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

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

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

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

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

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

1 year treated with doses from 200 to 400 mg every 2 weeks [43].

hearing loss to high frequency [44].

104 Cyclodextrin - A Versatile Ingredient

meningitis [32, 46].

20 months by lack of efficacy.

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 ongoing and no preliminary results have been yet published.

• 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: NCT01747135 [50].

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

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 and safety data.

As comparison control, a cohort of NPD-C subjects from Natural History study with longitudinal assessments was employed. These patients were not on HP-β-CD treatment. To explore a scheme every 2 weeks, three additional subjects were recruited with the same criteria mentioned above in Rush University Medical Center (RUMC-cohort).

(900, 1200, and 1800 mg) will be administered IT every 2 weeks for 8 weeks and 2 weeks for observation in 9 subjects; 3 subjects will receive sham treatment. The criteria for dose selection

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The objective of Part B is to evaluate, in a double-blind sham-controlled design, the progression of the neurologic manifestations of NPC-1 disease based on changes in the composite efficacy outcome (consisting of four components of the NNCSS: ambulation, fine motor skills, cognition, and swallowing), after 52 weeks of treatment in comparison to baseline. Part B will evaluate the safety and efficacy of the dose selected from Part A compared to sham control in

The objective of Part C is to evaluate the long-term safety, tolerability, and efficacy of the dose selected for Part B. This part is an open-label extension with IT treatment every 2 weeks to subjects who either complete Part B or are subjects in Part B who have met rescue therapy criteria. Additionally, subjects who are currently active in the NIH-sponsored Phase 1 protocol (NCT01747135, see above) will also be eligible to participate upon completion of their participation in the Phase 1 study. In this part, subjects will receive treatment until licensed

The primary outcome measure of the study is NNCSS with a time Frame of 52 weeks. Data for NPD-C score rating will be provided to a centralized independent blinded rater, who will analyze all NPD-C information for all subjects and assign the NNCSS rate. As secondary outcome measures are: clinician and caregiver clinical global impression of change, time to get up and go test, 9-hole peg test, percentage of patients with clinical worsening, and European Quality of Life-5 dimensions quality of life rating (EQ-5D QoL). Moreover, CSF and plasma

The design enables a selection of best dose based on efficacy, safety, and tolerability according to an evaluation by a Committee. The dose chosen will be evaluated using changes in a composite efficacy outcome in order to assess the neurologic progression in participants. Highlight is that, it is the first study that uses quality of life rating. Moreover, assessment of biochemical markers of response and also due to a sufficient dosing duration will be performed to assess the effectiveness of HP-β-CD in NPC-1. This is a global, multi-site study with the largest planned number of participants, and this will allow a better knowledge about

• A Phase I/II study to evaluate the safety and pharmacokinetics of intravenous Trappsol Cyclo (HP-β-CD) in patients with Niemann-Pick disease type C (NPC-1) and the pharmacodynamic effects of treatment upon markers of cholesterol metabolism and clinical outcomes (see ClinicalTrials.gov Identifier: NCT02912793 and EudraCT Number: 2015-005761-23). Phase 1/2, double-blind, randomized, multicentre, parallel group study based on data available and information from the administration via compassionate/named patient use in patients with NPC-1, and information of other cyclodextrin products in the literature. The study has two stages: the primary objective of Stage 1 is to compare the plasma pharmacokinetics (PK) of three different doses of IV HP-β-CD in the prevention/delay of NPC-1 progression whereas Stage 2 is to evaluate their efficacy and tolerability in the management of clinical

include safety and tolerability including a thorough audiological evaluation.

51 subjects (randomized 2:1), including the 12 subjects from Part A.

product or end of the program.

biomarkers will be measured.

NPD-C and efficacy treatment.

The primary outcome was changed in 24[S]-HC area under the curve (AUC8–72) response to drug administration compared with the response after saline administration. The AUC8–72 of plasma 24(S)-HC concentrations were established after its determinations at pre-dose, 8, 24, 30, 48, and 72 hours post-dose after either HP-β-CD of saline infusion.

As a secondary objective, NNCSS was used to assess clinical efficacy. Audiological assessments were obtained monthly before each infusion. Also the concentrations of fatty acid binding protein 3 (FABP3) and calbindin D in cerebrospinal fluid (CSF) were assayed.

Finally, 14 NIH-patients and 3 RUMC-patients were enrolled. Twenty-one patients with similar characteristics were identified from the historical database for comparing. For primary outcome (change in 24(S)-HC AUC8–72), 121 of 155 post-drug plasma value were greater than post-saline values. Despite the variability, the data suggest a dose-response relationship. All the patients of the study had either FABP3 or calbindin D, a significant negative linear regression slope (only one patient had a significant increase in calbindin D slope).

