Table 2.
Characteristics of Dose‐Finding Studies in Drugs for Metabolic Diseases
| Drug (Year) | Generic Name | Disease | Healthy Volunteers | End Points | Doses Tested in Phase 1–2 Studies | Dose in Phase 3 Studies | Studies in Special Populations | Dose SmPC | Dose Changes Postmarketing |
|---|---|---|---|---|---|---|---|---|---|
| Fabrazymeb (2001) | Agalsidase beta | Fabry disease | Noa | Plasma GL‐3 levels | EOW: 0.3, 1.0 or 3.0 mg/kg. EOD: 1.0 or 3.0 mg/kg | 1 mg/kg EOW | No | 1 mg/kg EOW | No |
| Replagalb (2001) | Agalsidase alfa | Fabry disease | Noa | Liver GL‐3 content and α‐Gal A activity, plasma + urine GL‐3 levels | 0.007, 0.014, 0.028, 0.056, 0.110 mg/kg | 0.2 mg/kg | No | 0.2 mg/kg EOW | No |
| Zavescab (2002) | Miglustat | Gaucher disease | No | Organ volume, biochemical parameters | 100 mg TID (In another study, 50 mg TID was used.) | 100 mg TID | Not reported | Adults: 100 mg TID | No |
| Aldurazymeb (2003) | Laronidase | MPS 1 | Noa | n/a | n/a | n/a | No, but justified | 100 U/kg EOW | No |
| Carbaglub (2003) | Carglumic acid | NAGS deficiency | Yes | n/a | n/a | n/a | Yes; children | Start: 100 mg/[kg·d], up to 250 mg/kg if necessary. Maintenance dose 10–100 mg/[kg·d]. | No |
| Carbaglub (2011) | Carglumic acid | Organic acidurias | Yes | n/a | n/a | n/a | Yes; children | Start: 100 mg/[kg·d], up to 250 mg/kg if necessary. Then individually adjusted. | No |
| Wilzin (2004) | Zinc | Wilson disease | Yes | Copper balance (the daily dietary intake of copper minus its daily excretion) | 25 mg OD, 25 mg BID, 25 mg TID, 25 QID, 25 mg 6 times/d, 37.5 mg BID, 50 mg OD, 50 mg BID, 50 mg TID, 50 mg 5 times/d, 75 mg OD | 50 mg TID | Yes; children, elderly. Patients with renal/hepatic impairment | Adults (>16 y): 50 mg TID with a maximum dose of 50 mg 5 times daily; 1–6 y: 25 mg BID; 6–16 y: 25 mg TID | No |
| Orfadinb (2005) | Nitisinone | Hereditary tyrosinemia type 1 | Yes | Urinary‐SA, Plasma‐SA, PBG‐synthase, urinary 5‐ALA, α‐fetoprotein, liver function, tyrosine | 0.1 to 0.6 mg/kg | 0.6 mg/kg | No | 1 mg/[kg·d] (divided in 2 doses) | Yes |
| Zavescab (2006) | Miglustat | Niemann‐Pick C | No | n/a | n/a | n/a | No, but justified | >12 y: 200 mg TID. <12 y: based on body surface area | n/a |
| Naglazymeb (2006) | Galsulfase | MPS 6 | Noa | 6‐MWT, FVC and FEV1, height, weight, JROM, grip strength, pinch gauge, urinary GAGs, hepatomegaly, bone mineral density, visual acuity, cardiac function, sleep apnea, CHAQ/HAQ | 0.2 and 1 mg/kg | 1 mg/kg | No | 1 mg/kg weekly | No |
| Myozyme (2006) | Alglucosidase alfa | Pompe disease | Noa | Primary: % patients alive and free of invasive ventilator support at 12 months of age. Secondary: cardiomyopathy (LVMI), weight, length, and head circumference. | 20 and 40 mg/kg EOW | 20 mg/kg | No | 20 mg/kg EOW | No |
| Elapraseb (2007) | Idursulfase | MPS 2 | NR | Liver and spleen volumes, pulmonary function, urinary GAGs, safety | 0.15, 0.5, or 1.5 mg/kg or pbo | 0.5 mg/kg | No | 0.5 mg/[kg·wk] | No |
| Cystadane (2007) | Betaine anhydrous | Homocystinuria | Yes | n/a | n/a | n/a | No | 100 mg/[kg·d] given in 2 doses daily | No |
| Kuvan (2008) | Sapropterin | PKU | Yes | Safety, tolerability, blood Phe levels | 5, 10 or 20 mg/[kg·d] | 10 and 20 mg/kg | No | Start: 10 mg/[kg·d], adjusted between 5 and 20 mg/[kg·d] | No |
| Vpriv (2010) | Velaglucerase alfa | Gaucher disease type 1 | Noa | Hgb, platelet counts, liver and spleen volume, chitotriosidase, CCL18, pulmonary function, bone density, bone marrow | 15, 30, and 60 U/kg | 60 U/kg | No | 60 U/kg EOW | No |
| Revestive (2012) | Teduglutide | Short bowel syndrome | Yes | Gastrointestinal absorption, structural changes in intestinal mucosa | 0.03, 0.10, 0.15, 0.10 or 0.15, 0.10 mg/[kg·d] | 0.05 mg/[kg·d] and 0.10 mg/[kg·d] | Yes; children, patients with renal/hepatic impairment | 0.05 mg/[kg·d] | No |
