Pompe Disease (Sanofi Portfolio in rare diseases, Ukraine)

1. Sanofi's portfolio in rare diseases (Ukraine). Focus on Pompe disease, differential diagnosis and treatment Oleksandr Illiuchok 04.12.2019 ?1

2. Outline ✤ Sanofi today, Sanofi Ukraiine ✤ Rare Diseases, Sanofi interest, Genzime ✤ Sanofi portfolio in rare disease ✤ Rare disease definition, criteria ✤ Pompe Disease ✤ Epedemiology ✤ Etiology ✤ Patogenesis ✤ Clinical manifestation ✤ Diagnostic methods ✤ Differential Diagnostic ✤ Management ✤ Sanofi-Genzime Humanitarian Program.

3. Sanofi Today (1,4) Founded; 20 August 2004. Headquarters: Paris, France (1) merger Sanofi-Synthélabo Aventis ✤ More than 100 000 employees ✤ Representing 145 nationalities ✤ Present in 100 countries ✤ 75 manufactoring sites in 33 countries ✤ Providing healthcare solutions in more than 170 countries around the World ✤ 5 Global business units and majors healthcare areas

4. Area of interest (5) SANOFI-Brochure-partnering-2019.pdf

5. ✤ Sanofi Ukraine(2) ✤ 26.12.2007 officially was registered in Ukraine(3) ✤ The company has been operating in Ukraine for over 20 years and is a leading international pharmaceutical company in the Ukrainian market. ✤ Nearly 450 employees work in Sanofi, Ukraine. ✤ Sanofi's main activity in Ukraine is focused on the following therapeutic areas: Diabetes, rare diseases, OTC drugs, cardiovascular disease, oncology, vaccines.

6. Rare Disease SANOFI-Brochure-partnering-2019.pdf

7. ✤ Sanofi’s portfolio in Rare Diseases ✤ Sanofi’s portfolio includes more than 25 specialized products aimed at providing innovative treatments for unmet medical needs worldwide. (6)

8. Portfolio of lysosomal diseases storage in Ukraine. (11,12)

9. Rare disease definition and characteristic (13) ✤ In Europe a disease or disorder is defined as rare when it affects less than 1 in 2000 citizens. (Orphan drug regulation 141/2000) (EURORDIS-Rare Diseases Europe). ✤ Rare diseases are often chronic, progressive, degenerative, and often life-threatening; ✤ Rare diseases are disabling: the quality of life of patients is often compromised by the lack or loss of autonomy; ✤ High level of pain and suffering for the patient and his/her family; ✤ No existing effective cure; ✤ There are between 6,000 and 8,000 rare diseases; ✤ 75% of rare diseases affect children; ✤ 30% of rare disease patients die before the age of 5; ✤ 80% of rare diseases have identified genetic origins; ✤ Other rare diseases are the result of infections (bacterial or viral), allergies and environment.

10. Lysosomal storage disorders and Pompe Disease(15,16,17,18,19) ✤ Lysosomal storage disorders (LSDs) are a group of inborn metabolic diseases caused by mutations in genes that encode proteins involved in different lysosomal functions, in most instances acidic hydrolases. ✤ Lysosomal storage disorders (LSDs) represent a heterogeneous group of more than 50 distinct diseases, each of which results from functional deficiency of a particular lysosomal protein. ✤ 15 of them known as Glycogen storage disease ✤ The first Glycogenesis was described in 1929 by Edgar von Hirke. Glycogenesis is the process of glycogen synthesis, in which glucose molecules are added to chains of glycogen for storage. ✤ First glycogen storage disease to be identified, in 1932 by the Dutch pathologist Joannes Cassianus Pompe ✤ Glycogen storage disease is a group of hereditary diseases caused by defects in enzymes and other proteins involved in glycogen metabolism. ✤ Pompe disease, Acid Alpha-Glucosidase Deficiency, Acid Maltase Deficiency, Glycogen Storage Disease Type II (GSD II), Glycogenosis Type II, affected are lysosomes of all organs. ✤ More than 200 mutations in the GAA gene have been identified in people with Pompe disease. Many of these mutations change one of the protein building blocks (amino acids) used to make acid alpha-glucosidase. Other mutations insert or delete genetic material in the GAA gene. Mutations in this gene significantly reduce the activity of acid alpha-glucosidase, preventing the enzyme from breaking down glycogen effectively. As a result, this complex sugar can build up to toxic levels in lysosomes. The abnormal buildup of glycogen damages organs and tissues throughout the body, particularly the muscles, leading to progressive muscle weakness, heart problems, and the other features of Pompe disease.

