Enzyme replacement therapy

Enzyme replacement therapy (ERT) refers to treatment of congenital enzyme deficiencies using purified human, animal or recombinant enzyme preparations. The enzymes are given parenterally, usually by intravenous infusion. The diseases treated are generally rare genetic disorders such as mucopolysaccharidosis (MPS) or lysosomal storage disease which lead to severe disability and premature death. The first effective treatment with enzyme replacement therapy was performed in patients with Gaucher disease ¹ and in the last 15 years enzyme replacement therapy has become available for other lysosomal storage disorders including some types of mucopolysaccharidoses (MPS) ². MPS I (Hurler, Hurler-Scheie, Scheie syndrome) was the first MPS type treated with enzyme replacement therapy (available since 2003); subsequently the treatment became available for MPS VI (Maroteaux-Lamy syndrome; 2005), MPS II (Hunter syndrome; 2006), and MPS IVA (Morquio A syndrome; 2014) (Table 1). Recently, the recombinant enzyme β-glucuronidase has been tested for patients with MPS VII (Sly syndrome) ³ and, to date, the treatment is available for commercial use in the United States where it was approved by the US Food and Drug Administration on 15 November 2017 ⁴.

Enzyme replacement therapy is typically used to replace a missing or deficient enzyme in a person with an inherited enzyme deficiency syndrome. The missing enzyme is replaced by infusions of an enzyme that is purified from human or animal tissue or blood or produced by novel recombinant techniques. Typically, the enzyme is modified to allow for a longer half-life, more potent activity, resistance to degradation or targeting to a specific organ, tissue or cell type. The first successful enzyme replacement therapies were for alpha-1-antitrypsin (A1AT) deficiency using plasma derived purified human A1AT. A1AT deficiency is associated with early onset emphysema attributed to the lack of leukocyte elastase inhibitor which leads to progressive pulmonary damage. Small prospective studies suggested a benefit from augmentation therapy, raising the levels of A1AT in serum by infusing the enzyme purified from human serum. This therapy was eventually shown to be beneficial, particularly in patients with early or intermediate pulmonary dysfunction and was quite safe, without the occurrence of viral hepatitis, despite being prepared from human plasma.

A second form of successful enzyme replacement therapy was established for Gaucher disease, an inherited deficiency of lysosomal acid β-glucocerebrosidase that leads to accumulation of the substrate (glucocerebroside and its other breakdown products such as ceramide) in lysosomes. The major tissues affected are liver, spleen and bone. The glucocerebrosidase was initially prepared from placental tissue and was modified to allow its specific uptake by macrophages and delivery into lysosomes. Subsequently, recombinant forms of glucocerebrosidase have been developed and now constitute the standard of care for type 1 Gaucher disease.

Subsequently, similar or related approaches have been taken to treat other enzyme deficiency syndromes such as adenosine deaminase deficiency, lysosomal acid lipase deficiency, Fabry disease, Pompe disease, Hurler and Hunter syndrome and several of the rarer forms of mucopolysaccharidoses. A list of enzymes approved for use in enzyme replacement therapy in the United States, the year of first approval, the generic and brand names of the product and the disease for which they are used are given in the Table 1.

The efficacy of enzyme replacement therapy has been evaluated in clinical trials and in many post-marketing studies with a long-term follow-up for MPS I (Hurler, Hurler-Scheie, Scheie syndrome), MPS II (Hunter syndrome), MPS IVA (Morquio A syndrome) and MPS VI (Maroteaux-Lamy syndrome). While enzyme replacement therapy is effective in reducing urinary glycosaminoglycans (GAGs) and liver and spleen volume, cartilaginous organs such as the trachea and bronchi, bones and eyes are poorly impacted by enzyme replacement therapy probably due to limited penetration in the specific tissue ². Enzyme replacement therapy in the present formulations also does not cross the blood–brain barrier, with the consequence that the central nervous system is not cured by enzyme replacement therapy. This is particularly important for severe forms of MPS I and MPS II characterized by cognitive decline. For severe MPS I patients (Hurler), early haematopoietic stem cell transplantation is the gold standard, while still controversial is the role of stem cell transplantation in MPS II. The use of enzyme replacement therapy in patients with severe cognitive decline is the subject of debate; the current position of the scientific community is that enzyme replacement therapy must be started in all patients who do not have a more effective treatment. Neonatal screening is widely suggested for treatable mucopolysaccharidosis (MPS), and many pilot studies are ongoing. The rationale is that early, possibly pre-symptomatic treatment can improve prognosis. All patients develop anti-enzyme replacement therapy antibodies but only a few have drug-related adverse reactions. It has not yet been definitely clarified if high-titer antibodies may, at least in some cases, reduce the efficacy of enzyme replacement therapy.

