manu/mldr-zoomed-100char-total-queries-documents

chunk_id stringlengths 3 9	chunk stringlengths 1 100
129_82	failure and respiratory weakness.
129_83	Late or later onset form occurs later than one to two years and progresses more slowly than
129_84	Infantile-onset form. One of the first symptoms is a progressive decrease in muscle strength
129_85	starting with the legs and moving to smaller muscles in the trunk and arms, such as the diaphragm
129_86	and other muscles required for breathing. Respiratory failure is the most common cause of death.
129_87	Enlargement of the heart muscles and rhythm disturbances are not significant features but do occur
129_88	in some cases.
129_89	Treatment
129_90	Cardiac and respiratory complications are treated symptomatically. Physical and occupational
129_91	therapy may be beneficial for some patients. Alterations in diet may provide temporary improvement
129_92	but will not alter the course of the disease. Genetic counseling can provide families with
129_93	information regarding risk in future pregnancies.
129_94	On April 28, 2006 the US Food and Drug Administration approved a Biologic License Application (BLA)
129_95	for alglucosidase alfa, rhGAA (Myozyme), the first treatment for patients with Pompe disease,
129_96	developed by a team of Duke University researchers. This was based on enzyme replacement therapy
129_97	using biologically active recombinant human alglucosidase alfa produced in Chinese Hamster Ovary
129_98	cells. Myozyme falls under the FDA Orphan Drug designation and was approved under a priority
129_99	review.
129_100	The FDA has approved Myozyme for administration by intravenous infusion of the solution. The safety
129_101	and efficacy of Myozyme were assessed in two separate clinical trials in 39 infantile-onset
129_102	patients with Pompe disease ranging in age from 1 month to 3.5 years at the time of the first
129_103	infusion. Myozyme treatment clearly prolongs ventilator-free survival and overall survival. Early
129_104	diagnosis and early treatment leads to much better outcomes. The treatment is not without side
129_105	effects which include fever, flushing, skin rash, increased heart rate and even shock; these
129_106	conditions, however, are usually manageable.
129_107	Myozyme costs an average of US$300,000 a year and must be taken for the patients' entire life, so
129_108	some American insurers have refused to pay for it. On August 14, 2006, Health Canada approved
129_109	Myozyme for the treatment of Pompe disease. On June 14, 2007 the Canadian Common Drug Review
129_110	issued their recommendations regarding public funding for Myozyme therapy. Their recommendation
129_111	was to provide funding to treat a very small subset of Pompe patients (Infants less one year of age
129_112	with cardiomyopathy).
129_113	On May 26, 2010 FDA approved Lumizyme, a similar version of Myozyme, for the treatment of
129_114	late-onset Pompe disease. Lumizyme and Myozyme have the same generic ingredient (alglucosidase
129_115	alfa) and manufacturer (Genzyme Corporation). The difference between these two products is in the
129_116	manufacturing process. Myozyme is made using a 160-L bioreactor, while Lumizyme uses a 4000-L
129_117	bioreactor. Because of the difference in the manufacturing process, the FDA claims that the two
129_118	products are biologically different. Moreover, Lumizyme is FDA approved as replacement therapy for
129_119	late-onset (noninfantile) Pompe disease without evidence of cardiac hypertrophy in people 8 years
129_120	and older. Myozyme is FDA approved for replacement therapy for infantile-onset Pompe disease.
129_121	In July 2021, the European Medicines Agency (EMA) recommended the authorization of avalglucosidase
129_122	alfa. Avalglucosidase alfa (Nexviazyme) was approved for medical use in the United States in August
129_123	2021.
129_124	Prognosis
129_125	The prognosis for individuals with Pompe disease varies according to the onset and severity of
129_126	symptoms, along with lifestyle factors. Without treatment the infantile form (which can typically
129_127	be predicted by mutation analysis) of the disease is particularly lethal - in these cases time to
129_128	get on treatment is critical, with evidence that days (not weeks or months) matter.
129_129	Myozyme (alglucosidase alfa) is a recombinant form of the human enzyme acid alpha-glucosidase, and
129_130	is also currently being used to replace the missing enzyme. In a study which included the largest
129_131	cohort of patients with Pompe disease treated with enzyme replacement therapy (ERT) to date
129_132	findings showed that Myozyme treatment clearly prolongs ventilator-free survival and overall