11. Pompe Disease Geographically (14,17,18) ✤ It is estimated that between 5,000 and 10,000 have Pompe Disease Worldwide. ✤ Incidence of infantile-onset Pompe disease in Australia 1:140000, Portugal 1:600000, Netherlands 1:40,000 combined 1:138,000 infantile onset1:57,000 adult onset, USA 1:40000, China and Taiwan 1:50000 and African-Americans Countries 1:14000, European descent 1:100,000 infantile onset, 1:60,000 late onset, ✤ As of 2019, there are eight patients in Ukraine diagnosed with Pompe disease. (23) 1: 5000000?

12. Causes (18,19) ✤ Pompe disease is inherited in an autosomal recessive manner. ✤ Pompe disease is caused by pathogenic variations in the acid alpha- glucosidase (GAA) gene. Close to 500 different GAA gene variations have been identified in families with this disorder. ✤ Males and females are equally likely to be affected. ✤ Carrier parents have a 1 in 4 or 25% chance with each pregnancy, to have an affected child, a 50% chance to have a child who is a carrier, and a 25% chance to have a child who is not affected nor a carrier. Parents who have had a child with Pompe disease are obligate carriers.

13. Clinical characteristics (17,18) Pompe disease can be classified by age of onset, organ involvement, severity, and rate of progression: muscle weakness (myopathy) poor muscle tone (hypotonia) enlarged liver (hepatomegaly heart defects infantile-onset (classic infantile,1\3 of all idividualss) fail to gain weight and grow at the expected rate (failure to thrive) and havebreathing problems. Pompe disease leads to death from heart failure in the first year of life. begins within a few months of birth The heart may be abnormally large (cardiomegaly), but affected individuals usually do not experience heart failure, one- third of all individuals, or damage to the heart muscle progresses more slowly. The muscle weakness in this disorder leads to serious breathing problems non-classic infantile- onset, delayed motor skills (such as rolling over and sitting) and progressive muscle weakness most children with non- classic infantile-onset Pompe disease live only into early childhood. usually appears by age 1 Most individuals with late-onset Pompe disease experience progressive muscle weakness, especially in the legs and the trunk, including the muscles that control breathing. usually milder than the infantile-onset forms of this disorder and is less likely to involve the heart. As the disorder progresses, breathing problems can lead to respiratory failure. may not become apparent until later in childhood adolescence, or adulthood late-onset

14. Nomenclature Description (22) ✤ Historically, IOPD (now defined as onset before age 12 months with cardiomyopathy) was further divided into classic form (severe with onset age <12 months with clinically significant cardiomyopathy) and “non- classic” or infantile form (onset age <12 months but without cardiomyopathy) [Slonim et al 2000]. Most children with “non-classic IOPD” are now classified as LOPD (i.e., onset age <12 months without cardiomyopathy as well as all individuals with onset of myopathy age >12 months).

15. The infantile-onset type of Pompe disease. Less than 2% of functional acid alpha-glucosidase enzyme (18,19,22) Hypotonia/muscle weakness 52%-96% Cardiomegaly 92%-100% Hepatomegaly 29%-90% Left ventricular hypertrophy 83%-100% Cardiomyopathy 88% Respiratory distress 41%-78% Murmur 46%-75% Enlarged tongue (macroglossia) 29%-62% Feeding difficulties 57% Failure to thrive 53% Absent deep tendon reflexes 33%-35% Normal cognition 95%

16. The late-onset form of Pompe disease. Between 2%-40% of functional acid alpha-glucosidase enzyme(18,19) Progressive proximal muscle weakness (95%) [Winkel et al 2005] Respiratory insufficiency Exercise intolerance Exertional dyspnea Orthopnea Sleep apnea Hyperlordosis and/or scoliosis Hepatomegaly (childhood and juvenile onset) Macroglossia (childhood onset) Difficulty chewing and swallowing GI symptoms, including irritable bowel-like symptoms Chronic pain Increased respiratory infections Decreased deep tendon reflexes

17. ✤ Suggestive Findings ✤ Infantile-onset and late-onset Pompe disease are suspected in individuals with the following clinical findings and supportive laboratory findings. ✤ Clinical Findings ✤ Infantile-onset Pompe disease: (Poor feeding/failure to thrive (44%-97% of cases) ✤ Motor delay/muscle weakness (20%-63%) ✤ Respiratory infections/difficulty (27%-78%) ✤ Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy) (50%-92%) ✤ Late-onset Pompe disease (LOPD) is suspected in infants, children, and adults with proximal muscular weakness and respiratory insufficiency without clinically apparent cardiac involvement.

