**4. Experience in humans: efficacy of the intravenous administration of cyclodextrin**

The first two patients who received IV HP-β-CD (Trappsol® Cyclo™) in USA were treated since April 2009 with 2500 mg/kg weekly over 8 hours, and later modified to administrations every 2 weeks for convenience. The twins were diagnosed at 3 years old with initial symptoms of hepatosplenomegaly, ataxia and seizure activity, and previously were treated with miglustat, without significant benefits. After 18 months of therapy, any objective improvement was reported, and the disease continued to progress as evidenced by positron emission tomography (PET) imaging and neurological assessments [26]. Both patients were described a transient appearance of slight scattered nodules in lungs during bronchoscopy, which were identified as xanthomas, a deposition of yellowish cholesterol-rich material typical of NPD-C, resolved without treatment changes in IV therapy [32].

In October 2010, the FDA allowed the addition of HP-β-CD IT administration at doses of 350 mg every 2 weeks (initial dose 175 mg/2 weeks) [32, 33]. During the first months of concurrent IV/IT therapy, a significant improvement was observed in the validated NIH NPC Clinical Severity Score (NNCSS), as well as in the brainstem auditory evoked response (BAER) [33]. After 18 months, ICV route was authorized by FDA in the twins through an Ommaya reservoir system. One of them tolerated perfectly the ICV and continues today with the treatment, whereas in her sister, ICV was discarded by insertion bleeding and IT route was recovered. Both patients have experienced improvements in alertness, swallow, head control, and ataxia [32, 34].

The second reported use of IV HP-β-CD (Trappsol® Cyclo™) was in two Brazilian sisters at age of 12 and 16 years old with concomitant miglustat treatment. Dr Vieira employed the same IV protocol with a dose escalation from 1200 to 2500 mg/kg/week. Both patients showed, after 1 year of treatment, objective benefits in PET and NNCSS, as well as improvements in motor dysfunction, cataplexy, psychiatric symptoms, behavior, cognitive functions, and memory [27]. Two later reports informed about the simultaneous treatment with IV weekly and IT twice monthly at least 3 years, maintaining the good results previously reported with IV infusions [35, 36]. No adverse events (AEs) were reported, although the published data were limited and only congress abstracts were reported [27, 35, 36].

than previous scores before initiation, whereas the other patient reported a stabilization of NNCSS after IV therapy. In two patients with IV/IT therapy significant decrease in NNCSS were observed comparing pre and post-therapy scores. In the other seven patients was only available post-therapy information, showing in most of the cases an initial de decrease in NNCSS followed with a progressive increase. Other significant improvements were reported, as reduction in hepatomegaly, restoration of language skills, resolution of interstitial lung disease and improvements in fine motor control. The tolerability was favorable,

**Other AEs of interest**

http://dx.doi.org/10.5772/intechopen.71970

103

Port-a-Cath infection Removal of Ommaya

Post-operative delayed Parenchymal hemorrhage

Reservoir

Use of 2-Hydroxypropyl-Beta-Cyclodextrin for Niemann-Pick Type C Disease

Meningitis

Despite the positive results observed in the compassionate use of IV HP-β-CD [26, 27, 32–39], there is no clear evidence to date that IV route has a clinical benefit in CNS symptoms of NPD-C in humans. Most of the reports with neurological improvements combined the use of IV and IT/ICV administrations, making it impossible to demonstrate that these benefits were exclusively associated to IV and not IT/ICV. In addition, doses 1000 times larger than the IT dose should be required to achieve the same concentrations in the CSF reached by IT administration with IV infusions of HP-β-CD. This dosage would probably be unsafe in humans.

**5. Experience in humans: efficacy of the intrathecal administration of** 

The IT route was proposed when the efficacy of IV infusions of HP-β-CD was questioned. The first cases of IT administrations were combined with IV, as we previously explained [33–37, 39]. At this point, IT route was proposed as the main route for NPD-C therapy. The first published case report of IT HP-β-CD (Trappsol® Cyclo™) administration was a Spanish girl diagnosed and treated at 2 years old. The dosage varied from 200 to 450 mg every 2 weeks. At 38 months an IT Ommaya reservoir (IT-OR) was implanted in order to increase patient convenience and reduce number of punctures, modifying the dosage to 400 mg every 2 weeks. The patient showed improvements in BAER test, whereas neurological symptoms and NNCSS were stabilized. The patient suffered two episodes of seizures with a fever with IT therapy, resolved without any change in treatment and which could be related to HP-β-CD, the pro-

although some AEs were reported during 6 years of therapy (**Table 1**).

**AEs associated with administration AEs recognized as features of** 

**Table 1.** Adverse events related to IV with/without IT HP-β-CD administrations.

**NPD-C**

Seizures Pneumonia Thrombocytopenia Viral illnesses Viral syndrome

**cyclodextrin**

Rash

Headache Nausea Stomach pain

Generalized rash (trunk, elbow) Tremor/chills/vomiting/fever

cedure or the disease [40].

Two reported cases of Japanese NPD-C patients diagnosed at 2 months and 13 years were initially treated at 4 and 14 years old with the IV "Oakland protocol", with doses from 80 mg to 2500 mg/kg/three or two times a week, respectively [37, 38]. These were the first published cases of VTS-270 use in NPD-C. The younger patient reported with IV administration, a mild decrease in hepatosplenomegaly and temporary improvements in EEG and stabilization of disability scores the first 6 months. However, rest of the 2 years with only IV infusions a rapid progression of neurological dysfunction and worsening of swallow, speech, rigidity, and seizures were reported [37]. Furthermore, repeated fever with transient diffuse pulmonary cloudiness episodes were observed, an AE probably related to HP-β-CD IV infusion. After 2 years of IV therapy, IT first and later ICV administrations were combined with IV infusions [38]. The combined therapy obtained objective benefits in EEG, PET and magnetic resonance spectroscopy (MRS), and CSF T-tau level reduction. Furthermore, improvements in eye movement, language, and speech were reported, as well as and stabilization of clinical progression for 2 years. No AEs were detected over the 2 years of IV/ICV combined therapy.

