Web Content Display
A Report: Two Cyclodextrin Products
Web Content Display
VTS-270 is Kleptose HPB.
Web Content Display
Trappsol® Cyclo™ and VTS-270:How Similar (or Different) Are They?
Web Content Display
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
Web Content Display
Molecular Fingerprints6 of Trappsol® Cyclo™ and VTS-270
Web Content Display
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
Web Content Display
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.
Web Content Display
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 |
Web Content Display
Intravenous (IV) and Intrathecal (IT): Which Route(s) of Administration to Use?
Web Content Display
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
Web Content Display
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
Web Content Display
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.
Web Content Display
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.