Results from clinical trials and the real-world setting confirm the efficacy and safety of enzyme replacement therapy in the treatment of these multisystem, progressive disorders ⁵. The major proportion of the infused recombinant enzymes for MPS is delivered to the visceral organs such as the liver, kidney, and spleen ⁶. The infused enzymes have a short half-life in the circulation due to rapid binding to M6P receptors and uptake into visceral organs. It is known that only a small fraction of the recombinant enzyme can reach the bone cartilage and the eye, explaining why improvements of these organ/systems are limited even after long-term treatment ⁷. Moreover, due to the inefficacy of recombinant enzymes to cross the blood–brain barrier (BBB), there are no benefits of enzyme replacement therapy for central nervous system (CNS) involvement ⁸.

The enzyme replacement therapy regimen for MPS requires weekly intravenous infusions of the recombinant enzyme. enzyme replacement therapy is a life-long therapy, and each infusion takes 3 to 4 hours depending on the enzyme and the dose. There is the potential for severe infusion reactions; life-threatening anaphylaxis has rarely occurred in patients receiving enzyme replacement therapy ⁹. Most infusions are given in a hospital setting because of this risk, but home infusions are reported to be feasible and safe for some patients and thus home treatment is now available for selected patients with MPS I and MPS II ¹⁰. The feasibility of home therapy for any MPS patient should be based on a risk/benefit evaluation by the treating physician, the patient, and the patient’s caregiver.

Natural purified and recombinant enzymes are generally well tolerated with minimal systemic adverse reactions. The usual major reactions to enzyme replacement therapy are local infusion reactions and hypersensitivity reactions. Hypersensitivity can be a difficult problem, not just in causing allergic symptoms but also in causing inactivity of the enzyme by cross reacting antibodies. Hypersensitivity reactions are generally more common and more severe in patients with total absence of the enzyme, rather than a deficiency or minor amino acid mutation that inactivates the protein. Hypersensitivity reactions can be severe with rash, fever, hypotension, angioneurotic edema, bronchospasm, anaphylaxis and cardio-pulmonary collapse. Most reactions, however, are mild and transient and may be prevented by premedication with antihistamines, antipyretics or corticosteroids.

Table 1. Enzyme replacement therapy drugs

Generic name	Brand name	Enzyme	Year	Disease
Alpha1-Proteinase inhibitor	Prolastin-C Glassia	Alpha1-Antitrypsin	2009 2010	A1AT Deficiency
Alglucerase alfa	Ceredase*	β-Glucocerebrosidase	1991	Gaucher
Imiglucerase	Cerezyme	β-Glucocerebrosidase	1995	Gaucher
Taliglucerase alfa	Elelyso	β-Glucocerebrosidase	2012	Gaucher
Velaglucerase alfa	VPRIV	β-Glucocerebrosidase	2010	Gaucher
Pegademase	Adagen	Adenosine Deaminase	2000	ADA Deficiency
Agalsidase beta	Fabrazyme	Alpha-Galactosidase A	2003	Fabry
Alglucosidase alfa	Lumizyme	Acid alpha-Glucosidase	2010	Pompe
Laronidase	Aldurazyme	α-L-Iduronidase	2003	Hurler, MPS I
Idursulfase	Elaprase	Iduronate-2-Sulfatase	2006	Hunter, MPS II
Elosulfase alfa	Vimizim	N-Acetylgalactosamine-6 Sulfatase	2014	Morquio Snydrome A, MPS IVA
Galsulfase	Naglazyme	N-Acetylgalactosamine-4 Sulfatase	2005	Maroteaux-Lamy, MPS VI
Sebelipase alfa	Kanuma	Lysosomal Acid Lipase	2015	Wolman, LAL Deficiency

Footnote: * Withdrawn from market. MPS=Mucopolysaccharidosis.