| Orphacolb (2013) | Cholic acid | Errors in bile acid synthesis | Yes | n/a | n/a | n/a | No | 5 to 15 mg/[kg·d] | n/a |
| Procysbi (2013) | Mercaptamine | Cystinosis | Yes | WBC cysteine levels, safety and tolerability | 75 mg procysbi vs 150 mg cystagon | Dose equal to approximately 70% of their usual dose of cystagon | No, but justified | Maintenance dose 1.3 g/[m2·d], in 2 divided doses | No |
| Kolbamb (2014) | Cholic acid | Errors in bile acid synthesis | Yes | n/a | n/a | n/a | No | 10–15 mg/[kg·d] | n/a |
| Vimizim (2014) | Elosulfase alfa | MPS 4a | Noa | 6‐MWT, 3‐MSCT, FVC, urine KS, HAQ | 0.1, 1, or 2 mg/[kg·wk] | 2 mg/[kg·wk] | No | 2 mg/[kg·wk] | No |
| Cerdelga (2015) | Eliglustat | Gaucher disease type 1 | Yes | n/a | n/a | n/a | Yes; elderly | 84 mg (100 mg eliglustat tartrate) OD in CYP2D6 PMs; 84 mg BID in CYP2D6 IMs and EMs | No |
| Kanuma (2015) | Sebelipase alfa | LAL deficiency | Noa | Safety, tolerability, PK, PD, survival at 12 months of age | 0.35, 1, and 3 mg/kg | 1 mg/kg EOW | Yes; patients with renal/hepatic impairment | <6 mo: 1 mg/[kg·wk]; >6 mo: 1 mg/kg EOW | No |
| Ravicti (2015) | Glycerol phenylbutyrate | Urea cycle disorders | Yes | n/a | n/a | n/a | Yes; patients with hepatic impairment | 4.5 mL/[m2·d] to 11.2 mL/[m2·d] | No |
| Strensiqb (2015) | Asfotase alfa | Hypophosphatasiab | No | n/a | n/a | n/a | No | 2 mg/kg 3 times per week or 1 mg/kg 6 times per week | No |
| Galafold (2016) | Migalastat | Fabry disease | Yes | α‐Gal A activity in leukocytes, PBMCs, kidney, and skin. GL‐3 in urine, kidney, plasma, and skin | BID: 25, 100, 250 mg. OD: 50 mg. EOD: 50, 150, 250 mg. 3 days on–4 days off: 250, 500 mg | 150 mg EOD | Yes; patients with renal impairment | 123 mg EOD | No |
| Ocalivac (2016) | Obeticholic acid | Biliary liver cirrhosis | Yes | Primary: % change in serum ALP from baseline | 10, 25, and 50 mg or pbo | 5 and 10 mg | Yes; elderly, patients with renal/hepatic impairment | 5 mg OD, increased to 10 mg OD | No |
| Chenodeoxycholic acidb (2017) | Chenodeoxycholic acid | CTX | No | n/a | n/a | n/a | No | Adults: 750 mg/d, increased to max 1000 mg/d. Infants (1 mo–18 y) 5 mg/[kg·d] in 3 divided doses | No |
| Brineurab (2017) | Cerliponase alfa | NCL | No | n/a | n/a | n/a | No, but justified | 300 mg EOW | No |
3‐MSCT indicates 3‐minute stair climb test; 5‐ALA, 5‐aminolevulinic acid; 6‐MWT, 6‐minute walk test; α‐Gal A, α‐galactosidase A; ALP, alkaline phosphatase; BID, twice daily; C, conditional; CCL18, CC chemokine ligand 18; CHAQ, Childhood Health Assessment Questionnaire; CTX, cerebrotendinous canthomatosis; CYP2D6, cytochrome P450 2D6; EM, extensive metabolizers; EOD, every other day; EOW, every other week; ERT, enzyme replacement therapy; F, full; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GAG, glycosaminoglycan; GL‐3, globotriaosylceramide; HAQ, health assessment questionnaire; Hgb, hemoglobin; IM, intermediate metabolizers; JROM, joint range of motion; KS, keratan sulfate; LAL, lysosomal acid lipase; LVMI, left ventricular mass index; MPS, mucopolysaccharidosis; n/a, not applicable; NAGS, N‐acetylglutamate synthetase; NCL, neuronal ceroid‐lipofuscinoses; NR, not reported; OD, once daily; PBG, porphobilinogen; PBMC, peripheral blood mononuclear cell; pbo, placebo; PD, pharmacodynamics; Phe, phenylalanine; PK, pharmacokinetics; PKU, phenylketonuria; PM, poor metabolizers; QID, 4 times daily; SA, succinylacetone; SmPC, summary of product characteristics; TID, 3 times daily; U, units; WBC, white blood cell.
ERTs are not tested in healthy subjects due to the risk of immunogenicity.
Marketing authorization under exceptional circumstances.
Conditional marketing authorization.