18. Diagnostic (18) 1. A diagnosis of Pompe disease is first suggested by a person’s symptoms such as muscle weakness, fatigue, and breathing problems. In adults, Pompe disease may be confused or misdiagnosed as other chronic muscle diseases such as multiple sclerosis, limb-girdle muscular dystrophy and polymyositis. 2. In infants and children, Pompe disease may be confused with other types of muscular dystrophy. Confirmation of the diagnosis can be made by examining the activity of acid alpha glucosidase in cultured skin cells, muscle, or blood. 3. Prenatal diagnosis is available for families who already have one affected child with Pompe disease is the disease-causing mutation has been previously identified. Genetic counseling is highly recommended for couples before achieving a pregnancy to discuss testing options. Standard prenatal chromosome analysis (from an amniocentesis or CVS) does NOT detect Pompe disease!

19. ✤ supportive laboratory findings.(22,24) ✤ Positive newborn screening (NBS) results. Rapid and sensitive analysis of acid alpha-glucosidase (GAA) enzyme activity can be performed on dried blood spots when using standard conditions, or molecular genetic testing, measurement of GAA activity in another tissue (e.g., cultured skin fibroblasts) has been regarded as a “gold standard” for enzymatic diagnosis of Pompe disease, newer methodology using mass spectrometry suggests that blood-based assays may be comparable. ✤ Serum creatine kinase (CK) concentration is elevated (as high as 2000 IU/L; normal: 60-305 IU/L) in all individuals with IOPD and in some with LOPD (it may be normal in LOPD) [Laforêt et al 2000, Kishnani et al 2006b]. Because elevated serum CK concentration is observed in many conditions, it must be considered nonspecific. ✤ Urinary oligosaccharides. Elevation of the specific urinary glucose, tetrasaccharide, is a highly sensitive finding in IOPD; however, it is also seen in other glycogen storage diseases [An et al 2000, Kallwass et al 2007, Young et al 2012]. Sensitivity is diminished in LOPD [Young et al 2009]. Of note: Urinary oligosaccharides have been useful in evaluating infants with an abnormal result on NBS ✤ Laboratory testing to help in the initial evaluation of a patient suspected of having Pompe disease, regardless of the type, should include serum creatine kinase (CK), AST, ALT, LDH, and urine for Glc4 may also be useful. ✤ Analysis of leukocyte vacuoles for glycogen by PAS staining is an inexpensive, quick and reliable test for Pompe disease used in some centers. ✤ Molecular analysis may be helpful in selected cases. Determination of the common late-onset splice site mutation is useful in Caucasians.

20. Other tests ✤ Electrophysiologic studies. Myopathy can be documented by electromyography (EMG) in all forms of Pompe disease although some muscles may appear normal. In adults, needle EMG of the paraspinal muscles may be required to demonstrate abnormalities [Hobson-Webb et al 2011]. ✤ Muscle biopsy. In contrast to the other glycogen storage disorders, Pompe disease is also a lysosomal storage disease. In Pompe disease glycogen storage may be observed in the lysosomes of muscle cells as vacuoles of varying severity that stain positively with periodic acid-Schiff. ✤ Genotype-Phenotype Correlations. GAA enzyme activity may correlate with age of onset and rate of progression

23. Differential Diagnosis Infantile-Onset Pompe Disease (IOPD) ✤ Late-Onset Pompe Disease ✤ (LOPD) Limb-girdle muscular dystrophy. Spinal muscular atrophy ✤ ✤ Duchenne-Becker muscular dystrophy Danon disease ✤ ✤ Polymyositis Carnitine uptake disorder ✤ ✤ Glycogen storage disease type V Glycogen storage disease type IIIa ✤ ✤ Glycogen storage disease type VI Glycogen storage disease type IV ✤ ✤ Hypertrophic cardiomyopathy ✤ Myocarditis ✤ Mitochondrial/respiratory chain disorders ✤

24. ✤ Management of Pompe Disease ✤ Pompe disease is a multi-system disorder and is best managed by a multidisciplinary team led by a physician with experience managing this disorder. ✤ Team members should include a metabolic disease specialist/ biochemical geneticist in addition to the specialists dictated by the disease manifestations, which might include a cardiologist, pulmonologist, neurologist, neuromuscular specialist, intensivist, orthopedist, respiratory therapist, physical therapist, occupational therapist, otolaryngologist speech therapist, audiologist, genetic counselor, and a metabolic dietitian. ✤Approch: Treatment of manifestations,Prevention of primary manifestations,Prevention of secondary complications

