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A Report: Two Cyclodextrin Products

There are two cyclodextrin products being evaluated as treatments for NPC disease: CTD's Trappsol® Cyclo™ and Vtesse's VTS-270. The two products are different but similar. Read on to find out about the contrasts between the two products and between two frequently-used routes of administration.

Disclaimer: The views and opinions expressed in this page are those of Fight NPC and do not necessarily reflect the views of the families and doctors featured on Fight NPC.

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VTS-270 is Kleptose HPB.

Kleptose HPB was the name of the drug evaluated during the Phase 1/2a clinical trial (NIH).

And according to a paper published in April 20171, Kleptose HPB is the active ingredient in VTS-270. This confirms that VTS-270 is a brand name of Kleptose HPB.

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Trappsol® Cyclo™ and VTS-270:
How Similar (or Different) Are They?

Safety: Trappsol® Cyclo™ and VTS-270 are different enough that Trappsol®'s safety is not proved by VTS-270's clinical safety record. (This does not mean that Trappsol® is unsafe. Trappsol® has been used for years by patients under compassionate use. However, compassionate use data is not equivalent to clinical trial data.)

Efficacy: Trappsol® Cyclo™ and VTS-270 are similar enough that Trappsol® seems likely to be effective. (Possibly even as effective as VTS-270.)

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Trappsol® Cyclo™ and VTS-270 are Different

Degrees of Substitution

Both Trappsol® Cyclo™ and VTS-270 are proprietary mixtures of cyclodextrins that have a range of degrees of substitution (DS). The DS for Trappsol® Cyclo™ and VTS-270 are different. The median DS is 7 to 8 for Trappsol® Cyclo™; the median DS is 4 to 5 for VTS-270.2, 3

Molecular Weight

The molecular weight (MW) for Trappsol® Cyclo™ and VTS-270 are different. The average MW is 1,548 for Trappsol® Cyclo™; the average MW is 1,383 for VTS-270. This is more than a 10% difference in MW.3, 4

Solution Properties, Safety & Efficacy

According to a 2001 published paper, cyclodextrins with different total degrees of substitution exhibit different properties in solution.5 Furthermore, the safety and efficacy of Trappsol® Cyclo™ cannot be assumed based on the safety and efficacy of VTS-270.

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Molecular Fingerprints6 of Trappsol® Cyclo™ and VTS-270

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VTS-270 Has Better Data Than Trappsol® Cyclo™

Efficacy

The efficacies of Trappsol® Cyclo™ and VTS-270 have not yet been shown in a published long-term NPC animal model study.7 For Trappsol® Cyclo™, the only efficacy data is from a short-term mouse study8 and from compassionate use,9 whereas VTS-270 efficacy was tested in the same short-term mouse study and in the Phase 1/2a clinical trial (NIH).10

Safety

The safeties of Trappsol® Cyclo™ and VTS-270 have not yet been shown in a published long-term NPC animal model study.7 The only safety data for Trappsol® Cyclo™ is from compassionate use11 and a study of normal (non-NPC) cats in which Trappsol® Cyclo™ was evaluated to see whether or not it caused deafness.12 VTS-270's safety has been tested in normal (non-NPC) juvenile dogs (GLP toxicology study)13 and in the Phase 1/2a clinical trial (NIH).10

Product Consistency

Based on chemical analysis of multiple samples obtained prior to 2013, Trappsol® Cyclo™ appeared to be manufactured by multiple labs because the molecular fingerprints of the samples varied one to another.3 (In 2012, CTD launched a liquid formulation for improved consistency and no sample of this current forumulation has been requested by any group for analysis.14) VTS-270 (Kleptose HPB) is manufactured by a single company (Roquette) and the molecular fingerprints of the samples were very consistent.3

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Trappsol® Cyclo™ and VTS-270 are Similar

Hydroxypropyl‐β‐Cyclodextrin (HPβCD)

Though the two products are clearly not identical, both Trappsol® Cyclo™ and VTS-270 are proprietary mixtures of hydroxypropyl-beta-cyclodextrins. In 2013, the FDA allowed NPC families using Trappsol® Cyclo™ on compassionate use to switch to VTS-270 (Kleptose HPB) without submitting a new protocol to the FDA.

