**3. Experience in humans: first experiences of compassionate use of cyclodextrin**

Based on the promising results of preclinical studies in animal models of NPD-C, in November 2008, Dr Hastings applied for individual investigator new drug exemptions (INDs) to the Food and Drug Administration (FDA) for the use of with HP-β-CD in humans. In January 2009, the first NPD-C patient in the world, an Indian child, was treated with HP-β-CD by intravenous (IV) route. Few months later, the first two INDs of HP-β-CD in USA were approved by FDA for two identical twins aged 5-year-old [26]. The "Oakland protocol" of IV HP-β-CD employed in USA was also used in two Brazilian sisters with NPD-C in January 2010 [27].

The orphan designation of HP-β-CD was obtained in May 2010 by FDA [28] and 2 months later by the European Medicines Agency (EMA) [29]. The orphan drug brand Trappsol® Cyclo™ was approved specifically for treating NPD-C. New findings suggested that the passage of HP-β-CD across the BBB was limited [21, 24, 25, 30], and physicians who treated the first patients reported slight benefit with IV route [26]. The FDA approved the request for IT delivery of HP-β-CD in September 2010 [31]. Another orphan drug of HP-β-CD was designated by FDA in February 2013, Kleptose™ (brand VTS-270). Both drugs were being evaluated in clinical trials, moreover compassionate use outside clinical trials has been reported worldwide [32].

Five different approaches have been employed in HP-β-CD therapy:

• IV only.

disease progression, and extends lifespan. Studies in adult Npc1−/− mice who received four weekly subcutaneous 4000 mg/kg body weight HP-β-CD at 49 days of age showed reduced whole-liver cholesterol content at 77 days. Comparable improvements were seen in other organs, such as spleen, and lifespan was extended [20]. On the whole, preclinical studies in animals showed that young animals respond more favorably, whereas the older ones may

Brain uptake of 2-hydroxypropyl-[14 C]-propyl-β-cyclodextrin was determined in Npc+/+ and Npc1−/− mice using two methods: *in situ* brain perfusion and multi-time-point regression analysis flowing intraperitoneal administration. None of the data collected indicated that HP-β-CD enters the brain [21]. Other experiments examining cyclodextrins with regard to permeability using an *in vitro* model of the BBB have indicated that a small percentage of

Intrathecal (IT) HP-β-CD (120 mg in 0.6 ml saline) every 2 weeks therapy of feline NPD-C delayed the clinical manifestations of neurological disease, but had no effect on hepatic or pulmonary disease. IT-treated cats showed amelioration of neuronal swelling and axonal spheroid formation in many but not all brain regions, and preservation of Purkinje cell numbers [23]. Research in mouse models of NPD-C also has shown that direct administration of HP-β-CD into the IT or intracerebroventricular (ICV) space at low concentrations has a similar or superior effect on delaying the onset of neurological symptoms as that observed

Recent researches in NPD-C cats showed that direct administration of HP-β-CD into the cisterna magna prevented the onset of cerebellar dysfunction for greater than a year and reduced in Purkinje cell loss and near normal concentrations of cholesterol and sphingolipids. Cats receiving 1000 mg/kg SC HP-β-CD had a similar occurrence of neurological dysfunction and survival than untreated cats. Nevertheless, cats that received 4000 mg/kg SC HP-β-CD showed modest amelioration of neurological disease and survived age than any untreated cats. Pulmonary toxicity limited the continued dosing of cats in the 8000 mg/kg group. Dose-dependent elevations in mean hearing threshold in cats receiving SC HP-β-CD were observed. In cats receiving intracisternal HP-β-CD, a significant elevation in the audi-

**3. Experience in humans: first experiences of compassionate use of** 

Based on the promising results of preclinical studies in animal models of NPD-C, in November 2008, Dr Hastings applied for individual investigator new drug exemptions (INDs) to the Food and Drug Administration (FDA) for the use of with HP-β-CD in humans. In January 2009, the first NPD-C patient in the world, an Indian child, was treated with HP-β-CD by intravenous (IV) route. Few months later, the first two INDs of HP-β-CD in USA were approved by FDA for two identical twins aged 5-year-old [26]. The "Oakland protocol" of IV HP-β-CD employed in USA was also used in two Brazilian sisters with NPD-C in January 2010 [27].

cyclodextrin may be transported across the barrier [22].

following high systemic doses [24].

tory threshold was also observed. [25].

**cyclodextrin**

benefit less.

100 Cyclodextrin - A Versatile Ingredient


The IV administration was the first route tested for HP-β-CD in humans. When different reports in animals demonstrated that HP-β-CD administered intravenously cross in very little proportion the BBB [21, 24, 25, 30], this route was changed or combined with IT/ICV administration of the same drug. Theoretically, IT and ICV routes deliver directly the drug in the central nervous system (CNS), the area mainly affected in NPD-C, especially in the neurological symptoms. There is still controversy over whether the IV route contributes in NPD-C therapy. Preclinical reports showed effectiveness in the peripheral manifestations of the disease in organs [20, 25], including the liver, the spleen, and, to a lesser extent, the lungs. However, the influence of HP-β-CD in CNS after IV infusion remains in humans unknown.
