**7. Experience in humans: potential toxicities of the different administration routes**

There are three possible administration routes for HP-β-CD: IV, IT, or ICV via an Ommaya reservoir. Some adverse events observed could be related to the administration route, the disease progression, or the cyclodextrin itself.

The review performed by the EMA regarding the use of HP-β-CD as an excipient indicated that the IV administrations had low toxicity, being the most prevalent issue of the renal toxicity, especially with high doses [51]. However, any patients showed renal toxicity with HP-β-CD therapy [32]. This was the first route employed, but later a change to IT route was requested due to the discovery that HP-β-CD not cross the BBB and only a little quantity is able to enter to the brain [21, 24, 25, 30].

Based on animal models, ICV route was proposed as an alternative with potential benefits and this route was chosen in the Phase I clinical trial (NCT01747135) using an Ommaya reservoir to facilitate the administration. Unfortunately, complications due to colonization by *P. acnes* led to change ICV route to IT [52]. Currently, IV route is being tested in two ongoing clinical trials, whereas IT route is analyzed in another ongoing trial and in the recently published trial [50].

Sensorineural hearing loss was present in all subjects of NIH-cohort (14 patients) and 2 of 3 RUMC-cohort, and according to the study results, it was associated with the administration of HP-β-CD. Moreover, the data obtained suggest that there is greater HP-β-CD ototoxicity in subjects who have not yet lost hearing due to NPD-C itself. Also, tinnitus was present in 6 of

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

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

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Until now, NPD-C treatment has been supportive and symptomatic with miglustat as the only disease-specific drug approved in some countries. HP-β-CD is a new option under investigation with two different products, Kleptose® and Trappsol Cyclo®, which are not chemically equivalent and therefore may not be biochemically equivalent or lead to comparable

Based on preclinical animal studies, HP-β-CD has been tested in humans affected by NPD-C during the last years. In compassionate use outside clinical trials, HP-β-CD has been administrated with either IV, IT, or ICV. Despite the positive results observed with IV HP-β-CD, there is no clear evidence to date that IV route has a clinical benefit in CNS symptoms of NPD-C as most of the reports combined IV and IT/ICV administrations. The reported cases of IT infusions obtained higher improvements reducing the disease

The results of a recently published clinical trial reproduced the findings observed with IT route. The trial has shown slowing of NPD-C progression in 14 patients with a dose escalation of IT HP-β-CD administrated monthly as well as in 3 patients with administration every

Some adverse events observed could be related to the administration route, the disease progression, or the cyclodextrin itself. The safety profile of HP-β-CD seems acceptable, being the loss of hearing (related to HP-β-CD) the most frequent adverse reported in the clinical trial and published cases. However, some severe toxicities have been reported including chemical

Furthermore, there are currently two IV HP-β-CD and one IT HP-β-CD ongoing clinical trials without published results. The findings of these trials will lead to an improvement in knowledge of HP-β-CD for NPD-C, setting the best route, dose, and posology. Currently, the short experience with HP-β-CD suggested that it could be effective in the management of NPD-C

We would like to thank Asociación para la Investigación, Desarrollo e Innovación en Farmacia

Hospitalaria (AIDIFH) for its economic support regarding the publication fees.

14 patients in NIH-cohort and 1 of 3 in RUMC-cohort [50].

formulations from a clinical development perspective.

2 weeks regarding a historical comparison cohort.

meningitis and fever although not in published clinical trial.

but the results of ongoing clinical trials will be definitive.

**8. Conclusions**

progression.

**Acknowledgements**

Megías-Vericat et al. reviewed the initial published cases of HP-β-CD treatment [32]. Regarding safety, 11 of 17 NPD-C patients included suffered AEs. Of the 17 AEs reported, 6 were related to the route of administration, specifically with the IT and ICV routes and 10 of them could be attributed by HP-β-CD. Six AEs associated to the route were: CNS bleed related to insertion of the Ommaya reservoir system in a patient treated with ICV HP-β-CD led to ICV administration suspended [34]; post lumbar puncture headache and vomiting resolved with switching a Whitacre spinal needles [41–43]; post lumbar puncture pain, headache, nausea, and vomiting resolved with symptomatic and postural treatment [44]; seizures with fever resolved without changes in treatment [40] and aspiration pneumonia; febrile syndrome; and candidiasis resolved with antibiotic and antifungal treatment [49].

Among AEs related to HP-β-CD itself, loss of hearing was reported in four reported cases of IT infusions [41–45], although it proved reversible in two of them. These patients were administered with reduced doses of HP-β-CD after hearing recovery, two times in one of them. In other two patients, despite delaying the next dose, hearing loss was not reversed. This AE was also observed in animal studies with IT [18], ICV [53], and intracisternal [25] routes of administration. At the dosage employed, hearing loss is an expected AE, as well as a well-known NPD-C symptom. At the clinical trial recently published, loss of hearing was reported in all the participants [50].

Four patients suffered from fever two or more times after HP-β-CD administrations [37, 40, 46, 49]. In one case, fever was accompanied by seizures [40], whereas another patient showed an infusion reaction with fever and transient diffuse pulmonary cloudiness [37]. In one patient, after intermittent fever episodes, a diagnosis of chemical meningitis was made after bacterial meningitis was discarded. The IT-OR was withdrawn, and HP-β-CD was reintroduced 2 months later because the patient's condition worsened [46]. Other patient showed two episodes of chemical meningitis (bacterial meningitis was discarded in both cases) after IT and IT-OR HP-β-CD administrations, although both were resolved quickly and without consequences [49]. This AE could be related to the method of administration or disease symptoms and not to HP-β-CD. However, the chemical meningitis observed seems to be associated to the drug after analyzed with the Naranjo algorithm [49]. Some acute neurological effects after the infusion of high doses that resolve after few days were described by some investigators in conferences (but unpublished yet).

Regarding the results of the first clinical trial published, no serious AEs were observed [50]. Marked expected AE included: ototoxicity (14 of 14 patients) and post lumbar puncture headache (9 of 14 patients). Among unexpected AE included, post-administration unsteadiness and fatigue occurs at doses above 600 mg. The degree of impairment varied between subjects but usually was transient and occurred 24–72 hours after administration.

Sensorineural hearing loss was present in all subjects of NIH-cohort (14 patients) and 2 of 3 RUMC-cohort, and according to the study results, it was associated with the administration of HP-β-CD. Moreover, the data obtained suggest that there is greater HP-β-CD ototoxicity in subjects who have not yet lost hearing due to NPD-C itself. Also, tinnitus was present in 6 of 14 patients in NIH-cohort and 1 of 3 in RUMC-cohort [50].