Compassionate Use

Many NPC parents who've used Trappsol® Cyclo™ or VTS-270 (Kleptose HPB) under compassionate use have reported them, anecdotally, to be safe and effective. It seems reasonable to expect that most US NPC families currently using VTS-270 under compassionate use would switch to Trappsol® Cyclo™ if VTS-270 were somehow no longer available, because Trappsol® Cyclo™ is the next-best treatment option.

Short-Term Mouse Study (Efficacy)

In a short-term study (two weeks) in Npc1 mice, Trappsol® Cyclo™ and VTS-270 (Kleptose HPB) showed equivalent cholesterol storage reduction (a measure of efficacy).8 While important, a short-term study does not provide as much insight into Trappsol® Cyclo™ and VTS-270 as a long-term study would.

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A Brief History of Cyclodextrin for Treatment of NPC Disease

Date Description Doctor Family Animal Model Human Cyclodextrin Route of Administration Footnote
Date
Dec 12, 2007
Description
First published paper on cyclodextrin for NPC disease (one-time SC injection).
Doctor
Dr. Benny Liu, M.D. et al.
Family
Animal Model
Npc1 Mouse
Human
Cyclodextrin
Sigma H107
Route of Administration
Subcutaneous (SC)
Footnote
7, 15
Date
Jan 26, 2009
Description
Second published paper on cyclodextrin for NPC disease (one-time SC injection).
Doctor
Dr. Benny Liu, M.D. et al.
Family
Animal Model
Npc1 Mouse
Human
Cyclodextrin
Sigma H107, Aldrich 332607
Route of Administration
Subcutaneous (SC)
Footnote
7, 16
Date
Jan 29, 2009
Description
First NPC patient in the world (India) to receive cyclodextrin
Doctor
Dr. Caroline Hastings, M.D.
Family
Dasgupta Family
Animal Model
Human
Aaditya
Cyclodextrin
???
Route of Administration
Intravenous (IV)
Footnote
-
Date
Mar 18, 2009
Description
First FDA approval to use cyclodextrin for NPC disease in humans.
Doctor
Dr. Caroline Hastings, M.D.
Family
Hempel Family
Animal Model
Human
Addi & Cassi
Cyclodextrin
Trappsol® Cyclo™
Route of Administration
Intravenous (IV)
Footnote
18
Date
Sep 11, 2009
Description
First published paper on cyclodextrin for NPC disease (weekly SC injections).
Doctor
Dr. Cristin Davidson, Ph.D. et al.
Family
Animal Model
Npc1 Mouse
Human
Cyclodextrin
Sigma H107
Route of Administration
Subcutaneous (SC)
Footnote
7, 19
Date
Jan 8, 2010
Description
First NPC patients outside the US (Brazil) to get cyclodextrin.
Doctor
Dr. Camilo Vieira
Family
Pessoa Family
Animal Model
Human
Marcela & Natália
Cyclodextrin
Trappsol® Cyclo™
Route of Administration
Intravenous (IV)
Footnote
21
Date
May 16, 2010
Description
Orphan Drug Status from FDA for Trappsol® Cyclo™
Doctor
Dr. Caroline Hastings, M.D.
Family
Hempel Family
Animal Model
Human
NPC Patients
Cyclodextrin
Trappsol® Cyclo™
Route of Administration
Footnote
22
Date
July 2010
Description
First published paper on cyclodextrin in NPC1 cats.
Doctor
Dr. Charles Vite, D.V.M., Ph.D. et al.
Family
