Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints

Kakkis, Emil D; O’Donovan, Mary; Cox, Gerald; Hayes, Mark; Goodsaid, Federico; Tandon, PK; Furlong, Pat; Boynton, Susan; Bozic, Mladen; Orfali, May; Thornton, Mark

doi:10.1186/s13023-014-0195-4

Orphanet Journal of Rare Diseases

Table 2 Example of pathophysiologic maps linking disease cause to final clinical outcomes

From: Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints

Disease	Cause (gene or protein level)	1° Pathophys. (cell level)	2° Pathophys. (tissue level)	Clinical Physiology (system/organ)	Early Clinical (integrated systems)	Late Clinical (final major outcome/events)
Mucopolysaccharidosis type 1 (MPS 1)	IDUA gene mutations Reduce iduronidase enzymatic activity	Accumulation of heparan sulfate and dermatan sulfate GAG in cells and tissues	GAG infiltration of upper airway tissue	Sleep apnea, ↓O2	Sleep deprivation	Right heart failure
			GAG infiltration of lungs, liver, rib and spine development	Impaired PFT	Pulmonary insufficiency	Hospitalization/oxygen Increased respiratory infections
			Synovial storage	Joint ROM defect Nerve compression	Difficult hand mobility	Unable to do ADL Carpal tunnel syndrome requiring surgery
			Thick heart valve	Echocardiogram	Enlarged heart	Congestive heart failure
			Abnormal bone/joints formation	MR	Joint pain, stiffness, contractures	Wheelchair bound
				Dysostosis multiplex	Reduced growth rate	Orthopedic interventions
				Dysostosis multiplex	Reduced growth rate	Short stature
Phenylketonuria	Defect in PAH gene that expresses PAH that metabolizes Phe	↓Phe destruction leads to ↑Phenylalanine in blood	↑Phenylalanine causes cytotoxic effects	White matter abnormalities	Mild cognitive impairment	Advanced cognitive impairment
Phenylketonuria	Defect in PAH gene that expresses PAH that metabolizes Phe	↓Phe destruction leads to ↑Phenylalanine in blood	Myelin abnormalities	Altered neuro function	Mild cognitive impairment	Advanced cognitive impairment
Myasthenia gravis	Antibody to the AchR	Inhibition of Ach-based signaling	Muscle weakness	Drooping eyelids	Difficulty keeping eyes open for vision	Wheelchair bound Loss of ambulation
Myasthenia gravis	Antibody to the AchR	Inhibition of Ach-based signaling	Muscle weakness	Weak legs	Difficulty walking	Wheelchair bound Loss of ambulation
Duchenne muscular dystrophy	Genetic defect in dystrophin gene	Deficiency of dystrophin protein	Rupture of myofibrils	Muscle weakness	Gower’s sign
			Myopathy	Heart abnormality	Fatigue Decreased play	Heart failure Death
			Centrilobular nuclei	Decreased FVC Impaired PFT	Respiratory insufficiency	Ventilatory support
Alpha Dystroglycan related muscular dystrophy	Hypo-glycosylation of alpha dystroglycan	Defective binding to extracellular matrix, sarcolemmal membrane instability	Stem cell regenerative defect Muscle cell death	Decreased balance, walking, climbing stairs, rising from chair	Muscle weakness, impaired mobility	Wheelchair bound
Fabry Disease	Mutation α- galactosidase gene	Accumulation GL3 in lysosome	Multiple cells storage Small vessels storage (cardiomyocytes, podocytes etc.)	PNS	Acroparesthesia
				CNS	Stroke	Neurologic deficits
				Kidney	Proteinuria/injury	Renal failure
				Heart	Arrhythmia	Cardiac death

The table outlines 6 diseases as examples for pathophysiologic maps. The first column represents the disease, then the cause, the primary pathophysiologic outcome of the cause through other causes, clinical physiology and clinical outcomes. The table is intended to capture the known steps in a process, from which the location and relevance of a biomarker might be established and compared against. ADL is activities of daily living, CNS is central nervous system, FVC is forced vital capacity during pulmonary function testing, GAG is glycosaminoglycan, GI is gastrointestinal, PAH is phenylalanine hydroxylase, PNS is peripheral nervous system.

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ISSN: 1750-1172

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