25. ✤Treatment of manifestations(21) ✤ Management guidelines from the American College of Medical Genetics: individualized care of cardiomyopathy as standard drugs may be contraindicated and risk for tachyarrhythmia and sudden death is high; physical therapy for muscle weakness to maintain range of motion and assist in ambulation; surgery for contractures as needed; nutrition/feeding support. Respiratory support may include inspiratory/expiratory training in affected adults, CPAP, BiPAP, and/or tracheostomy.

26. Treatment of manifestations (19,21) At this time there is no cure for Pompe disease. There is one FDA approved treatment called Myozyme which is an enzyme replacement therapy produced by Genzyme Therapeutics. Enzyme replacement therapy (ERT) works by replacing some of the missing enzyme in Pompe disease patients’ bodies through lifetime IV infusions of Myozyme every other week. ERT improves the symptoms of Pompe disease in many patients but not all. In some patients ERT will decrease heart size, maintain normal heart function, improve muscle function, tone, and strength, and reduce glycogen accumulation. ✤ ERT requires lifelong intravenous infusion, with frequent hospital admissions, need for central venous devices (and related risk of infections), and high costs ✤ ERT shows limitations, particularly in terms of restricted bioavailability, insufficient correction of disease pathology in some muscles, tolerability issues, and immunogenicity.

27. ✤ Prevention of primary manifestations ✤ Prevention of primary manifestations: Begin enzyme replacement therapy (ERT) with alglucosidase alfa as soon as the diagnosis is established. Of note, ERT can be accompanied by infusion reactions (which are treatable) as well as anaphylaxis. Infants at high risk for development of antibodies to the therapeutic enzyme are likely to need immunomodulation early in the treatment course. ✤ IOPD. In the pivotal trial, a majority of infants in whom ERT was initiated before age six months and before the need for ventilatory assistance showed improved survival, ventilator-independent survival, improved acquisition of motor skills, and reduced cardiac mass compared to untreated controls. More recent data suggest that initiation of ERT before age two weeks may improve motor outcomes in the first two years of life, even when compared to infants in whom treatment was initiated only ten days later. ✤ LOPD. ERT may stabilize the functions most likely to be lost: respiration and motor ability.

28. ✤ Prevention of secondary complications ✤ Prevention of secondary complications: Aggressive management of infections; keeping immunizations up to date; annual influenza vaccination of the affected individual and household members; respiratory syncytial virus (RSV) prophylaxis (palivizumab) in the first two years of life; use of anesthesia only when absolutely necessary. ✤ Surveillance: Routine monitoring of respiratory status, cardiovascular status, musculoskeletal function (including bone densitometry), nutrition and feeding, renal function, and hearing. ✤ Agents/circumstances to avoid: Digoxin, ionotropes, diuretics, and afterload- reducing agents, as they may worsen left ventricular outflow obstruction in some stages of the disease; hypotension and volume depletion; exposure to infectious agents.

29. Prospective treatment of Pompe Disease (8,9,20) ✤ Registration of Avalglucosidase alfa - for Late Onset Pompe Disease is expected in second Quartal 2020, by resulting of 4 trials. ✤ BioMarin Pharmaceutical Company. Late-onset Pompe Disease. Drug: BMN 701. Phase 3. Terminated (Sponsor decision) ✤ Pharmacological chaperone therapy (PCT) is an emerging approach based on small-molecule ligands that selectively bind and stabilize mutant enzymes, increase their cellular levels, and improve lysosomal trafficking and activity. A Study to Evaluate the Effects of Pharmacological Chaperones in Cells From Patients With Pompe Disease 2007-2008, Amicus Therapeutics. No result published ✤ Drug-drug Interaction Study. Drug: Duvoglustat and Drug: rhGAA (recombinant human alpha-glucosidase). Sponsor:. Amicus Therapeutics. Results 2011, abated 02.10.2018 ✤ A Pilot Study of Zavesca® in Patients With Pompe Disease and Infusion Associated Reaction. Sponsor: University of Florida. Collaborator: Amicus Therapeutics. Terminated (Participants not interested in enrolling.) December 5, 2018 ✤

