Correspondence
Treatment of Gaucher's Disease
N Engl J Med 1993; 328:1564-1568May 27, 1993
- Article
To the Editor:
We are pleased that Figueroa et al. (Dec. 3 issue)1 have reaffirmed the effectiveness of alglucerase (Ceredase) in reducing the manifestations of Gaucher's disease with a previously published,2,3 relatively low-dose regimen. However, we believe that the data presented are not adequate to conclude that a lower-dose regimen with frequent administration is equivalent to a higher-dose regimen given every two weeks. The comparison of the data obtained in this study with those in other studies,4,5 though suggestive, is less than rigorous in providing convincing evidence of comparable responses to therapy. The variability in the progression and manifestations of Gaucher's disease makes comparisons between studies difficult, particularly when such small numbers of patients are included. Admittedly, the rarity of this disease does not encourage large-scale comparative trials. Thus, questions remain whether this lower-dose regimen provides an equivalent frequency, rate, or extent of response in patients with Gaucher's disease. Although some patients may respond to this regimen, others may require higher doses to achieve meaningful responses within reasonable time frames. In view of these difficulties it would be lamentable if the study by Figueroa et al. was used to limit access to effective doses of alglucerase for those patients who require it.
Endeavors to reduce the cost of this therapy are important. The use of doses of 60 U per kilogram of body weight every 2 weeks is likely to prove necessary only during the initial 6 to 12 months of therapy for severely ill patients. Progressive reductions in the dose should occur over each 6- to 12-month period; eventually, doses of 7.5 to 15 U per kilogram will be given every 2 weeks. Already most patients have had reductions in their doses toward the lower maintenance doses. Ironically, the regimen suggested by Figueroa et al. may prove more expensive over time. They may have underestimated the cost of infusion itself. Regimens requiring 156 to 365 infusions per year, rather than 26 per year, will prove more costly over the lifetime of the patient. The added inconvenience and effect on the lives of patients who must adhere to such frequent infusion schedules should not be considered lightly.
5 ReferencesRichard A. Moscicki, M.D.
Alison Taunton-Rigby, Ph.D.
Genzyme Corporation, Cambridge, MA 021391
Figueroa ML ,Rosenbloom BE ,Kay AC , et al. A less costly regimen of alglucerase to treat Gaucher's disease. N Engl J Med 1992;327:1632-1636
Full Text | Web of Science | Medline2
Beutler E ,Kay AC ,Saven A ,Garver P ,Thurston DW ,Rosenbloom BE . Enzyme-replacement therapy for Gaucher's disease. N Engl J Med 1991;325:1809-1810
Full Text | Web of Science | Medline3
Beutler E ,Kay A ,Saven A , et al. Enzyme replacement therapy for Gaucher disease. Blood 1991;78:1183-1189
Web of Science | Medline4
Barton NW ,Brady RO ,Dambrosia JM , et al. Replacement therapy for inherited enzyme deficiency -- macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med 1991;324:1464-1470
Full Text | Web of Science | Medline5
Fallet S ,Grace ME ,Sibille A , et al. Enzyme augmentation in moderate to life-threatening Gaucher disease. Pediatr Res 1992;31:496-502
Web of Science | Medline
To the Editor:
We have previously demonstrated in a single patient that the initial rate of clinical improvement and magnitude of response to alglucerase are dose-dependent1-3. Recently, we treated 10 patients with type 1 Gaucher's disease with alglucerase in an ongoing clinical trial at a dose of 10 U per kilogram every two weeks. The results were compared with the responses observed in patients given 60 U per kilogram every two weeks4. Only patients with spleens were chosen for study since the relative organ distribution of alglucerase in any given patient is likely to be influenced substantially by the presence or absence of the spleen. Clinical responses occurred at a dose of 10 U of alglucerase per kilogram every two weeks, but greater increases in hemoglobin concentration and reductions in organ volume occurred with the larger dose (Table 1Table 1
Hematologic and Visceral Responses after Six Months of Treatment with Various Doses of Alglucerase.).When these data are compared with those of Figueroa et al., the low-dose, high-frequency regimen is inferior to the dose of 60 U per kilogram given every two weeks except in terms of the reduction in liver volume. The hemoglobin response and reduction in splenic volume are either indistinguishable or slightly better with the higher dose than with the lower dose. This conclusion is inescapable when patients are scored as responding or not responding on the basis of clinical criteria (data not shown). Any advantages conferred by the low-dose, high-frequency regimen could well be explained by the larger cumulative dose of enzyme delivered (28 vs. 20 U every four weeks).