Animal Model
NPC1 Cat
Human
Cyclodextrin
Sigma H107
Route of Administration
Intrathecal (IT), Subcutaneous (SC)
Footnote
7, 12
Date
Sep 23, 2010
Description
First FDA approval to inject cyclodextrin directly into the CSF in NPC patients.
Doctor
Dr. Caroline Hastings, M.D.
Family
Hempel Family
Animal Model
Human
Addi & Cassi
Cyclodextrin
Trappsol® Cyclo™
Route of Administration
Intrathecal (IT)
Footnote
23
Date
Oct 2010
Description
Second published paper on cyclodextrin for NPC disease (weekly SC injections).
Doctor
Dr. Benny Liu, M.D. et al.
Family
Animal Model
Npc1 Mouse
Human
Cyclodextrin
Sigma H107
Route of Administration
Subcutaneous (SC)
Footnote
7, 24
Date
Dec 2010
Description
Second US family to get cyclodextrin for NPC disease.
Doctor
Dr. Diane Williams, M.D.
Family
Hadley Family
Animal Model
Human
Peyton & Kayla
Cyclodextrin
Trappsol® Cyclo™
Route of Administration
Intravenous (IV)
Footnote
25
Date
Feb 2011
Description
First NPC patients outside the US (Brazil) to inject cyclodextrin directly into the CSF.
Doctor
Dr. Camilo Vieira
Family
Pessoa Family
Animal Model
Human
Marcela & Natália
Cyclodextrin
Trappsol® Cyclo™
Route of Administration
Intrathecal (IT)
Footnote
-
Date
May 2011
Description
First NPC patients in the world (Brazil) to inject cyclodextrin directly into the brain.
Doctor
Dr. Camilo Vieira
Family
Pessoa Family
Animal Model
Human
Marcela & Natália
Cyclodextrin
Trappsol® Cyclo™
Route of Administration
Intracerebroventricular (ICV)
Footnote
-
Date
Jun 22, 2011
Description
First published paper on cyclodextrin injected directly into the brains of Npc1 mice.
Doctor
Dr. Benny Liu, M.D. et al.
Family
Animal Model
Npc1 Mouse
Human
Cyclodextrin
Sigma H107
Route of Administration
Intracerebroventricular (ICV)
Footnote
7, 26
Date
Aug 30, 2011
Description
Orphan Designation from EMA for Trappsol® Cyclo™
Doctor
Dr. Caroline Hastings, M.D.
Family
French Family
Animal Model
Human
NPC Patients
Cyclodextrin
Trappsol® Cyclo™
Route of Administration
Footnote
-
Date
Jan 31, 2012
Description
Second US NPC family to get cyclodextrin injected directly into the CSF.
Doctor
Dr. Caroline Hastings, M.D.
Family
Hadley Family
Animal Model
Human
Peyton & Kayla
Cyclodextrin
Trappsol® Cyclo™
Route of Administration
Intrathecal (IT)
Footnote
27
Date
2012
Description
First NPC patient in Europe (Spain) to get cyclodextrin.
Doctor
Dr. Antonio Muñoz
Family
Lopez Family
Animal Model
Human
Alberto
Cyclodextrin
Trappsol® Cyclo™
Route of Administration
Intrathecal (IT)
Footnote
28
Date
2012
Description
GLP toxicology study in juvenile dogs to support Phase 1/2a clinical trial (NIH).
Doctor
NPC TRND Team
Family
Animal Model
Dog (non-NPC)
Human
Cyclodextrin
VTS-270 (Kleptose HPB)
Route of Administration
Intrathecal (IT)
Footnote
13
Date
2012
Description
Janssen (J&J) provides Kleptose HPB for free for future NPC1 cat studies.
Doctor
Dr. Charles Vite, D.V.M., Ph.D. et al.
Family