Regarding clinical efficacy, the total NNCSS for NIH-cohort increased at a slower rate than comparison cohort. These data show a significant reduction in disease progression in the cohort of HP-β-CD treated patients. In a secondary responder analysis, cohorts of treated and comparison subjects were classified as responders when their NNCSS minus hearing was stable or improved. Seven of 14 NIH-cohort subjects were classified as responders, 3 of 3 RUMC-cohort subjects were classified as responders, and none of 21 patients of comparison cohort were classified as responders. Safety will be discussed in Section 7.

The added value of this study was to provide a neurological disease progression comparison among a cohort of NPD-C subjects treated with IT HP-β-CD and a control cohort of NPD-C subjects from Natural History study, indicating a decrease rate of neurological disease progression in the treated cohort. Moreover, this study provides information on the safety of IT administered HP-β-CD and the measurement of biomarkers provided additional support for decreased neuronal damage and improved neuronal cholesterol homeostasis.

• A Phase 2b/3 prospective, randomized, double-blind, sham-controlled trial of VTS-270 (HPβ-CD) in subjects with neurologic manifestations of Niemann-Pick type C1 (NPC-1) disease. (See ClinicalTrials.gov identifier: NCT02534844 and EudraCT Number: 2015-002548-15).

Multicenter, multinational, prospective, randomized, double-blind, sham-controlled, threepart, efficacy and safety trial of HP-β-CD, administered by the lumbar IT route every 2 weeks, with a planned enrollment of approximately 51 subjects with NPC-1 disease. This study is ongoing, but not recruiting participants (male or female subjects, aged 4–21 years of age at time of screening with onset of neurological symptoms prior to 15 years of age).

This study has three parts with different objectives. The objective of Part A is to select the dose of HP-β-CD to be used in Part B and Part C. Three different HP-β-CD lumbar IT doses (900, 1200, and 1800 mg) will be administered IT every 2 weeks for 8 weeks and 2 weeks for observation in 9 subjects; 3 subjects will receive sham treatment. The criteria for dose selection include safety and tolerability including a thorough audiological evaluation.

As comparison control, a cohort of NPD-C subjects from Natural History study with longitudinal assessments was employed. These patients were not on HP-β-CD treatment. To explore a scheme every 2 weeks, three additional subjects were recruited with the same criteria men-

The primary outcome was changed in 24[S]-HC area under the curve (AUC8–72) response to drug administration compared with the response after saline administration. The AUC8–72 of plasma 24(S)-HC concentrations were established after its determinations at pre-dose, 8, 24,

As a secondary objective, NNCSS was used to assess clinical efficacy. Audiological assessments were obtained monthly before each infusion. Also the concentrations of fatty acid bind-

Finally, 14 NIH-patients and 3 RUMC-patients were enrolled. Twenty-one patients with similar characteristics were identified from the historical database for comparing. For primary outcome (change in 24(S)-HC AUC8–72), 121 of 155 post-drug plasma value were greater than post-saline values. Despite the variability, the data suggest a dose-response relationship. All the patients of the study had either FABP3 or calbindin D, a significant negative linear regres-

Regarding clinical efficacy, the total NNCSS for NIH-cohort increased at a slower rate than comparison cohort. These data show a significant reduction in disease progression in the cohort of HP-β-CD treated patients. In a secondary responder analysis, cohorts of treated and comparison subjects were classified as responders when their NNCSS minus hearing was stable or improved. Seven of 14 NIH-cohort subjects were classified as responders, 3 of 3 RUMC-cohort subjects were classified as responders, and none of 21 patients of comparison

The added value of this study was to provide a neurological disease progression comparison among a cohort of NPD-C subjects treated with IT HP-β-CD and a control cohort of NPD-C subjects from Natural History study, indicating a decrease rate of neurological disease progression in the treated cohort. Moreover, this study provides information on the safety of IT administered HP-β-CD and the measurement of biomarkers provided additional support for

• A Phase 2b/3 prospective, randomized, double-blind, sham-controlled trial of VTS-270 (HPβ-CD) in subjects with neurologic manifestations of Niemann-Pick type C1 (NPC-1) disease. (See ClinicalTrials.gov identifier: NCT02534844 and EudraCT Number: 2015-002548-15). Multicenter, multinational, prospective, randomized, double-blind, sham-controlled, threepart, efficacy and safety trial of HP-β-CD, administered by the lumbar IT route every 2 weeks, with a planned enrollment of approximately 51 subjects with NPC-1 disease. This study is ongoing, but not recruiting participants (male or female subjects, aged 4–21 years of age at