The other patient, a girl of 14 years old at the time of HP-β-CD therapy onset, was only treated with IV infusions for 3 years. At the beginning of the treatment the patient showed benefits in EEG, MRS and visual evoked potential (VEP), but after 3 months disappeared. A decrease in hepatosplenomegaly was observed in abdominal ultrasound and body computed tomography (CT). The general condition, neurological tests, and seizure control were stabilized with therapy, reporting only an improvement in alertness. Tolerance of IV therapy was excellent [37].

Drs Hrynkow and Hastings recently reported in a Congress the clinical experience with 11 patients initially treated with IV HP-β-CD more than 6 years [39]. Two of these patients were only treated with IV infusions, whereas in nine patients IT therapy was added later. In the two patients with only IV therapy, one showed a progression in NNCSS similar


**Table 1.** Adverse events related to IV with/without IT HP-β-CD administrations.

In October 2010, the FDA allowed the addition of HP-β-CD IT administration at doses of 350 mg every 2 weeks (initial dose 175 mg/2 weeks) [32, 33]. During the first months of concurrent IV/IT therapy, a significant improvement was observed in the validated NIH NPC Clinical Severity Score (NNCSS), as well as in the brainstem auditory evoked response (BAER) [33]. After 18 months, ICV route was authorized by FDA in the twins through an Ommaya reservoir system. One of them tolerated perfectly the ICV and continues today with the treatment, whereas in her sister, ICV was discarded by insertion bleeding and IT route was recovered. Both patients have experienced improvements in alertness, swallow, head

The second reported use of IV HP-β-CD (Trappsol® Cyclo™) was in two Brazilian sisters at age of 12 and 16 years old with concomitant miglustat treatment. Dr Vieira employed the same IV protocol with a dose escalation from 1200 to 2500 mg/kg/week. Both patients showed, after 1 year of treatment, objective benefits in PET and NNCSS, as well as improvements in motor dysfunction, cataplexy, psychiatric symptoms, behavior, cognitive functions, and memory [27]. Two later reports informed about the simultaneous treatment with IV weekly and IT twice monthly at least 3 years, maintaining the good results previously reported with IV infusions [35, 36]. No adverse events (AEs) were reported, although the published data

Two reported cases of Japanese NPD-C patients diagnosed at 2 months and 13 years were initially treated at 4 and 14 years old with the IV "Oakland protocol", with doses from 80 mg to 2500 mg/kg/three or two times a week, respectively [37, 38]. These were the first published cases of VTS-270 use in NPD-C. The younger patient reported with IV administration, a mild decrease in hepatosplenomegaly and temporary improvements in EEG and stabilization of disability scores the first 6 months. However, rest of the 2 years with only IV infusions a rapid progression of neurological dysfunction and worsening of swallow, speech, rigidity, and seizures were reported [37]. Furthermore, repeated fever with transient diffuse pulmonary cloudiness episodes were observed, an AE probably related to HP-β-CD IV infusion. After 2 years of IV therapy, IT first and later ICV administrations were combined with IV infusions [38]. The combined therapy obtained objective benefits in EEG, PET and magnetic resonance spectroscopy (MRS), and CSF T-tau level reduction. Furthermore, improvements in eye movement, language, and speech were reported, as well as and stabilization of clinical progression for 2 years. No AEs were detected over the 2 years of IV/ICV combined therapy. The other patient, a girl of 14 years old at the time of HP-β-CD therapy onset, was only treated with IV infusions for 3 years. At the beginning of the treatment the patient showed benefits in EEG, MRS and visual evoked potential (VEP), but after 3 months disappeared. A decrease in hepatosplenomegaly was observed in abdominal ultrasound and body computed tomography (CT). The general condition, neurological tests, and seizure control were stabilized with therapy, reporting only an improvement in alertness. Tolerance of IV therapy was excellent [37]. Drs Hrynkow and Hastings recently reported in a Congress the clinical experience with 11 patients initially treated with IV HP-β-CD more than 6 years [39]. Two of these patients were only treated with IV infusions, whereas in nine patients IT therapy was added later. In the two patients with only IV therapy, one showed a progression in NNCSS similar

were limited and only congress abstracts were reported [27, 35, 36].

control, and ataxia [32, 34].

102 Cyclodextrin - A Versatile Ingredient

than previous scores before initiation, whereas the other patient reported a stabilization of NNCSS after IV therapy. In two patients with IV/IT therapy significant decrease in NNCSS were observed comparing pre and post-therapy scores. In the other seven patients was only available post-therapy information, showing in most of the cases an initial de decrease in NNCSS followed with a progressive increase. Other significant improvements were reported, as reduction in hepatomegaly, restoration of language skills, resolution of interstitial lung disease and improvements in fine motor control. The tolerability was favorable, although some AEs were reported during 6 years of therapy (**Table 1**).

Despite the positive results observed in the compassionate use of IV HP-β-CD [26, 27, 32–39], there is no clear evidence to date that IV route has a clinical benefit in CNS symptoms of NPD-C in humans. Most of the reports with neurological improvements combined the use of IV and IT/ICV administrations, making it impossible to demonstrate that these benefits were exclusively associated to IV and not IT/ICV. In addition, doses 1000 times larger than the IT dose should be required to achieve the same concentrations in the CSF reached by IT administration with IV infusions of HP-β-CD. This dosage would probably be unsafe in humans.