Animal Model
NPC1 Cat
Human
Cyclodextrin
VTS-270 (Kleptose HPB)
Route of Administration
Intrathecal (IT)
Footnote
-
Date
2012
Description
Janssen (J&J) provides Kleptose HPB for free to US NPC families.
Doctor
Family
Animal Model
Human
US NPC Patients
Cyclodextrin
VTS-270 (Kleptose HPB)
Route of Administration
Footnote
-
Date
Jan 2013
Description
Orphan Drug Status from FDA for Kleptose HPB
Doctor
NPC TRND Team
Family
Animal Model
Human
NPC Patients
Cyclodextrin
VTS-270 (Kleptose HPB)
Route of Administration
Footnote
13
Date
Feb 2013
Description
Orphan Designation from EMA for Kleptose HPB
Doctor
NPC TRND Team
Family
INPDA
Animal Model
Human
NPC Patients
Cyclodextrin
VTS-270 (Kleptose HPB)
Route of Administration
Footnote
13
Date
Feb 2013
Description
First Phase 1/2a clinical trial (NIH) to test cyclodextrin for NPC1 disease.
Doctor
Dr. Forbes D. Porter, M.D., Ph.D. et al.
Family
Animal Model
Human
NPC Patients
Cyclodextrin
VTS-270 (Kleptose HPB)
Route of Administration
Intrathecal (IT), switched from Intracerebroventricular (ICV)
Footnote
10, 13
Date
Jan 7, 2015
Description
The NIH partners with Vtesse for NPC cyclodextrin clinical trial.
Doctor
Dr. Forbes D. Porter, M.D., Ph.D. et al.
Family
Animal Model
Human
NPC Patients
Cyclodextrin
VTS-270 (Kleptose HPB)
Route of Administration
Intrathecal (IT)
Footnote
29
Date
Feb 25, 2015
Description
First published paper on increased lifespan in cyclodextrin-treated NPC1 cats.
Doctor
Dr. Charles Vite, D.V.M., Ph.D. et al.
Family
Animal Model
NPC1 Cat
Human
Cyclodextrin
Sigma H107
Route of Administration
Intrathecal (IT)
Footnote
7, 30
Date
Sep 28, 2015
Description
First Phase 2b/3 clinical trial (Vtesse) to test cyclodextrin for NPC1 disease.
Doctor
Dr. Elizabeth Berry-Kravis, M.D., Ph.D. et al.
Family
Animal Model
Human
NPC Patients
Cyclodextrin
VTS-270 (Kleptose HPB)
Route of Administration
Intrathecal (IT)
Footnote
31
Date
Jan 6, 2016
Description
Breakthrough Therapy Designation from FDA for VTS-270
Doctor
Family
Animal Model
Human
NPC Patients
Cyclodextrin
VTS-270 (Kleptose HPB)
Route of Administration
Footnote
32
Date
Apr 20, 2016
Description
First published paper comparing Trappsol® Cyclo™ and VTS-270 (short-term study)
Doctor
Dr. Cristin Davidson, Ph.D. et al.
Family
Animal Model
Npc1 Mouse
Human
Cyclodextrin
Trappsol® Cyclo™ and VTS-270 (Kleptose HPB)
Route of Administration
Subcutaneous (SC)
Footnote
8
Date
May 23, 2016
Description
Vtesse selects dose for final portion of Phase 2b/3 clinical trial.
Doctor
Family
Animal Model
Human
NPC Patients
Cyclodextrin
VTS-270 (Kleptose HPB)
Route of Administration
Intrathecal (IT)
Footnote
33
Date
Sep 6, 2016
Description
Second Phase 1/2a clinical trial (CTD Holdings) to test cyclodextrin for NPC1 disease.
Doctor
Dr. Caroline Hastings, M.D. et al.
Family
Animal Model
Human
NPC Patients
Cyclodextrin
Trappsol® Cyclo™
Route of Administration
Intravenous (IV)
Footnote
34