This study has three parts with different objectives. The objective of Part A is to select the dose of HP-β-CD to be used in Part B and Part C. Three different HP-β-CD lumbar IT doses

ing protein 3 (FABP3) and calbindin D in cerebrospinal fluid (CSF) were assayed.

sion slope (only one patient had a significant increase in calbindin D slope).

cohort were classified as responders. Safety will be discussed in Section 7.

decreased neuronal damage and improved neuronal cholesterol homeostasis.

time of screening with onset of neurological symptoms prior to 15 years of age).

tioned above in Rush University Medical Center (RUMC-cohort).

106 Cyclodextrin - A Versatile Ingredient

30, 48, and 72 hours post-dose after either HP-β-CD of saline infusion.

The objective of Part B is to evaluate, in a double-blind sham-controlled design, the progression of the neurologic manifestations of NPC-1 disease based on changes in the composite efficacy outcome (consisting of four components of the NNCSS: ambulation, fine motor skills, cognition, and swallowing), after 52 weeks of treatment in comparison to baseline. Part B will evaluate the safety and efficacy of the dose selected from Part A compared to sham control in 51 subjects (randomized 2:1), including the 12 subjects from Part A.

The objective of Part C is to evaluate the long-term safety, tolerability, and efficacy of the dose selected for Part B. This part is an open-label extension with IT treatment every 2 weeks to subjects who either complete Part B or are subjects in Part B who have met rescue therapy criteria. Additionally, subjects who are currently active in the NIH-sponsored Phase 1 protocol (NCT01747135, see above) will also be eligible to participate upon completion of their participation in the Phase 1 study. In this part, subjects will receive treatment until licensed product or end of the program.

The primary outcome measure of the study is NNCSS with a time Frame of 52 weeks. Data for NPD-C score rating will be provided to a centralized independent blinded rater, who will analyze all NPD-C information for all subjects and assign the NNCSS rate. As secondary outcome measures are: clinician and caregiver clinical global impression of change, time to get up and go test, 9-hole peg test, percentage of patients with clinical worsening, and European Quality of Life-5 dimensions quality of life rating (EQ-5D QoL). Moreover, CSF and plasma biomarkers will be measured.

The design enables a selection of best dose based on efficacy, safety, and tolerability according to an evaluation by a Committee. The dose chosen will be evaluated using changes in a composite efficacy outcome in order to assess the neurologic progression in participants. Highlight is that, it is the first study that uses quality of life rating. Moreover, assessment of biochemical markers of response and also due to a sufficient dosing duration will be performed to assess the effectiveness of HP-β-CD in NPC-1. This is a global, multi-site study with the largest planned number of participants, and this will allow a better knowledge about NPD-C and efficacy treatment.

• A Phase I/II study to evaluate the safety and pharmacokinetics of intravenous Trappsol Cyclo (HP-β-CD) in patients with Niemann-Pick disease type C (NPC-1) and the pharmacodynamic effects of treatment upon markers of cholesterol metabolism and clinical outcomes (see ClinicalTrials.gov Identifier: NCT02912793 and EudraCT Number: 2015-005761-23).

Phase 1/2, double-blind, randomized, multicentre, parallel group study based on data available and information from the administration via compassionate/named patient use in patients with NPC-1, and information of other cyclodextrin products in the literature. The study has two stages: the primary objective of Stage 1 is to compare the plasma pharmacokinetics (PK) of three different doses of IV HP-β-CD in the prevention/delay of NPC-1 progression whereas Stage 2 is to evaluate their efficacy and tolerability in the management of clinical manifestations. Secondary objectives include investigation of the effect of three different doses of HP-β-CD IV upon serum and lymphocytic markers of cholesterol metabolism (Stages 1 and 2) and evaluation of concentrations in the CSF following IV administration (Stage 1), evaluation of the impact of treatment upon behavioral aspects and the impact of treatment upon measures of neurological function including ataxia, aphasia, and saccadic eye movements of NPC-1 (Stage 2). The outcome measures are: plasma and CSF concentrations of HP-β-CD following IV administration, serum cholesterol markers, global impression of disease, quality of life scores, change in NNCSS, and changes in hepatic and splenic morphology.

lymphocytic markers of cholesterol metabolism and evaluation of HP-β-CD concentrations in the CSF following IV administration, evaluation of the impact of treatment upon measures of neurological function including aphasia, ataxia, and saccadic eye movements, and the impact