Enzyme replacement therapy side effects

Overall, enzyme replacement therapys for mucopolysaccharidoses are generally well tolerated and have an acceptable safety profile ¹¹. Most infusion associated reactions were mild to moderate and included rash, urticaria, angio-edema, bronchoconstriction, rhinitis, pyrexia, nausea, vomiting ¹¹. They were easily resolved by interrupting or slowing down the rate of infusion and/or by the administration of anti-histamines, antipyretics and/ or corticosteroids. Most patients who experienced infusion associated reactions received and tolerated subsequent infusions. infusion associated reactions were reported in around 35–70% mucopolysaccharidosis patients on enzyme replacement therapy, but only 1–2% were considered severe ¹². Very rare serious adverse reactions, including life-threatening anaphylaxis have been reported, both in clinical studies and in postmarking experience, even after several dozen infusions of enzyme replacement therapy ¹³. However, infusion associated reactions episodes were shown to decrease progressively with time during treatment in the extension studies ¹⁴.

To minimize the risk of infusion associated reactions, pretreatment is recommended 30–60 minutes prior to the start of the infusion and may include antihistamines, antipyretics, and/or steroids as well as careful consideration of the patient’s clinical status prior to administration ¹⁵.

In the case of recurrent infusion associated reactions, with failure of pre-medication to prevent hypersensitivity reactions, desensitization is indicated. This is a process inducing a state of temporary tolerance through sequential exposure to increasing doses of the drug tricking the immune system into accepting it. Desensitization should be performed in an appropriate setting with the support of an allergologist and /or immunologist, due to the possible reactions. It is usually indicated in patients who have an IgE-mediated reaction appearing within a few hours after the start of infusion ¹⁶. Effective desensitization has been reported in patients treated with laronidase, idursulfase, galsulfase and elosulfase ¹⁷.

There is little information about the safety of enzyme replacement therapy during pregnancy and lactation. In the very few cases reported, no adverse effects of enzyme replacement therapy on pregnancy and on breastfed infants have been observed in any of treated patients with MPSI, MPS IV, and MPS VI ¹⁸.

Gaucher disease enzyme replacement therapy

Gaucher disease is genetic, multisystem disease caused by an inherited deficiency in the lysosomal enzyme, β-glucocerebrosidase. Gaucher disease is named for the French physician who first described it (Philippe Gaucher: 1882). Clinical features include anemia, thrombocytopenia, enlargement of the liver and spleen and bone dysplasia. Some forms have neurologic involvement as well. Symptoms are caused by the accumulation of glucosylceramide in lysosomes of the reticuloendothelial system, predominantly in macrophages of bone, liver and spleen. Gaucher disease is categorized into three clinical forms. Type 1 or adult, non-neuropathic Gaucher disease is the most common form and typically presents with splenomegaly, anemia and thrombocytopenia in adolescence or adulthood. Type 2 or acute infantile neuropathic Gaucher disease presents in the perinatal period with enlargement of the liver and spleen, and progressive neurologic involvement and disability leading to death in the first years of life. Type 3 or childhood, chronic neuropathic Gaucher disease is intermediate in severity between types 1 and 2, and presents in childhood or early adulthood with neurologic and liver involvement which can be progressive. Gaucher disease affects an estimated 1 in 50,000 to 100,000 persons, over 90% being type 1. Therapies have been developed for type 1 Gaucher disease which ameliorate its course and improve symptoms. There is no specific cure of Gaucher disease.

The initial and now standard therapy of Gaucher disease is enzyme replacement, based upon regular infusions of the missing enzymes, glucocerebrosidase. The active enzyme can be prepared from human tissue (placentas) or produced by recombinant DNA technology. Recently, new approaches to therapy have been introduced including substrate restriction, based upon inhibiting enzymes upstream of glucocerebrosidase and, thus, limiting the damaging accumulation of its ultimate harmful substrate, glucosylceramide, which normally is metabolized to glucocerebroside upon which the enzyme acts. Future therapies might employ drugs that modify the folding or trafficking of glucocerebrosidase inside the cell, making it more effective. Ultimately, gene therapy to replace the abnormal enzyme may become a reality.

Current therapies for Gaucher disease include the following:

• Glucocerebrosidase (Enzyme Replacement Therapy)
  • Alglucerase alfa (Ceredase: 1991)
  • Imiglucerase (Cerezyme: 1995)
  • Taliglucerase alfa (Elelyso: 2012)
  • Velaglucerase alfa (Vpriv: 2010)
• Glucosylceramide Synthase Inhibitors (Substrate Restriction Therapy)
  • Eliglustat (Cerdelga: 2014)
  • Miglustat (Zavesca: 2003).