30. Myozyme (25,26) ✤ How is Myozyme given? ✤ Myozyme is injected into a vein through an IV. A healthcare provider will give you this injection. Myozyme must be given slowly, and the IV infusion can take up to 4 hours to complete. ✤ This medicine is usually given once every 2 weeks. ✤ Before each injection, tell your doctor if you have recently been sick with a cold, flu, or other illness. ✤ If you need surgery, tell the surgeon ahead of time that you are using Myozyme. ✤ Myozyme can have long lasting effects on your body. Your blood will need to be tested every 3 months for 2 years and then once every year after that. ✤ Myozyme dosing information ✤ Usual Adult Dose of Myozyme for Pompe disease: ✤ 20 mg/kg via IV infusion every 2 weeks ✤ MYOZYME should be diluted in 0.9% Sodium Chloride for Injection ✤ The total volume of infusion is determined by the patient’s body weight and should be administered over approximately 4 hours. (2mg\30 - max 7/mg/ kg/30min) 01

31. (10)

32. SanofiGenzyme Sofiyka Baranovska is one of eight patients in Ukraine diagnosed with Pompe disease.

33. ✤ Sanofi Genzyme ✤ For over 35 years, Sanofi Genzyme has been one of the world's leading players in the field of biotechnology, specializing in the development and manufacture of rare disease drugs. ✤ Our commitment is to provide patients with not just medicines but complex therapeutic solutions. These include: ✤ Sponsoring surveillance programs for patients with Gaucher, Fabry, MPS I, and Pompe disease to obtain up-to-date clinical data worldwide to improve medical understanding of these diseases. ✤ Improve diagnosis of rare diseases by training physicians, educational programs and supporting testing and screening initiatives. ✤ Collaborate with patient organizations around the world to better understand the needs of patients with rare diseases. ✤ Supporting a global humanitarian program to facilitate access to treatment for patients in need when treatment access is restricted.

34. ✤ Sofiyka Baranovska is one of eight patients in Ukraine diagnosed with Pompe disease. ✤ In order to be fully lived she is require weekly therapy. ✤ Medication is provided by the state, but there are interruptions in deliveries. Then Sonia weakens, failures begin to occur in her organs, and all successes in development are nullified. ✤ This would not have happened if it had not been for the public procurement procedure - medicines can only be ordered after they begin to expire. ✤ And before delivery has yet to survive. And so - every time.

35. ✤ Sofia outwardly is actually no different from other children of this age. Although she is a little thinner than others, she does not visit gardens, but loves to interact with peers, draw, watch cartoons, and play with dishes. The only thing that catches the eye of the playground is she is crawling, and her other five-year-olds are long gone. ✤ When Sophia was diagnosed with Pompe disease, she was 7 months old. For the first few months, her mother, Daria, was crying continuously, and her father was silent. "We didn't talk to anyone, we didn't play on the playgrounds, because it was hard to look at healthy kids," Darya recalls. and small. " ✤ It only got worse. The baby stopped growing and weakened in the eyes. And then she got bronchitis and went to hospital. Doctors noticed that all internal organs in Sofia were enlarged, suspected pathology of the heart. ✤ You can say that Sony is lucky. The day before in Cherkassy, Sanofi Genzyme held a conference for doctors on the topic of genetic diseases. "We were told something similar at a conference," one of the doctors doubted when she saw the symptoms and advised her to go to Kiev in Ohmatdit. There, Sonja was examined by cardiologists, neurologists and geneticists and two weeks later diagnosed with Pompe disease. ✤ The first two years, we received the drug as a humanitarian aid from the pharmaceutical company "Sanofi Genzyme", - says Dasha. - It saved Sonia's life

36. Conclusions ✤ The diagnostic and differentiation of Pompe Disease is quite difficult and required medical awareness, good equipment and implementation of the newest screening tests. (NBS) ✤ As soon diagnoses were established ERT therapy should start. The “gold standard" is Myozyme drug ✤ For support, normal quality of Life, a Team of specialist should provide Management of a patient with Pompe Diseases ✤ If you are parents, keep preventive care, but try to treat your child as a normal kid, it helps avoid psychological problems which dramatically aggravate Disease. ✤ Because of all burdens, the State should support patients like this through Life. Also, provide an informational campaign about Stigma bias.