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This study is currently recruiting participants. It is planned to recruit a total of 12 patients (all adults) which will be randomized 1:1 to one of the two dose levels (1500 mg/kg or 2500 mg/kg; 6 patients per dose level). Treatment will be administered every 2 weeks by slow IV infusion

As primary outcome measures are pharmacokinetics parameters: Tmax, Cmax, volume of distribution, and t1/2 of HP-β-CD in plasma from NPC-1 patients by measurement at preinfusion then 2, 4, 6, 8, 8.5, 9, 10, 11, 12, 16, and 20 hours after the start of the infusions at weeks

The design of the proposed study thus enables a better knowledge about pharmacokinetics of IV HP-β-CD administration, an early assessment of potential biochemical markers of response but allows for a sufficient dosing duration to enable the short-term effectiveness of

In conclusion, there is a published clinical trial results, using IT administration of HP-β-CD and shows moderate response thought slowed disease progression with an acceptable safety profile. Another IT HP-β-CD clinical trial and two IV HP-β-CD clinical trials are ongoing but not results are been published yet. Regarding the route of administration, exist a debate, and treatment with HP-β-CD has used four different paradigms: IV only, IV followed by the addition of IT sequential, IV and IT initiated concurrently, and IT only. The main reason for IT route is that HP-β-CD does not cross the BBB, however, in animal models systemic HP-β-CD positively affects CNS disease thus CNS penetration may not be essential for neurologic efficacy. The ongoing clinical trials will lead to an improvement in knowledge of HP-β-CD for

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

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

NPD-C treatment, setting the best route, dose and posology for NPD-C patients.

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

of treatment upon behavioral aspects of NPC-1.

HP-β-CD in NPD-C to be assessed.

**administration routes**

disease progression, or the cyclodextrin itself.

able to enter to the brain [21, 24, 25, 30].

1 and 12.

over 8 hours. Patients will receive treatment for a total of 12 weeks.

In order to achieve these objectives, the primary endpoint of Stage 1 is plasma concentrations (at 0, 2, 4, 6, and 8 hours after the start of infusion and 30 minutes, 1, 2, 4, 8, and 12 hours after the end of the infusion) of HP-β-CD during and following infusion to evaluate time to maximum concentration (T max), maximum concentration (Cmax), volume of distribution and elimination half-life (t1/2). The primary endpoint of Stage 2 is the change from baseline in global impression of disease severity at 48 weeks and the proportion of patients at 48 weeks with a reduction from baseline of at least one point in two or more domains of the NNCSS.

Patients taking miglustat are not excluded of the study because this drug is an approved treatment for NPC-1 in Europe and it would be unethical, but it is planned to balance randomization across groups for its use.

This clinical trial is already recruiting patients in United Kingdom and it is planned to recruit 12 patients (3 children of 2–11 years, 3 of 12–17, and 6 adults 18–64 years). Patients will be randomized 1:1:1 to one of the three dose levels (1500, 2000, or 2500 mg/kg; four patients per dose level). Treatment will be administered over 8 hours by slow IV infusion at a concentration of 250 mg/mL every 2 weeks. Patients completing Stage 1 of the study will continue into Stage 2 and receive treatment for 48 weeks.

The design enables early assessment of biochemical markers of response and also due to a sufficient dosing duration, to assess the effectiveness of HP-β-CD in NPC-1 and its pharmacokinetics.

• A Phase I study to evaluate the single and multiple-dose pharmacokinetics of intravenous Trappsol Cyclo (HP-Beta-CD) in patients with Niemann-Pick disease type C (NPC-1) and the effects of dosing upon biomarkers of NPC disease. (See ClinicalTrials.gov Identifier: NCT02939547).

Phase I, double-blind, randomized, single-center, parallel group study based on information and data available from the administration of HP-β-CD via compassionate/named patient use in patients with NPC-1, and data on other cyclodextrin products in the scientific literature.

The study has a first phase of screening (up to 4 weeks), a treatment phase of 12 weeks and a later phase of follow-up of 4 weeks. The primary objective is to compare the plasma pharmacokinetics of single and multiple doses of two different levels of IV HP-β-CD. Secondary objectives include investigation of the effect of different doses of IV HP-β-CD upon serum and lymphocytic markers of cholesterol metabolism and evaluation of HP-β-CD concentrations in the CSF following IV administration, evaluation of the impact of treatment upon measures of neurological function including aphasia, ataxia, and saccadic eye movements, and the impact of treatment upon behavioral aspects of NPC-1.