129_133	survival in patients with infantile-onset Pompe disease as compared to an untreated historical
129_134	control population. Furthermore, the study demonstrated that initiation of ERT prior to 6 months of
129_135	age, which could be facilitated by newborn screening, shows great promise to reduce the mortality
129_136	and disability associated with this devastating disorder. Taiwan and several states in the United
129_137	States have started the newborn screening and results of such regimen in early diagnosis and early
129_138	initiation of the therapy have dramatically improved the outcome of the disease; many of these
129_139	babies have reached the normal motor developmental milestones.
129_140	Another factor affecting the treatment response is generation of antibodies against the infused
129_141	enzyme, which is particularly severe in Pompe infants who have complete deficiency of the acid
129_142	alpha-glucosidase. Immune tolerance therapy to eliminate these antibodies has improved the
129_143	treatment outcome.
129_144	A Late Onset Treatment Study (LOTS) was published in 2010. The study was undertaken to evaluate the
129_145	safety and efficacy of aglucosidase alfa in juvenile and adult patients with Pompe disease. LOTS
129_146	was a randomized, double-blind, placebo-controlled study that enrolled 90 patients at eight primary
129_147	sites in the United States and Europe. Participants received either aglucosidase alfa or a placebo
129_148	every other week for 18 months. The average age of study participants was 44 years. The primary
129_149	efficacy endpoints of the study sought to determine the effect of Myozyme on functional endurance
129_150	as measured by the six-minute walk test and to determine the effect of aglucosidase alfa on
129_151	pulmonary function as measured by percent predicted forced vital capacity.
129_152	The results showed that, at 78 weeks, patients treated with aglucosidase alfa increased their
129_153	distance walked in six minutes by an average of approximately 25 meters as compared with the
129_154	placebo group which declined by 3 meters (P=0.03). The placebo group did not show any improvement
129_155	from baseline. The average baseline distance walked in six minutes in both groups was approximately
129_156	325 meters.
129_157	Percent predicted forced vital capacity in the group of patients treated with aglucosidase alfa
129_158	increased by 1.2 percent at 78 weeks. In contrast, it declined by approximately 2.2 percent in the
129_159	placebo group (P=0.006).
129_160	There is an emerging recognition of the role that diet and exercise can play in functionally
129_161	limiting symptom progression. This is an area for further study, as there is not a clear consensus
129_162	guideline, but rather a body of case study work that suggests that appropriate physical activity
129_163	can be an effective tool in managing disease progression. In one such study, side-alternating
129_164	vibration training was used 3 times per week for 15 weeks. The results showed that, at 15 weeks,
129_165	the patient had a 116 meter (70%) improvement to their 6MWT, which is significant compared with the
129_166	results from the aforementioned LOTS study.
129_167	Epidemiology The disease affects approximately 1 in 13,000. History
129_168	The disease is named after Joannes Cassianus Pompe, who characterized it in 1932. Pompe described
129_169	accumulation of glycogen in muscle tissue in some cases of a previously unknown disorder. This
129_170	accumulation was difficult to explain as the enzymes involved in the usual metabolism of glucose
129_171	and glycogen were all present and functioning.
129_172	The basis for the disease remained a puzzle until Christian de Duve's discovery of lysosomes in
129_173	1955 for which he won the Nobel Prize in 1974. His co-worker Henri G. Hers realised in 1965 that
129_174	the deficiency of a lysosomal enzyme (alpha glucosidase) for the breakdown of glycogen could
129_175	explain the symptoms of Pompe disease. This discovery led to establishing the concept of lysosomal
129_176	storage diseases, of which 49 have been described (to date).
129_177	Despite recognizing the basis for the disease, treatment proved difficult. Administration of the
129_178	enzyme lead to its uptake by the liver and not the muscle cells where it is needed. In the early
129_179	1990s Dutch scientists Arnold Reuser and Ans van der Ploeg were able to show that using
129_180	alpha-glucosidase containing phosphorylated mannose residues purified from bovine testes increased
129_181	the enzyme's activity in normal mouse muscles.

