"Today, the U.S. Food and Drug Administration approved Kanuma (sebelipase alfa) as the first treatment for patients with a rare disease known as lysosomal acid lipase (LAL) deficiency.
Patients with LAL deficiency (also known as Wolman disea"...
Alpha1-antitrypsin deficiency is a chronic, hereditary, usually fatal, autosomal recessive disorder in which a low concentration of alpha1-PI (alpha1-antitrypsin) is associated with slowly progressive, severe panacinar emphysema that most often manifests itself in the third to fourth decades of life.2-9 [Although the terms “alpha1- Proteinase Inhibitor” and “alpha1-antitrypsin” are used interchangeably in the scientific literature, the hereditary disorder associated with a reduction in the serum level of alpha1-PI is conventionally referred to as “alpha1- antitrypsin deficiency” while the deficient protein is referred to as “Alpha1-Proteinase Inhibitor”10]. The emphysema is typically worse in the lower lung zones.4,8,9 The pathogenesis of development of emphysema in alpha1-antitrypsin deficiency is not well understood at this time. It is believed, however, to be due to a chronic biochemical imbalance between elastase (an enzyme capable of degrading elastin tissues, released by inflammatory cells, primarily neutrophils, in the lower respiratory tract) and alpha1-PI (the principal inhibitor of neutrophil elastase), which is deficient in alpha1-antitrypsin disease.11-15 As a result, it is believed that alveolar structures are unprotected from chronic exposure to elastase released from a chronic, low-level burden of neutrophils in the lower respiratory tract, resulting in progressive degradation of elastin tissues.11-15 The eventual outcome is the development of emphysema. Neonatal hepatitis with cholestatic jaundice appears in approximately 10% of newborns with alpha1-antitrypsin deficiency.15 In some adults, alpha1- antitrypsin deficiency is complicated by cirrhosis.15
A large number of phenotypic variants of alpha1-antitrypsin deficiency exists.15 The most severely affected individuals are those with the PiZZ variant, typically characterized by alpha1-PI serum levels 35%normal.15 Epidemiologic studies of individuals with various phenotypes of alpha1-antitrypsin deficiency have demonstrated that individuals with endogenous serum levels of alpha1-PI 50 mg/dL (based on commercial standards) have a risk of 80% of developing emphysema over a lifetime.3-6,8,9,16 However, individuals with endogenous alpha1-PI levels 80 mg/dL, in general, do not manifest an increased risk for development of emphysema above the general population background risk.5,15 From these observations, it is believed that the “threshold” level of alpha1-PI in the serum required to provide adequate anti-elastase activity in the lung of individuals with alpha1-antitrypsin deficiency is about 80 mg/dL (based on commercial standards for immunologic assay of alpha1-PI).12,15,17
In clinical studies of Alpha1-Proteinase Inhibitor (Human), Prolastin (alpha) , 23 subjects with the PiZZ variant of congenital deficiency of alpha1-antitrypsin deficiency and documented destructive lung disease participated in a study of acute and/or chronic replacement therapy with Prolastin.18 The mean in vivo recovery of alpha1-PI was 4.2 mg (immunologic)/dL per mg (functional)/kg body weight administered.18,19 The half-life of alpha1-PI in vivo was approximately 4.5 days.18,19 Based on these observations, a program of chronic replacement therapy was developed. Nineteen of the subjects in these studies received Prolastin (alpha) replacement therapy, 60 mg/kg body weight, once weekly for up to 26 weeks (average 24 weeks of therapy). With this schedule of replacement therapy, blood levels of alpha1-PI were maintained above 80 mg/dL (based on the commercial standards for alpha1-PI immunologic assay).18-20 Within a few weeks of commencing this program, bronchoalveolar lavage studies demonstrated significantly increased levels of alpha1-PI and functional antineutrophil elastase capacity in the epithelial lining fluid of the lower respiratory tract of the lung, as compared to levels prior to commencing the program of chronic replacement therapy with Alpha1-Proteinase Inhibitor (Human), Prolastin (alpha) .18-20
All 23 individuals who participated in the investigations were immunized with Hepatitis B Vaccine and received a single dose of Hepatitis B Immune Globulin (Human) on entry into the investigation. Although no other steps were taken to prevent hepatitis, neither hepatitis B nor non-A, non-B hepatitis occurred in any of the subjects.18,19 All subjects remained seronegative for HIV antibody. None of the subjects developed any detectable antibody to alpha1-PI or other serum protein.