Fabry disease enzyme replacement therapy

Fabry disease is an inherited disorder that results from the buildup of a particular type of fat, called globotriaosylceramide, in the body’s cells. Beginning in childhood, this buildup causes signs and symptoms that affect many parts of the body. Characteristic features of Fabry disease include episodes of pain, particularly in the hands and feet (acroparesthesias); clusters of small, dark red spots on the skin called angiokeratomas; a decreased ability to sweat (hypohidrosis); cloudiness or streaks in the front part of the eye (corneal opacity or corneal verticillata); problems with the gastrointestinal system; ringing in the ears (tinnitus); and hearing loss. Fabry disease also involves potentially life-threatening complications such as progressive kidney damage, heart attack, and stroke. Some affected individuals have milder forms of the disorder that appear later in life and affect only the heart or kidneys.

Fabry disease causes multi-organ dysfunction and patients need a comprehensive, multi-disciplinary treatment plan that is individually tailored and includes specific therapies that target abnormal substrate accumulation and adjuvant therapies that address end-organ damage ¹⁹.

Enzyme replacement therapy is the cornerstone for treatment of Fabry disease and synthetic enzyme, produced by recombinant DNA technology, is infused intravenously. Two forms of the recombinant enzyme are available, agalsidase alpha (Replagal®, Shire pharmaceuticals) and agalsidase beta (Fabrazyme®, Sanofi Genzyme). Fabrazyme is the only enzyme replacement therapy approved by the Food and Drug Administration (FDA) in 2003. Both Replagal and Fabrazyme are available in Europe and other regions of the world. enzyme replacement therapy replaces the missing enzyme and reduces the accumulated glycolipids in cells throughout the body. Double-blind, placebo-controlled Phase 3 and 4 clinical trials have demonstrated the safety and effectiveness of Fabrazyme ²⁰.

Enzyme replacement therapy has been shown to slow or prevent the decline of renal function especially if initiated early before advanced kidney damage, improve neuropathic pain and heat intolerance ²⁰. Globotriaosylceramide accumulation is cleared from various cell types in the kidney following enzyme replacement therapy ²¹. Early initiation of enzyme replacement therapy is important especially in type 1 classically affected males. enzyme replacement therapy initiation is currently recommended for type 1 Classic males with clnical manifestations at any age, or if asymptomatic, by age 15 ¹⁹. Recombinant enzyme “biosimilars” are available in certain countries including Korea and Japan. Several other recombinant enzyme preparations are in clinical development.

An oral therapy, Galafold (migalastat, Amicus Therapeutics) was approved in the EU (2017) and in the US (2018) to treat adults with Fabry disease. The drug is a pharmacologic chaperone that can bind to, stabilize, and enhance the residual enzymatic activity of certain missense mutations ²². Clinical studies have demonstrated the effectiveness of this approach (Germain 2016). Future studies will determine the clinical and biochemical effectiveness of specific missense mutations with residual activity.

Adjunct therapies include low daily doses of diphenylhydantoin, carbamazepine, or neurontin, to help to manage the acroparesthesia ²³. Other later complications (e.g., kidney failure or heart problems) should be treated symptomatically after consultation with a physician who is experienced in the care of patients with Fabry disease. Hemodialysis and kidney (renal) transplantation may be necessary in cases that have progressed to kidney failure ²⁴.

Pancreatic enzyme replacement therapy

The pancreas is a soft, finely lobulated gland located behind the peritoneum on the posterior abdominal wall and has both endocrine and exocrine functions. It plays an essential role in the digestion, absorption, and metabolism of carbohydrates, fats, and proteins. Exocrine pancreatic insufficiency (EPI) refers to a reduction in pancreatic enzyme activity (mainly pancreatic lipase) in the intestinal lumen below the threshold required for digestive functions. These changes could be due to inadequate pancreatic stimulation of pancreatic secretion, insufficient secretion of pancreatic digestive enzymes by the pancreatic acinar cells, or outflow obstruction of the pancreatic duct and inadequate mixing of the pancreatic enzymes with food.

Patients with exocrine pancreatic insufficiency (EPI) may present with clinical manifestations such as steatorrhea, flatulence, weight loss, and abdominal pain of variable location and severity. The disease is associated with impairment of quality of life, increased risk of complications due to malnutrition and changes in bone density, and increased risk of motility. While pancreatic malfunction could affect both endocrine and exocrine functions of the pancreas, the term pancreatic insufficiency usually refers to exocrine rather than endocrine deficiency. In this activity, we will focus on exocrine pancreatic insufficiency.