5 ReferencesNorman W. Barton, M.D., Ph.D.
Roscoe O. Brady, M.D.
James M. Dambrosia, Ph.D.
National Institute of Neurological Disorders and Stroke, Bethesda, MD 208921
Barton NW ,Furbish FS ,Murray GJ ,Garfield M ,Brady RO . Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci U S A 1990;87:1913-1916
CrossRef | Web of Science | Medline2
Parker RI ,Barton NW ,Read EJ ,Brady RO . Hematologic improvement in a patient with Gaucher disease on long-term enzyme replacement therapy: evidence for decreased splenic sequestration and improved red blood cell survival. Am J Hematol 1991;38:130-137
CrossRef | Web of Science | Medline3
Barton NW ,Brady RO ,Dambrosia JM , et al. Dose-dependent responses to macrophage-targeted glucocerebrosidase in a child with Gaucher disease. J Pediatr 1992;120:277-280
CrossRef | Web of Science | Medline4
Barton NW ,Brady RO ,Dambrosia JM , et al. Replacement therapy for inherited enzyme deficiency -- macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med 1991;324:1464-1470
Full Text | Web of Science | Medline5
Brownlee KA. Statistical theory and methodology in science and engineering. 2nd ed. New York: John Wiley, 1965:299-305.
To the Editor:
The article by Figueroa et al. confirms the effectiveness of alglucerase therapy in reversing the visceral manifestations of type 1 Gaucher's disease1-3. However, their low-dose data do not support the claim of equivalent or greater efficacy as compared with high-dose regimens1,3. Similarly, Garber's contention (Dec. 3 issue)4 that the low-dose regimen “should be considered the new standard” is unwarranted. Formal statistical analyses of the data of Figueroa et al. comparing liver-volume changes during low- and high-dose treatment with alglucerase (Table 2 of their article) would have shown a power of only 11 to 20 percent to support their claims. Also, approximately 70 percent of the selected patients from other studies (Figure 1 of their article) who received high doses1,3 had greater reductions in splenic volume than the three patients reported on by Figueroa et al. These considerations and the large variations in patient responses show that the data of Figueroa et al. are insufficient to make meaningful conclusions about comparative efficacy. Several hundred study patients would be needed to reach statistically significant conclusions. Furthermore, the calculations of the volume changes in visceral organs are flawed. The use of the percent change in excess volume greatly exaggerates the real decreases; for example, an absolute reduction of 30 percent in a patient whose liver volume is 130 percent of normal would produce a 100 percent decrease in the percent change in excess volume. Indeed, the two patients with relatively small livers had approximately 95 percent and 43 percent decreases in the percent change in excess volume, but the absolute decreases were only approximately 26 percent and 12 percent. Since the patients receiving high and low doses were not matched for liver volumes, direct comparisons of the percent change in excess volume were inappropriate.
The data of Figueroa et al. do confirm previous studies by the same group as well as others1-3 that demonstrate the efficacy of alglucerase. These studies further substantiate the great usefulness of alglucerase therapy for Gaucher's disease as well as the need to obtain stronger scientific data on its use and optimal effectiveness.