Long-term controlled clinical trials to evaluate the effect of chronic replacement therapy with Prolastin (alpha) on the development of or progression of emphysema in patients with congenital alpha1-antitrypsin deficiency have not been performed. Estimates of the sample size required of this rare disorder and the slow, progressive nature of the clinical course have been considered impediments in the ability to conduct such a trial.21 Studies to monitor the long-term effects will continue as part of the postapproval process.
2. Laurell CB, Eriksson S: The electrophoretic alpha1-globulin pattern of serum in alpha1-antitrypsin deficiency. Scand J Clin Lab Invest 15:132-40, 1963.
3. Eriksson S: Pulmonary emphysema and alpha1-antitrypsin deficiency. Acta Med Scand 175(2):197-205, 1964.
4. Eriksson S: Studies in alpha1-antitrypsin deficiency. Acta Med Scand Suppl 432:1-85, 1965.
5. Kueppers F, Black LF: alpha1-antitrypsin and its deficiency. Am Rev Respir Dis 110(2):176-94, 1974.
6. Morse JO: alpha1-antitrypsin deficiency. N Engl J Med 299:1045-8; 1099-105, 1978.
7. Black LF, Kueppers F: alpha1-antitrypsin deficiency in nonsmokers. Am Rev Respir Dis 117(3):421-8, 1978.
8. Tobin MJ, Cook PJ, Hutchison DC: alpha1-antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z. A survey by the British Thoracic Association. Br J Dis Chest 77(1):14-27, 1983.
9. Larsson C: Natural history and life expectancy in severe alpha1-antitrypsin deficiency, Pi Z. Acta Med Scand 204(5): 345-51, 1978.
10. Pannell R, Johnson D, Travis J: Isolation and properties of human plasma alpha1-proteinase inhibitor. Biochemistry13(26):5439-45, 1974.
11. Lieberman J: Elastase, collagenase, emphysema, and alpha1-antitrypsin deficiency. Chest 70(1):62-7, 1976.
12. Gadek JE, Fells GA, Zimmerman RL, et al: Antielastases of the human alveolar structures: implications for the protease-antiprotease theory of emphysema. J Clin Invest 68(4):889-98, 1981.
13. Beatty K, Bieth J, Travis J: Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin. J Biol Chem 255(9):3931-4, 1980.
14. Janoff A, White R, Carp H, et al: Lung injury induced by leukocytic proteases. Am J Pathol 97(1):111-36, 1979.
15. Gadek JE, Crystal RG: alpha1-antitrypsin deficiency. In: Stanbury JB, Wyngaarden JB, Frederickson DS, et al, eds.: The Metabolic Basis of Inherited Disease. 5th ed. New York, McGraw-Hill, 1983, p.1450-67.
16. Larsson C, Dirksen H, Sundstrom G, et al: Lung function studies in asymptomatic individuals with moderately (Pi SZ) and severely (Pi Z) reduced levels of alpha1-antitrypsin. Scand J Respir Dis 57(6):267-80, 1976.
17. Gadek JE, Klein HG, Holland PV, et al: Replacement therapy of alpha1-antitrypsin deficiency: reversal of pro- tease-antiprotease imbalance within the alveolar structures of PiZ subjects. J Clin Invest 68(5): 1158-65, 1981.
18. Data on file.
19. Wewers MD, Casolaro MA, Sellers SE, et al: Replacement therapy for alpha1-antitrypsin deficiency associated with emphysema. N Engl J Med 316(17): 1055-62,1987.
20. Wewers MD, Casolaro MA, Crystal RG: Comparison of alpha-1-antitrypsin levels and antineutrophil elastase capacity of blood and lung in a patient with the alpha-1-antitrypsin phenotype null-null before and during alpha-1-antitrypsin augmentation therapy. Am Rev Respir Dis 135(3):539-43, 1987.
21. Burrows B: A clinical trial of efficacy of antiproteolytic therapy: can it be done? Am Rev Respir Dis 127(2:2): S42-3, 1983.
Last reviewed on RxList: 10/6/2008
This monograph has been modified to include the generic and brand name in many instances.
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