is required to ascertain the safety and effectiveness of ERT.

Approaches to Gene Therapy for Galactosemia:

The application of gene therapy to the treatment of galactosemia possesses significant therapeutic potential. This strategy entails the introduction of a functional copy of the gene responsible for galactosemia mutation, which is to remedy the genetic defect and restore enzyme activity. While preclinical studies have shown promising results, additional clinical trials are required to confirm the safety and efficacy of galactosemia gene therapy.

Innovations in Newborn Screening Methods:

Early diagnosis and treatment are essential for effectively managing galactosemia. Screening newborns plays a crucial role in identifying affected individuals early, resulting in better long-term outcomes. Typically, a blood test assesses the activity of the enzyme responsible for galactose breakdown. Recent innovations in neonatal screening methods, such as tandem mass spectrometry, have increased the sensitivity and specificity of galactosemia screening. This technology enables the simultaneous measurement of multiple analytes, thereby enhancing screening precision and decreasing false positives and negatives.

Integration of Telehealth Technologies for Remote Patient Administration:

Telehealth solutions are becoming increasingly vital in the management of rare diseases such as galactosemia. These solutions provide remote access to healthcare services, which reduces the burden of frequent clinic visits and improves patient outcomes. Telehealth facilitates virtual consultations and remote monitoring in the context of galactosemia. Virtual consultations improve access to specialized care, while remote monitoring allows for immediate feedback on dietary management and early detection of complications of Galactosemia.

Clinical Trial Assessment-

A comprehensive study of clinical trial data and crucial product positioning includes a trial design, main and secondary outcomes, dose, and schedules, recruitment status, inclusion, and exclusion criteria, and essentially covers adverse events that are recorded. The trial analysis plays a major role in identifying the important assets' potential as well as their likely filing and launch date.

Conclusion -

DiseaseLandscape Insights (DLI) helps companies build and run effective strategies to prevent and control ACC epidemics. Furthermore, as awareness and anticipated epidemics grow, there is a growing demand for diagnostic tools, clinical evaluations, and novel therapeutics.

Major players involved in the production of medicinal items might benefit from the Galactosaemic information and experience provided by DiseaseLandscape Insights. The assistance provided by DLI facilitates patient recruitment strategies, regulatory compliance, and the planning and execution of clinical trials for novel medications and pharmaceuticals.

The qualitative data from this study demonstrates the significant burden of disease and challenges associated with Galactosemia across all core aspects of life. The impact on patients and caregivers highlights the significance of pharmaceutical intervention and the gravity of the unmet medical need.

This ultimately motivates the leaders to conduct qualitative research, investigate manufacturing companies, and find out about raw material sources. All industry participants gain a stronger foothold in galactosemia and keep one step ahead with the help of DiseaseLandscape Insights.