4 ReferencesGregory A. Grabowski, M.D.
Children's Hospital Medical Center, Cincinnati, OH 452291
Barton NW ,Brady RO ,Dambrosia JM , et al. Replacement therapy for inherited enzyme deficiency -- macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med 1991;324:1464-1470
Full Text | Web of Science | Medline2
Beutler E ,Kay A ,Saven A , et al. Enzyme replacement therapy for Gaucher disease. Blood 1991;78:1183-1189
Web of Science | Medline3
Fallet S ,Grace ME ,Sibille A , et al. Enzyme augmentation in moderate to life-threatening Gaucher disease. Pediatr Res 1992;31:496-502
Web of Science | Medline4
Garber AM . No price too high? N Engl J Med 1992;327:1676-1678
Full Text | Web of Science | Medline
To the Editor:
We report our experience with frequently administered low doses of alglucerase in nine adults with type 1 Gaucher's disease. The results after six months of treatment are presented in Table 1Table 1
Response of Patients with Gaucher's Disease to Alglucerase Treatment.. Patients 1, 2, 3, and 4 were treated with 4 U of alglucerase per kilogram three times weekly (total dose, 50 U per kilogram per month). A reduction in organomegaly, determined by ultrasonography (maximal length of liver, spleen, or both), and hematologic improvement occurred in all patients except Patient 1, whose spleen had been removed and whose blood-cell counts were unchanged.These satisfying results, as much as the importance of cost reduction, encouraged us to initiate a study to establish the lowest effective dose for every patient. For this reason, patients initially receive a very low dose of enzyme (1.15 U per kilogram three times weekly; total dose, 15 U per kilogram per month). At six-month intervals, the dose is adjusted according to hematologic and organ-volume responses. To allow for a more precise measurement of the change in organ size, computed tomography is performed instead of ultrasonography. The responses of patients 5, 6, 7, 8, and 9, treated with 1.15 U per kilogram of alglucerase for six months, are presented in Table 1 and show that even with an initial dose that is half that used by Figueroa et al., substantial therapeutic effects can be achieved.
Carla E.M. Hollak, M.D.
J.M.F.G. Aerts, Ph.D.
M.H.J. van Oers, M.D., Ph.D.
Academic Medical Centre, 1105 AZ Amsterdam, the NetherlandsTo the Editor:
We propose that the benefits of enzyme-replacement therapy with alglucerase are due to the direct clearance of glucocerebroside from plasma, rather than to either the targeting of mannose to macrophages1 or the interaction with high-affinity mannose receptors2.
Our hypothesis is supported by studies3 with unmodified glucocerebrosidase, in which both normalization of red-cell levels of glucocerebroside and reduction of hepatic glucocerebroside were observed within days after treatment with single infusions of “non-targeted” human placental enzyme. However, no clinical improvement accompanied the biochemical changes at these doses. The administration of significantly higher doses (60 IU per kilogram every two weeks) of mannose-terminated glucocerebrosidase1 improves hematologic variables, reduces hepatic and splenic volumes, and decreases plasma and red-cell concentrations of glucocerebroside, but generally only after four to six months of treatment. These results suggest that the erythrocyte and plasma glucocerebroside pools are in equilibrium with those of tissue. Similarly, the clinical response to the more frequent, lower doses administered by Figueroa et al. is consistent with our premise that alglucerase may not be acting through macrophage targeting, but rather by the clearance of glucocerebroside from plasma during the short time the enzyme remains in that compartment.
3 ReferencesEllen Sidransky, M.D.
Brian Martin, Ph.D.
Edward I. Ginns, M.D., Ph.D.
National Institute of Mental Health, Bethesda, MD 208921
Barton NW ,Brady RO ,Dambrosia JM , et al. Replacement therapy for inherited enzyme deficiency -- macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med 1991;324:1464-1470
Full Text | Web of Science | Medline2
Figueroa ML ,Rosenbloom BE ,Kay AC , et al. A less costly regimen of alglucerase to treat Gaucher's disease. N Engl J Med 1992;327:1632-1636
Full Text | Web of Science | Medline3
Brady RO ,Pentchev PG ,Gal AE ,Hibbert SR ,Dekaban AS . Replacement therapy for inherited enzyme deficiency: use of purified glucocerebrosidase in Gaucher's disease. N Engl J Med 1974;291:989-993
Full Text | Web of Science | Medline
To the Editor:
As a student, I naturally deplore flagrant profiteering by anyone in the medical community. Yet, as a Genzyme shareholder, I (and my educational creditors) have been well served by the sales of alglucerase and the financial acumen of Genzyme's officers. As with the subject of physician self-referral, perhaps it is time we reexamined not only the ethics of medical investment, but also the ethics of the companies in which we invest. Turning a profit is not a crime; turning a blind eye is.