129_82

failure and respiratory weakness.

129_83

Late or later onset form occurs later than one to two years and progresses more slowly than

129_84

Infantile-onset form. One of the first symptoms is a progressive decrease in muscle strength

129_85

starting with the legs and moving to smaller muscles in the trunk and arms, such as the diaphragm

129_86

and other muscles required for breathing. Respiratory failure is the most common cause of death.

129_87

Enlargement of the heart muscles and rhythm disturbances are not significant features but do occur

129_88

in some cases.

129_89

Treatment

129_90

Cardiac and respiratory complications are treated symptomatically. Physical and occupational

129_91

therapy may be beneficial for some patients. Alterations in diet may provide temporary improvement

129_92

but will not alter the course of the disease. Genetic counseling can provide families with

129_93

information regarding risk in future pregnancies.

129_94

On April 28, 2006 the US Food and Drug Administration approved a Biologic License Application (BLA)

129_95

for alglucosidase alfa, rhGAA (Myozyme), the first treatment for patients with Pompe disease,

129_96

developed by a team of Duke University researchers. This was based on enzyme replacement therapy

129_97

using biologically active recombinant human alglucosidase alfa produced in Chinese Hamster Ovary

129_98

cells. Myozyme falls under the FDA Orphan Drug designation and was approved under a priority

129_99

review.

129_100

The FDA has approved Myozyme for administration by intravenous infusion of the solution. The safety

129_101

and efficacy of Myozyme were assessed in two separate clinical trials in 39 infantile-onset

129_102

patients with Pompe disease ranging in age from 1 month to 3.5 years at the time of the first

129_103

infusion. Myozyme treatment clearly prolongs ventilator-free survival and overall survival. Early

129_104

diagnosis and early treatment leads to much better outcomes. The treatment is not without side

129_105

effects which include fever, flushing, skin rash, increased heart rate and even shock; these

129_106

conditions, however, are usually manageable.

129_107

Myozyme costs an average of US$300,000 a year and must be taken for the patients' entire life, so

129_108

some American insurers have refused to pay for it. On August 14, 2006, Health Canada approved

129_109

Myozyme for the treatment of Pompe disease. On June 14, 2007 the Canadian Common Drug Review

129_110

issued their recommendations regarding public funding for Myozyme therapy. Their recommendation

129_111

was to provide funding to treat a very small subset of Pompe patients (Infants less one year of age

129_112

with cardiomyopathy).

129_113

On May 26, 2010 FDA approved Lumizyme, a similar version of Myozyme, for the treatment of

129_114

late-onset Pompe disease. Lumizyme and Myozyme have the same generic ingredient (alglucosidase

129_115

alfa) and manufacturer (Genzyme Corporation). The difference between these two products is in the

129_116

manufacturing process. Myozyme is made using a 160-L bioreactor, while Lumizyme uses a 4000-L

129_117

bioreactor. Because of the difference in the manufacturing process, the FDA claims that the two

129_118

products are biologically different. Moreover, Lumizyme is FDA approved as replacement therapy for

129_119

late-onset (noninfantile) Pompe disease without evidence of cardiac hypertrophy in people 8 years

129_120

and older. Myozyme is FDA approved for replacement therapy for infantile-onset Pompe disease.

129_121

In July 2021, the European Medicines Agency (EMA) recommended the authorization of avalglucosidase

129_122

alfa. Avalglucosidase alfa (Nexviazyme) was approved for medical use in the United States in August

129_123

2021.

129_124

Prognosis

129_125

The prognosis for individuals with Pompe disease varies according to the onset and severity of

129_126

symptoms, along with lifestyle factors. Without treatment the infantile form (which can typically

129_127

be predicted by mutation analysis) of the disease is particularly lethal - in these cases time to

129_128

get on treatment is critical, with evidence that days (not weeks or months) matter.