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Intravenous (IV) and Intrathecal (IT): Which Route(s) of Administration to Use?

Both IV and IT cyclodextrin treatment are important for NPC disease.

IT cyclodextrin is for the central nervous system (CNS).

IV cyclodextrin is for the peripheral organs.

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Intrathecal (IT) Cyclodextrin: The Most Important (Usually)

Neurological Disease

The most debilitating aspect of NPC disease is its neurological component, namely its impact on the central nervous system (CNS). Some of the neurological symptoms of NPC disease include dementia, ataxia, supranuclear vertical gaze palsy and gelastic cataplexy.35

Treats the CNS

IT cyclodextrin is injected directly into the cerebrospinal fluid (CSF) in order to treat the CNS, namely the brain and spinal cord.

Strong Data

NPC1 cats treated with cyclodextrin (IT) lived eight times longer than untreated cats and showed improved motor skills.30 Npc1 mice that received cyclodextrin injections into the brain (ICV) showed complete prevention of neurodegeneration and prolonged lifespan.26

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Intravenous (IV) Cyclodextrin: Also Important (Usually)

Systemic Disease

NPC disease also has a visceral component that affects peripheral organs such as the liver, spleen and sometimes the lungs.35 The peripheral nervous system, which controls bodily functions that are not consciously directed (e.g. breathing, heartbeat and digestive processes), is also affected by NPC disease.

Treats the Peripheral Organs

IV cyclodextrin is infused into the bloodstream and circulates to all parts of the body outside the CNS, including the liver and the spleen.

Strong Data

Npc1 mice having hepatosplenomegaly were treated with cyclodextrin (SC), resulting in a substantially smaller liver and spleen, as well as in reduced cholesterol storage in the liver, spleen and kidneys.36 NPC1 cats, when treated with very high doses of cyclodextrin (SC), showed improvement in liver function and reduced total cholesterol storage, but also evidence of pulmonary (lung) toxicity.30

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Does Systemic Administration of Cyclodextrin Benefit the CNS?

Yes, In Mice (SC)

Npc1 mice treated with cyclodextrin (SC) showed delayed onset of ataxia and weight-loss, along with reduced cholesterol storage in neurons.19

Yes (A Little),
In Cats (SC)

NPC1 cats treated with very high doses of cyclodextrin (SC) showed improved Purkinje cell survival, reduction in ataxia and tremor, and increased longevity, but also pulmonary (lung) toxicity.30 The increase in longevity for systemically-treated (SC) cats, however, was far less (average 15-25 weeks) than for intrathecally-treated (IT) cats (over 3 years).

Not Proven,
in Humans (IV)

There is no scientifically rigorous evidence to date that IV cyclodextrin, as delivered clinically, has CNS benefit in humans. NPC severity score data presented by CTD Holdings9 included many NPC patients using both IV and IT cyclodextrin, making it impossible to show that the neurological benefit was due to IV (and not IT) cyclodextrin.

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Does Systemic Administration of Cyclodextrin Cross the BBB?

Yes (Very Little),
In Mice (SC)

There is evidence that a very small percentage of cyclodextrin (SC) crosses the blood brain barrier (BBB) in Npc1 mice.37 However, cyclodextrin does not appear to actively bind to a receptor (active transport) and hence likely involves a passive mechanism.38

Yes (Very Little),
In Cats (SC)

There is also evidence that a very small percentage of cyclodextrin (SC) crosses the BBB in NPC1 cats.30 One possible explanation for this result in Npc1 mice and NPC1 cats is that they received "bolus" injections (SC) – meaning a large volume of cyclodextrin in only 2-3 minutes – that likely caused high concentrations of cyclodextrin in the blood for a short time, during which a small amount of cyclodextrin crossed the BBB passively.

Not Proven,
in Humans (IV)

There is no scientifically rigorous evidence to date that IV cyclodextrin, as delivered clinically, crosses the BBB in humans. There is no "bolus" when administering slow IV infusions of cyclodextrin over 6 hours.39 It is estimated that in order to achieve cyclodextrin concentrations in the CSF reached by IT administration, the required IV dose would be 1,000 times larger than the IT dose, which would likely be toxic.