David Ronald Freiwald
Tulane University, New Orleans, LA 70118To the Editor:
In his editorial Garber cited a figure of $231 million as the cost of bringing a “new chemical entity” to market. This number comes from a study by DiMasi and coworkers1. However, there are good reasons to believe that the cost for most drugs is substantially less. DiMasi et al. only considered new chemical entities researched and developed entirely by the company marketing the drug. The sample therefore left out new drugs that were developed conjointly with, or entirely by, government institutions, nonprofit institutions, and universities and drugs licensed from other companies. In fact, according to the DiMasi paper, research-and-development outlays for licensed or acquired new chemical entities were only one quarter of those for new chemical entities originated by the company marketing the drug. Only about 40 percent of all the new chemical entities introduced by American-owned companies are developed by the company marketing the drug. Furthermore, DiMasi et al. looked only at costs to U.S.-owned companies, excluding foreign-owned firms that may have different cost structures.
Over half the research-and-development costs computed by DiMasi et al. are “opportunity costs.” In the case of pharmaceutical manufacturing, opportunity costs are the value of the productive opportunities foregone by the decision to use the available resources to make drugs rather than invest the resources in some other endeavor.
The DiMasi study has recently been questioned by the Office of Technology Assessment2. A survey of 49 leading pharmaceutical companies in Europe, Japan, and the United States reinforces the skepticism of the Office of Technology Assessment. Of the 39 companies that responded to questions on the cost of researching and developing a new chemical entity, 13 firms gave estimates of less than $100 million, 19 companies estimated costs of $100 to $200 million, and the remaining 7 gave costs of more than $200 million3.
3 ReferencesJoel Lexchin, M.D.
121 Walmer Rd., Toronto, ON M5R 2X8, Canada1
DiMasi JA ,Hansen RW ,Grabowski HG ,Lasagna L . Cost of innovation in the pharmaceutical industry. J Health Econ 1991;10:107-142
CrossRef | Web of Science | Medline2
US OTA queries industry R&D cost data. Scrip No. 1614/15. May 8/10, 1991:20.
3
R&D strategy analysed. Scrip No. 1751. September 9, 1992:10-1.
Author/Editor Response
The authors reply:
To the Editor: Barton et al. studied only patients with Gaucher's disease who had not undergone splenectomy, although most patients with disease severe enough to treat have had their spleens removed, and Fallet et al.1 concluded that there was no difference in response between patients who had undergone splenectomy and those who had not. Nonetheless, Barton et al. have arbitrarily ignored 11 of our 14 patients and focused their analysis on merely 3. In spite of this, the data in their table clearly confirm the conclusion that there is virtually no difference between an alglucerase dose of 2.3 U per kilogram given three times weekly and one of 60 U per kilogram given every two weeks. The results of treatment with 10 U every two weeks are clearly inferior, indicating that the frequency of the dose is important, as we suggested.
The excellent results that Hollak et al. have obtained using low-dose fractionated therapy should reassure the correspondents who expressed concern about the number of patients studied. Figure 1Figure 1
Mean (±SE) Relative Reductions in Liver and Spleen Volumes (Corrected for Body Weight) after Six Months of Alglucerase Treatment at Various Dosages. summarizes all the available data. Frequent low-dose therapy is as effective as high-dose, low-frequency therapy, and statistical analysis rejects a hypothetical 20 percent advantage for low-frequency treatment with a dose that is 400 percent to 900 percent as large.We do not understand how anyone can predict with any confidence the maintenance dose of a drug that has been on the market for less than two years, especially when untreated patients commonly have no measurable disease progression for many years3. If, in fact, the large dose can be reduced, so can the smaller, equally effective dose that we recommend. We have begun to explore this possibility, and some of our patients are now receiving infusions only once or twice weekly.
