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Table 1 FDA approved compounds for lysosomal storage disorders, endpoints and design of clinical trials

From: Pressure for drug development in lysosomal storage disorders – a quantitative analysis thirty years beyond the US orphan drug act

Disease

Compound

Therapeutic class

Endpoints in pivotal studies

Primary neurological endpoints

Biomarker endpoints

Regulatory precedent

Pivotal trial design

Ref.

MPS I

Laronidase

Enzyme

Forced vital capacity (% of predicted), 6 min walk distance

No

No

No

RCT, 26 weeks, N = 45, mean age 15.5 years (range 6 – 43 years)

[24]

MPS II

Idursulfase

Enzyme

Forced vital capacity (% of predicted), 6 min walk distance

No

No

Yes

RCT, 53 weeks, N = 96, mean age 14.2 years (range 5–31 years)

[25]

MPS VI

Galsulfase

Enzyme

12 min walk distance, 3 min stair climb test (stairs/min)

No

No

Yes

RCT, 24 weeks, N = 39, (age range 5–29 years)

[26]

Gaucher disease type I

Alglucerase

Enzyme

Liver and spleen volume change, Hematologic deficiencies, improved mineralization of bone, cachexia and wasting

No

Yes

No

OLT, 36 – 52 weeks, N = 13, mean age 20.3 years (range 7–42 years)

[27]

Gaucher disease

Imiglucerase

Enzyme

Anemia and thrombocytopenia, liver and spleen volume change, decreased cachexia

No

Yes

Yes

RCT, 26 weeks, N = 30, mean age 32.7 years (range 12 – 69 years)

[28]

Gaucher disease

Taliglucerase alfa

Enzyme

Hemoglobin concentration, platelet count, liver and spleen volume change

No

Yes

Yes

RCT, 36 weeks, N = 32, mean age 36.2 years (range 19 – 74 years)

[29]

Gaucher disease

Velaglucerase alfa

Enzyme

Hemoglobin concentration, platelet count, liver and spleen volume change

No

Yes

Yes

RCT, N = 25, 52 weeks, median age 25 years, (range 4–62 years)

[30]

Gaucher disease

Miglustat

Substrate reduction

Liver and spleen volume change, hemoglobin concentration, platelet count

No

Yes

Yes

OLT, 52 weeks, N = 28, mean age 44 years (range 22–69 years)

[31]

Fabry disease

Agalsidase beta

Enzyme

Reduction of GL-3 inclusions in capillary endothelium of kidney, heart and skin

No

Yes

No

RCT, 20 weeks, N = 58, mean age 30.2 years (range 16–61 years)

[32]

Pompe disease

Alglucosidase alfa

Enzyme (bioreactor size: 160 L)

Number of patients who died or needed invasive ventilator support

No

No

No

OLT, 52–106 weeks, N = 18, age range 1 month to 3.5 years

[33]

Pompe disease

Alglucosidase alfa

Enzyme (bioreactor size: 4000 L)

Forced vital capacity (% of predicted), 6 min walking distance

No

No

No

RCT, 78 weeks, N = 90, mean age 44.4 years (range 10–70 years)

[34]

Cystinosis

Cysteamine bitartrate IR

Small molecule

Serum creatinine, calculated creatinine clearance, growth (height)

No

Yes

No

OLT, N = 94, mean age 3.8 years

[35]

Cystinosis

Cysteamine ophtalmic solution

Small molecule

Corneal Cystine Crystal Score

No

Yes

No

OLT, N = 283 (three studies)

[36]

Cystinosis

Cysteamine bitartrate DR

Small molecule

White blood cell cystine

No

Yes

Yes

RCT, N = 43, mean age 12 years (range 6 – 26 years)

[37]

  1. RCT – randomized controlled trial, OLT – open label trial, IR – immediate release, DR – delayed-release, GL-3 – globotriaosylceramide.