The principal two causes of exocrine pancreatic insufficiency are chronic pancreatitis in adults and cystic fibrosis in children. Other causes include- acute pancreatitis, pancreatic tumors, diabetes mellitus, celiac disease, inflammatory bowel disease, bariatric surgery, HIV/AIDS, and genetic and congenital causes ²⁵.

Alcohol excess is a well-recognized cause for chronic pancreatitis. In the United States, heavy drinkers have a triple risk of developing chronic pancreatitis, and the risk was further increased in drinkers who are also heavy smokers ²⁶.

The pancreas is one of the primary organs affected in cystic fibrosis. About 85% of cystic fibrosis patients have Exocrine pancreatic insufficiency, usually acquired soon after birth. All patients, regardless of age, need to be tested for exocrine pancreatic insufficiency ²⁷.

Exocrine pancreatic insufficiency could present in a small number of patients with celiac disease; however, it usually resolves after dietetic control. Exocrine pancreatic insufficiency should be excluded in patients with celiac disease who remain symptomatic despite a gluten-free diet ²⁸.

Exocrine pancreatic insufficiency is not uncommon in inflammatory bowel disease. It could result from the effect of disease activity (autoimmune changes) or secondary to medications used in the treatment. Both acute and chronic pancreatitis has increased incidence among inflammatory bowel disease patients ²⁹.

Exocrine pancreatic insufficiency is a well-known complication after bariatric surgery and could impose an important entity due to the increasing number of such surgeries worldwide. Altered anatomy and intersecting symptoms with the surgery itself make distinction difficult. Bariatric surgery includes bypassing a portion of the gastrointestinal tract; the extent of malabsorption depends on the length of the part removed ³⁰.

Exocrine pancreatic insufficiency has been associated with HIV infection and considered an important cause of chronic diarrhea in patients with HIV. Screening for exocrine pancreatic insufficiency should be performed in patients with HIV presenting with chronic diarrhea ³¹.

Treatment for exocrine pancreatic insufficiency includes avoidance of malnutrition-related complications and improvement of the patient’s quality of life. Documentation of body weight and body mass index along with anthropometric measurements, Dual-energy X-ray absorptiometry scan and screening for nutritional deficiencies (albumin, international normalized ratio, vitamins D, A, and E level, vitamins B and folate) should be performed for all patients diagnosed with Exocrine pancreatic insufficiency at presentation and at least every year to assess the response to replacement therapy and progression of the disease ³².

Pancreatic enzyme replacement therapy is recommended to treat exocrine pancreatic insufficiency and resultant malnutrition. it could be enhanced by increasing doses, enteric coating, gastric acid suppression, and proper administration during meals ³³. There is a need to treat the underlying cause of Exocrine pancreatic insufficiency along with lifestyle advice, including abstinence from alcohol, smoking cessation, and dietary modifications in the form of small frequent meals and avoidance of indigestible foods. Also, the supplementation of fat-soluble vitamins if required ²⁶.

Pancreatic enzyme replacement therapy (PERT) is the main treatment of exocrine pancreatic insufficiency. A combination of pancreatic enzymes (lipase, amylase, and protease) provides prevention of malabsorption and restores the normal physiological digestive process. The enteric coating of the enzymatic supplement provides protection from gastric acidity and dissolves afterward in the duodenum in response to alkaline pH. some patients might require reducing gastric acidity in the case of reduced bicarbonate secretion in order to allow dissolving of the enteric coat ³⁴.

The dose needed for enzyme replacement differs between patients depending on the severity of the deficiency and individual needs. Moreover, high doses of supplements don’t come without complications, so the lowest effective dose should be used. The current recommendation is of 25,000 to 40,000 units of lipase taken with meals or half with snacks, then titrated according to response to a maximum of 75,000 to 90,000 units of lipase per meal. In the case of poor response, the use of gastric acid suppression and excluding other potential causes for symptoms should be considered ³⁵.

Dietetic management includes advice about keeping with a normal diet as possible, along with small frequent meals, avoidance of fat restriction, and very high fiber diets. A referral is recommended to a dietician for review of dietetic history along with anthropometric measures plus counseling and support ³⁶.

Exocrine pancreatic insufficiency in cystic fibrosis can be treated by pancreatic enzyme replacement with cautious dosage increments in line with energy consumption ³⁷. Evidence suggests that replacement therapy improves survival among pancreatic cancer patients for both operable and non-operable tumors ³⁸.

A promising approach is the use of stem cell technology. It includes the use of pluripotent stem cells to produce pancreatic exocrine cells, but it still under research ³⁶.

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