129_129

Myozyme (alglucosidase alfa) is a recombinant form of the human enzyme acid alpha-glucosidase, and

129_130

is also currently being used to replace the missing enzyme. In a study which included the largest

129_131

cohort of patients with Pompe disease treated with enzyme replacement therapy (ERT) to date

129_132

findings showed that Myozyme treatment clearly prolongs ventilator-free survival and overall

129_133

survival in patients with infantile-onset Pompe disease as compared to an untreated historical

129_134

control population. Furthermore, the study demonstrated that initiation of ERT prior to 6 months of

129_135

age, which could be facilitated by newborn screening, shows great promise to reduce the mortality

129_136

and disability associated with this devastating disorder. Taiwan and several states in the United

129_137

States have started the newborn screening and results of such regimen in early diagnosis and early

129_138

initiation of the therapy have dramatically improved the outcome of the disease; many of these

129_139

babies have reached the normal motor developmental milestones.

129_140

Another factor affecting the treatment response is generation of antibodies against the infused

129_141

enzyme, which is particularly severe in Pompe infants who have complete deficiency of the acid

129_142

alpha-glucosidase. Immune tolerance therapy to eliminate these antibodies has improved the

129_143

treatment outcome.

129_144

A Late Onset Treatment Study (LOTS) was published in 2010. The study was undertaken to evaluate the

129_145

safety and efficacy of aglucosidase alfa in juvenile and adult patients with Pompe disease. LOTS

129_146

was a randomized, double-blind, placebo-controlled study that enrolled 90 patients at eight primary

129_147

sites in the United States and Europe. Participants received either aglucosidase alfa or a placebo

129_148

every other week for 18 months. The average age of study participants was 44 years. The primary

129_149

efficacy endpoints of the study sought to determine the effect of Myozyme on functional endurance

129_150

as measured by the six-minute walk test and to determine the effect of aglucosidase alfa on

129_151

pulmonary function as measured by percent predicted forced vital capacity.

129_152

The results showed that, at 78 weeks, patients treated with aglucosidase alfa increased their

129_153

distance walked in six minutes by an average of approximately 25 meters as compared with the

129_154

placebo group which declined by 3 meters (P=0.03). The placebo group did not show any improvement

129_155

from baseline. The average baseline distance walked in six minutes in both groups was approximately

129_156

325 meters.

129_157

Percent predicted forced vital capacity in the group of patients treated with aglucosidase alfa

129_158

increased by 1.2 percent at 78 weeks. In contrast, it declined by approximately 2.2 percent in the

129_159

placebo group (P=0.006).

129_160

There is an emerging recognition of the role that diet and exercise can play in functionally

129_161

limiting symptom progression. This is an area for further study, as there is not a clear consensus

129_162

guideline, but rather a body of case study work that suggests that appropriate physical activity

129_163

can be an effective tool in managing disease progression. In one such study, side-alternating

129_164

vibration training was used 3 times per week for 15 weeks. The results showed that, at 15 weeks,

129_165

the patient had a 116 meter (70%) improvement to their 6MWT, which is significant compared with the

129_166

results from the aforementioned LOTS study.

129_167

Epidemiology The disease affects approximately 1 in 13,000. History

129_168

The disease is named after Joannes Cassianus Pompe, who characterized it in 1932. Pompe described

129_169

accumulation of glycogen in muscle tissue in some cases of a previously unknown disorder. This

129_170

accumulation was difficult to explain as the enzymes involved in the usual metabolism of glucose

129_171

and glycogen were all present and functioning.

129_172

The basis for the disease remained a puzzle until Christian de Duve's discovery of lysosomes in

129_173

1955 for which he won the Nobel Prize in 1974. His co-worker Henri G. Hers realised in 1965 that

129_174

the deficiency of a lysosomal enzyme (alpha glucosidase) for the breakdown of glycogen could

129_175

explain the symptoms of Pompe disease. This discovery led to establishing the concept of lysosomal

129_176

storage diseases, of which 49 have been described (to date).

129_177

Despite recognizing the basis for the disease, treatment proved difficult. Administration of the

129_178

enzyme lead to its uptake by the liver and not the muscle cells where it is needed. In the early

129_179

1990s Dutch scientists Arnold Reuser and Ans van der Ploeg were able to show that using

129_180

alpha-glucosidase containing phosphorylated mannose residues purified from bovine testes increased

129_181

the enzyme's activity in normal mouse muscles.