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

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 procedure or the disease [40].

Dr. Berry-Kravis reported the clinical outcomes of the use of IT HP-β-CD (Trappsol® Cyclo™) in three patients with NPD-C in several congresses [41–43]. Two of them were a couple siblings of 14 and 15 years old who were unable to be enrolled in the Phase 1 clinical trial (NCT01747135) and were treated as a compassionate use. The younger sibling with doses from 200 to 500 mg every 2 weeks obtained improvements in NNCSS, instrumented timed up and go (gait test) and Mullen Scales of Early Learning (cognitive scale), as well as benefits in cognitive functions, seizures, swallow, language and speech [40–43]. The other sibling received doses from 200 to 600 mg every 2 weeks but the benefit was poor, with stabilization of NNCSS, CFS reduction of lysozyme and improvement in cognitive functions [40–43]. After the first three IT infusions were reported post lumbar puncture headache and vomiting in both siblings, but it was not related to the drug and disappeared after a switch to use of Whitacre spinal needles. The clinical information regarding the third patient was insufficient to evaluate the efficacy, although an improvement in balance and gait was reported after 1 year treated with doses from 200 to 400 mg every 2 weeks [43].

reported improvement in NPD-C scales, balance and gait, language and speech, and swallow. In addition, reductions in oxysterol serum concentrations were observed in both patients, a sterol storage biomarker. No AEs were reported in these patients [32, 48]. The worse outcomes observed in two cases reported by García-Robles et al. could be related to the age (49 and 39 years old) and advanced disease at the HP-β-CD onset. The dosages of IT HP-β-CD (Trappsol® Cyclo™) ranged from 175 to 700 mg and 50 to 875 mg every 2 weeks, also using IT-OR route in the second patient. Any objective or subjective improvements were reported in both patients. The older patient received only four doses with optimal tolerance, but HP-β-CD therapy was discontinued when neuropsychiatric symptoms progressed. The other patient suffered two episodes of toxic meningitis as well as worsening respiratory symptoms and swallow. After second chemical meningitis and neurologic progression of the disease,

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

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Four clinical trials using cyclodextrin for the treatment of NPD-C have been found. One of them has been completed and their results have been published [50] and three are currently

• Intrathecal 2-hydroxypropyl-β-cyclodextrin (VTS-270) for Niemann-Pick type C1 (NPC-1) disease. A non-randomized, open-label, Phase 1–2 trial. See ClinicalTrials.gov Identifier:

Phase 1–2, non-randomized, open-label, study, to assess the tolerability, safety, feasibility, and PK of HP-β-CD administered IT monthly via lumbar injection to drug naive cohorts of NPC-1 patients at doses of 50 mg escalated to a maximum of 1200 mg. The objective is to determine an active dose of HP-β-CD as measured by changes in plasma 24-(S)-hydroxycholesterol (24(S)-HC) concentration and to evaluate the use of biomarkers and potential clinical outcomes of NPC-1. NNCSS is used to assess clinical efficacy. The decision to dose-escalate is based on safety and biochemical data. Safety is assessed by the appearance of AEs with performance of clinical laboratory tests, physical examinations, and with special attention to audiological evaluation. Biochemical efficacy is measured by change from baseline in plasma 24(S)-HC. The PK analysis is assessed for plasma HP-β-CD concentrations. This is the only

Eligible patients were aged 2–25 years and had NPC-1 with neurological manifestations. Fourteen patients were enrolled from National Institutes of Health (NIH-cohort). Cohort size was three participants for initial IT doses of 50, 200, 300, 400, and 900 mg (only two patients) administrated IT every month. Three participants were initially dosed with 50 mg ICV via an Ommaya reservoir approximately 6 months prior to initiation of the IT trial. Use of the Ommaya reservoirs was discontinued due to *P. acnes* infection/colonization in two subjects. Due to this problem, initial protocol was amended and ICV route was changed by IT. After initial dosing at the specified cohort dose, participants were dose-escalated based on tolerance

HP-β-CD treatment was discontinued [49].

NCT01747135 [50].

and safety data.

**6. Experience in humans: ongoing clinical trials**

ongoing and no preliminary results have been yet published.

clinical trials of HP-β-CD with published results.

The use of IT HP-β-CD with a fixed dose of 200 mg every 2 weeks was reported by Maarup et al. in a single case report. After 18 months of the therapy, the boy showed an improvement in vertical gaze (eye movement) and the consequent decrease in the NNCSS. This study also reported an increase in 24-OH cholesterol, a biomarker of cholesterol redistribution in CNS. On the other hand, an AE was associated to HP-β-CD administration, the well-known hearing loss to high frequency [44].

The use of IT-OR HP-β-CD in two Spanish boys diagnosed of NPD-C at 6 and 10 years old was briefly reported in congresses [45, 46]. The first patient was treated at 11 years with doses from 125 to 525 mg (Trappsol® Cyclo™) every 2 weeks for at least 37 months. Benefits in muscle tone and a decrease in seizures frequency were observed with IT-OR therapy. Initially was reported an improvement in BAER test, although it was alternated with auditory deteriorations [32, 45]. In the other case report, a 16 years patient received IT-OR fixed-doses of 350 mg every 2 weeks for 20 months. The objectives results included BAER tests and NNCSS. Furthermore, improvements in language and speech, ataxia and quality of life were obtained. The most relevant toxicities were intermittent fever and a suspicion of chemical meningitis [32, 46].

A recently published article described the IT therapy of a young NPD-C girl of 22 months [47]. The dosage of HP-β-CD was 175–325 mg every 2 weeks for 20 months. The treatment only achieved improvements in visual contact and motor function with the first doses, as well as slight retardation of disease progression and in the NPD-C disability scale during the first year. After the first year, MRI showed a progression of cerebral atrophy, which was consistent with a clinical disease progression (epilepsy, dysphagia, and worsening motor function). Despite the initial response and the absence of AEs, the IT HP-β-CD was discontinued after 20 months by lack of efficacy.

The employment of HP-β-CD in adult-onset NPD-C has been described with variable results in two publications [48, 49]. Sakiyama et al. reported the IT treatment (VTS-270) of two adult patients of 37 and 28 years with doses from 100 to 400 mg every month. The older patient showed better eye movement and neurological stabilization, whereas the younger patient reported improvement in NPD-C scales, balance and gait, language and speech, and swallow. In addition, reductions in oxysterol serum concentrations were observed in both patients, a sterol storage biomarker. No AEs were reported in these patients [32, 48]. The worse outcomes observed in two cases reported by García-Robles et al. could be related to the age (49 and 39 years old) and advanced disease at the HP-β-CD onset. The dosages of IT HP-β-CD (Trappsol® Cyclo™) ranged from 175 to 700 mg and 50 to 875 mg every 2 weeks, also using IT-OR route in the second patient. Any objective or subjective improvements were reported in both patients. The older patient received only four doses with optimal tolerance, but HP-β-CD therapy was discontinued when neuropsychiatric symptoms progressed. The other patient suffered two episodes of toxic meningitis as well as worsening respiratory symptoms and swallow. After second chemical meningitis and neurologic progression of the disease, HP-β-CD treatment was discontinued [49].