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2. Going from general to specific, here is information about "degrees of substitution".
Cyclodextrin – Cyclodextrins are a family of ring-shaped sugar molecules made of multiple glucose units connected together. The outer surface of the cyclodextrin ring "likes" water; the inner surface of the cyclodextrin ring "likes" oils (e.g. cholesterol). This feature makes cyclodextrins useful as pharmaceutical excipients by helping non-water-soluble solids dissolve in water.
2-Hydroxypropyl-Beta-Cyclodextrin (HPBCD) – Other molecules can be "substituted" (or added) onto the beta-cyclodextrin ring. If the molecules added to the ring are "hydroxypropyl chains" (or "hydroxypropyl groups"), then the resulting cyclodextrin is a called "2-Hydroxypropyl-Beta-Cyclodextrin" (HPBCD). There are many other types of cyclodextrins besides HPBCD, which are not considered potential treatments for NPC disease and may in fact be toxic.
Degrees of Substitution (DS) – The number of hydroxypropyl chains added to the beta-cyclodextrin ring is referred to as the "degrees of substitution" for that cyclodextrin molecule. (Example: If a 2-Hydroxypropyl-Beta-Cyclodextrin molecule has a total of four hydroxypropyl chains added to it, it has "four degrees of substitution".)
Mixture – In reality, any HPBCD product – including Trappsol® Cyclo™ or VTS-270 – consists of a mixture of "2-Hydroxypropyl-Beta-Cyclodextrin" molecules with varying DS. (Example: A hypothetical HPBCD product could have a mixture of "2-Hydroxypropyl-Beta-Cyclodextrin" molecules; some with three DS, some with four DS, some with five DS, some with six DS.)
Median Degrees of Substitution – Through mass spectrometry, the specific mixture of HPBCD molecules in a product can be determined. The median DS is "the middle" DS number and is one valid representation of the DS for the mixture. (Example: A hypothetical HPBCD product with a mixture of HPBCD molecules is found to have the following range of DS: 3 DS, 3 million molecules; 4 DS, 5 million molecules; 5 DS, 5 million molecules; 6 DS, 3 million molecules. The median DS would be 4.5.)
3. The batches of Trappsol® Cyclo™ and VTS-270 (Kleptose HPB) that were analyzed for the molecular fingerprint shown on this webpage provide the basis for these statements.
4. The more hydroxypropyl chains added to the cyclodextrin molecule, the higher the "degrees of substitution" and the heavier the beta-cyclodextrin ring (because more chains mean more mass). For Trappsol® Cyclo™ and VTS-270, here is the calculation for the percent difference in molecular weight: (1,548 - 1,383) / 1,383 = 12%.
6. The term "molecular fingerprints" refers here to the mass spectrum of each product.
7. Sigma H107 – not Trappsol® Cyclo™ nor VTS-270 (Kleptose HPB) – is the HPBCD that was used in the majority of published studies in NPC animal models. (See "A Brief History of Cyclodextrin for Treatment of NPC Disease" on this page.) Sigma H107 is an HPBCD product made by Sigma Aldrich for laboratory research-use only. The average molecular weight of Sigma H107 (1396) is much closer to VTS-270 (Kleptose HPB, 1,383) than to Trappsol® Cyclo™ (1,548).
10. See Hydroxypropyl Beta Cyclodextrin for Niemann-Pick Type C1 Disease. (Prior to July 19, 2016, the clinicaltrials.gov webpage listed “2-hydroxypropyl-beta-cyclodextrin” as the interventional drug in the Phase 1/2a trial. On July 19, 2016, this was updated to “VTS-270”.)
14. From 2009 to 2012, CTD distributed a powdered version of endotoxin-controlled HPBCD called Trappsol® for compassionate use. Compounding pharmacists worked with patients to solubilize the Trappsol® powder, but not all pharmacists used the same techniques, which potentially introduced some variability in final product consistency.
In 2012, to help the patient community, CTD developed a liquid formulation of Trappsol®, now called Trappsol® Cyclo™, that would be consistent and predictable in its application. From 2012 to 2017, CTD distributed both the powdered version and the liquid formulation of Trappsol® Cyclo™ for compassionate use.
CTD's clinical trials in the US and in Europe use the liquid formulation of Trappsol® Cyclo™.
17. (Not used)
20. (Not used)
27. See Hadley Hope, January Update, dated January 24, 2012.