The fact that the responses of different patients to drugs vary certainly does not justify starting therapy with the world's most expensive drug at the highest possible dose. Patients with severe disease respond to small doses as rapidly as those with mild disease; we have observed no treatment failures and have heard of only one. The cost of enzyme administration is minimized by the use of home therapy, which has, in our experience, been safe, effective, and economical. We know of more than 9000 low-dose infusions that have been given without a serious untoward event.
The hope is expressed that insurance companies will not be influenced by our results. But if insurance companies do not control the costs, who will?
We share the skepticism that Sidransky et al. express about the mode of action of alglucerase. In recent studies we found that only negligible amounts of alglucerase are taken up by macrophages in vitro or in vivo after large infusions. Binding is not to the classic mannose receptor, but rather to another receptor with a high copy number and wide distribution in tissue4. Since alglucerase is only very weakly targeted to macrophages, if at all, other approaches to treatment may prove to be more effective and less expensive.
4 ReferencesErnest Beutler, M.D.
Michael Figueroa, M.D.
James Koziol, Ph.D.
Scripps Research Institute, La Jolla, CA 920371
Fallet S ,Grace ME ,Sibille A , et al. Enzyme augmentation in moderate to life-threatening Gaucher disease. Pediatr Res 1992;31:496-502
Web of Science | Medline2
Zimran A ,Abrahamov A ,Goldberg M ,Beutler K . Home treatment with intravenous enzyme replacement therapy for patients with Gaucher disease. Blood 1992;80:428A-428A3
Zimran A ,Kay AC ,Gelbart T , et al. Gaucher disease: clinical, laboratory, radiologic, and genetic features of 53 patients. Medicine (Baltimore) 1992;71:337-353
CrossRef | Web of Science | Medline4
Sato Y, Beutler E. Binding, internalization and degradation of mannose-terminated glucocerebrosidase by macrophages. J Clin Invest (in press).
Author/Editor Response
Dr. Garber replies:
To the Editor: As Dr. Lexchin notes, estimates of the research-and-development costs of drugs vary widely. But there is no doubt that Genzyme spent less to develop alglucerase than is typical for a new drug. The Office of Technology Assessment recently reported that the average research-and-development costs are about $194 million1. Differences in the methods of imputing costs account for little of the $164 million by which this figure exceeds the amount that Genzyme spent.
When they claim that the Scripps regimen2 “may prove more expensive over time,” Drs. Moscicki and Taunton-Rigby assume that the dose will remain fixed, whereas the dose used in the low-frequency (National Institutes of Health [NIH]) regimen3 will progressively decline. But a dose reduction is possible with both regimens. Furthermore, a patient who begins treatment with the Scripps regimen could switch to a low-frequency maintenance regimen if and when the latter offered comparable effectiveness at lower cost. I do not know whether many patients could be switched, though, because the doses would have to be well below the ranges reported for low-frequency regimens. Regardless of the maintenance strategy, the expense of high initial doses makes the lifetime costs of the NIH regimen dramatically higher.
One can hope that more effective and less expensive alternative treatments will soon be available. Until then, how should patients with moderate or severe Gaucher's disease be treated? Available information suggests that as initial treatments, the NIH and Scripps regimens have roughly equivalent effectiveness. A potential exception is the hemoglobin concentration, which rose by 16 percent in the Scripps study, 36 percent in the study by Barton et al., and 30 percent in the study by Fallet and colleagues4. But blood transfusions confound the interpretation of the hemoglobin concentration. Patients treated with the Scripps regimen had decreases in liver volume (-18 percent) and increases in platelet counts (+37 percent) comparable to those reported by Barton et al. (-11 percent and +45 percent, respectively) and by Fallet et al. (-20 percent and +39 percent, respectively). Furthermore, because the NIH patients were treated for 9 to 12 months, as compared with 6 months in the Scripps study, they would be expected to have more favorable responses.