37. References ✤ 1. https://www.sanofi.com/en ✤ 2. https://www.sanofi.ua/uk/about-us/sanofi-in-ukraine ✤ 3. 3. https://youcontrol.com.ua/catalog/company_details/35648623/- YouControl — сервісперевіркиконтрагентів. ✤ 4. https://www.sanofi.ua/-/media/Project/One-Sanofi-Web/Websites/Europe/Sanofi-UA/uk/about-us/our-responsibility/Code-of- Conduct-for-Suppliers.pdf ✤ 5. https://www.sanofi.com/-/media/Project/One-Sanofi-Web/Websites/Global/Sanofi-COM/Home/common/docs/science-and- innovation/SANOFI-Brochure-partnering-2019.pdf?la=en&hash=1D2BEBA71A0FE278626028B4CDF0C57C ✤ 6. https://www.sanofigenzyme.com/en/products-research/product-portfolio ✤ 7. https://www.sanofi.com/-/media/Project/One-Sanofi-Web/Websites/Global/Sanofi-COM/Home/en/investors/docs/press-releases/ Q42018results.pdf?la=en&hash=9E677FE77C61BB895BCC44A229407ED8 ✤ 8. https://www.slideshare.net/Sanofi/q3-2019-results ✤ 9. https://www.sanofi.com/en/investors/financial-results-and-events/financial-results/Q3-results-2019 ✤ 10. https://www.adlittle.at/en/maximizing-rare-chance-launch-success-orphan-drugs. Arthur D Little Austria. Maximizing the rare chance of launch success with orphan drugs. A strategic approach to achieving launch excellence and success for rare-disease medicines. January 2019 ✤ 11. Громадськаспілка"ОрфаннізахворюванняУкраїни”, https://www.facebook.com/orphandisua/

38. ✤ 12. МІНІСТЕРСТВООХОРОНИЗДОРОВ'ЯУКРАЇНИ. Департаментфармацевтичноїдіяльності. Державнийекспертний центрМіністерстваохорониздоров'яУкраїни. ”ДержавнийреєстрлікарськихзасобівУкраїни”. Інформаційнийфонд. 02.12.2019 http://www.drlz.com.ua/ibp/ddsite.nsf/all/shlist?opendocument ✤ 13. EURORDIS-Rare Diseases Europe. https://www.eurordis.org/content/what-rare-disease ✤ 14. Global Pompe Disease Market Insights, Epidemiology and Market Forecast Re[prt 2019-2028https://www.prnewswire.com/ news-releases/global-pompe-disease-market-insights-epidemiology-and-market-forecast-reprt-2019-2028-300907752.html ✤ 15. https://uk.wikipedia.org/wiki/ %D0%93%D0%BB%D1%96%D0%BA%D0%BE%D0%B3%D0%B5%D0%BD%D0%BE%D0%B7%D0%B8#CITEREFNelson_et_al2008. Глікогенози ✤ 16. https://en.wikipedia.org/wiki/Glycogen_storage_disease#Types ✤ 17. Pompe disease diagnosis and management guideline. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110959/pdf/ 16702877.pdf. 2006. ✤ 18. Emonu University School of medicine . Department of Rare diseases. Emory Lysosomal and Peroxisomal Storage Disease center » Pompe Disease. http://genetics.emory.edu/patient-care/lysosomal-storage-disease-center/pompe-disease.html ✤ 19. Pompe Disease Incidence. Pompe Disease News. https://pompediseasenews.com/pompe-disease-incidence-varies-by-world- region-and-ethnicity/ Sedef Iskit. ✤ 20. US National Library of Medicine. https://www.clinicaltrials.gov/ct2/results? cond=Pompe+Disease&age_v=&gndr=&type=&rslt=With&phase=2&phase=3&Search=Apply ✤ 21. Pharmacological Chaperone Therapy: Preclinical Development, Clinical Translation, and Prospects for the Treatment of Lysosomal Storage Disorders. Giancarlo Parenti,1,2,* Generoso Andria,1 and Kenneth J Valenzano3. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC4817787/. ✤ 22. Pompe Disease. Synonyms: Acid Alpha-Glucosidase Deficiency, Acid Maltase Deficiency, GAA Deficiency, Glycogen Storage Disease Type II (GSD II), Glycogenosis Type II. Pompe Disease. https://www.ncbi.nlm.nih.gov/books/NBK1261/. ✤ 23. УкраїнськаПравда. https://life.pravda.com.ua/projects/sanofi/2019/08/19/237926/.

39. 24. Pompe disease diagnosis and management guideline. 2006. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC3110959/ ✤ 25. https://gm-global.in/products/intravenous-infusion/myozyme-alglucosidase-alfa-50mg/ ✤ 26. https://www.drugs.com/dosage/myozyme.html ✤

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