manifestations. Secondary objectives include investigation of the effect of three different doses of HP-β-CD IV upon serum and lymphocytic markers of cholesterol metabolism (Stages 1 and 2) and evaluation of concentrations in the CSF following IV administration (Stage 1), evaluation of the impact of treatment upon behavioral aspects and the impact of treatment upon measures of neurological function including ataxia, aphasia, and saccadic eye movements of NPC-1 (Stage 2). The outcome measures are: plasma and CSF concentrations of HP-β-CD following IV administration, serum cholesterol markers, global impression of disease, quality of

In order to achieve these objectives, the primary endpoint of Stage 1 is plasma concentrations (at 0, 2, 4, 6, and 8 hours after the start of infusion and 30 minutes, 1, 2, 4, 8, and 12 hours after the end of the infusion) of HP-β-CD during and following infusion to evaluate time to maximum concentration (T max), maximum concentration (Cmax), volume of distribution and elimination half-life (t1/2). The primary endpoint of Stage 2 is the change from baseline in global impression of disease severity at 48 weeks and the proportion of patients at 48 weeks with a reduction from baseline of at least one point in two or more domains of the

Patients taking miglustat are not excluded of the study because this drug is an approved treatment for NPC-1 in Europe and it would be unethical, but it is planned to balance randomiza-

This clinical trial is already recruiting patients in United Kingdom and it is planned to recruit 12 patients (3 children of 2–11 years, 3 of 12–17, and 6 adults 18–64 years). Patients will be randomized 1:1:1 to one of the three dose levels (1500, 2000, or 2500 mg/kg; four patients per dose level). Treatment will be administered over 8 hours by slow IV infusion at a concentration of 250 mg/mL every 2 weeks. Patients completing Stage 1 of the study will continue into Stage 2

The design enables early assessment of biochemical markers of response and also due to a sufficient dosing duration, to assess the effectiveness of HP-β-CD in NPC-1 and its

• A Phase I study to evaluate the single and multiple-dose pharmacokinetics of intravenous Trappsol Cyclo (HP-Beta-CD) in patients with Niemann-Pick disease type C (NPC-1) and the effects of dosing upon biomarkers of NPC disease. (See ClinicalTrials.gov Identifier:

Phase I, double-blind, randomized, single-center, parallel group study based on information and data available from the administration of HP-β-CD via compassionate/named patient use in patients with NPC-1, and data on other cyclodextrin products in the scientific

The study has a first phase of screening (up to 4 weeks), a treatment phase of 12 weeks and a later phase of follow-up of 4 weeks. The primary objective is to compare the plasma pharmacokinetics of single and multiple doses of two different levels of IV HP-β-CD. Secondary objectives include investigation of the effect of different doses of IV HP-β-CD upon serum and

life scores, change in NNCSS, and changes in hepatic and splenic morphology.

NNCSS.

tion across groups for its use.

108 Cyclodextrin - A Versatile Ingredient

and receive treatment for 48 weeks.

pharmacokinetics.

NCT02939547).

literature.

This study is currently recruiting participants. It is planned to recruit a total of 12 patients (all adults) which will be randomized 1:1 to one of the two dose levels (1500 mg/kg or 2500 mg/kg; 6 patients per dose level). Treatment will be administered every 2 weeks by slow IV infusion over 8 hours. Patients will receive treatment for a total of 12 weeks.

As primary outcome measures are pharmacokinetics parameters: Tmax, Cmax, volume of distribution, and t1/2 of HP-β-CD in plasma from NPC-1 patients by measurement at preinfusion then 2, 4, 6, 8, 8.5, 9, 10, 11, 12, 16, and 20 hours after the start of the infusions at weeks 1 and 12.

The design of the proposed study thus enables a better knowledge about pharmacokinetics of IV HP-β-CD administration, an early assessment of potential biochemical markers of response but allows for a sufficient dosing duration to enable the short-term effectiveness of HP-β-CD in NPD-C to be assessed.

In conclusion, there is a published clinical trial results, using IT administration of HP-β-CD and shows moderate response thought slowed disease progression with an acceptable safety profile. Another IT HP-β-CD clinical trial and two IV HP-β-CD clinical trials are ongoing but not results are been published yet. Regarding the route of administration, exist a debate, and treatment with HP-β-CD has used four different paradigms: IV only, IV followed by the addition of IT sequential, IV and IT initiated concurrently, and IT only. The main reason for IT route is that HP-β-CD does not cross the BBB, however, in animal models systemic HP-β-CD positively affects CNS disease thus CNS penetration may not be essential for neurologic efficacy. The ongoing clinical trials will lead to an improvement in knowledge of HP-β-CD for NPD-C treatment, setting the best route, dose and posology for NPD-C patients.