Clearly, we need larger, well-designed comparative studies to learn how each regimen affects the quality of life and mortality. But do existing data suggest that the NIH regimen is worth as much as $300,000 more in the first year of treatment for an adult? If there ever was a time when health care costs could be ignored, surely it has passed. Advocates of high-dose alglucerase regimens have yet to prove that better clinical results justify the staggering costs of their recommendations.
4 ReferencesAlan M. Garber, M.D., Ph.D.
Stanford University School of Medicine, Stanford, CA 943051
Office of Technology Assessment. Pharmaceutical R&D: costs, risks, and rewards. Washington, D.C.: Government Printing Office, 1993. (OTA-H-522).
2
Figueroa ML ,Rosenbloom BE ,Kay AC , et al. A less costly regimen of alglucerase to treat Gaucher's disease. N Engl J Med 1992;327:1632-1636
Full Text | Web of Science | Medline3
Barton NW ,Brady RO ,Dambrosia JM , et al. Replacement therapy for inherited enzyme deficiency -- macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med 1991;324:1464-1470
Full Text | Web of Science | Medline4
Fallet S ,Grace ME ,Sibille A , et al. Enzyme augmentation in moderate to life-threatening Gaucher disease. Pediatr Res 1992;31:496-502
Web of Science | Medline
- Citing Articles (13)
Citing Articles
1
Neal J Weinreb. (2008) Imiglucerase and its use for the treatment of Gaucher's disease. Expert Opinion on Pharmacotherapy 9:11, 1987-2000
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Ernest Beutler. (2006) Lysosomal storage diseases: Natural history and ethical and economic aspects. Molecular Genetics and Metabolism 88:3, 208-215
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Graham Sinclair, Tom A Pfeifer, Thomas A Grigliatti, Francis Y.M Choy. (2006) Secretion of human glucocerebrosidase from stable transformed insect cells using native signal sequences. Biochemistry and Cell Biology 84:2, 148-156
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Ernest Beutler. (2006) Gaucher disease: multiple lessons from a single gene disorder. Acta Paediatrica 95, 103-109
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Jin-Sung Lee. (2006) Treatment and management of patients with inherited metabolic diseases. Korean Journal of Pediatrics 49:11, 1152
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DP Germain. (2004) Gaucher's disease: a paradigm for interventional genetics. Clinical Genetics 65:2, 77-86
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Beate Harrison, Anne Margaret Moody, Paul L Harper. (1998) Were there metastases?. The Lancet 351:9113, 1402
CrossRef8
Carla E.M. Hollak, Ludo Evers, Johannes M.F.G. Aerts, Marinus H.J. van Oers. (1997) Elevated Levels of M-CSF, sCD14 and IL8 in Type 1 Gaucher Disease. Blood Cells, Molecules, and Diseases 23:2, 201-212
CrossRef9
Gregory M. Pastores, Sylvan Wallenstein, Robert J. Desnick, Marjorie M. Luckey. (1996) Bone density in type 1 gaucher disease. Journal of Bone and Mineral Research 11:11, 1801-1807
CrossRef10
DANUTA BALICKI, ERNEST BEUTLER. (1995) Gaucher Disease. Medicine 74:6, 305-323
CrossRef11
M Klein, P Kaminsky, M Duc. (1995) La maladie de Gaucher: aspects actuels. La Revue de Médecine Interne 16:6, 447-456
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C.E.M. Hollack, R. Goudsmith, M. Ek, A.E.R.Kr. von dem Borne, M.H.J. van Oers, J.M.F.G. Aerts, S. van Meely, S.S.K.S. Phoa. (1995) Individualised low-dose alglucerase therapy for type 1 Gaucher's disease. The Lancet 345:8963, 1474-1478
CrossRef13
B Bembi, E Agosti, M Zanatta, M Carrozzi, R Gornati, B Berra, F Baralle. (1994) Enzyme replacement treatment in type 1 and type 3 Gaucher's disease. The Lancet 344:8938, 1679-1682
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