Adrabetadex (VTS-270): A Comprehensive Review of its Development for Niemann-Pick Disease Type C1

I. Introduction to Adrabetadex (VTS-270)

A. Overview of the Compound

Adrabetadex represents an investigational therapeutic agent developed primarily for Niemann-Pick Disease Type C (NPC). It is the United States Adopted Name (USAN) for a specific formulation of (2-hydroxypropyl)-β-cyclodextrin (HPβCD).[1] HPβCD is a chemically modified cyclic oligosaccharide derived from β-cyclodextrin, belonging to the chemical class of beta-cyclodextrins and ethers.[2] Although classified as a small molecule for regulatory and database purposes [4], HPβCD itself is not a single molecular entity but rather a complex mixture of β-cyclodextrin molecules with varying degrees of hydroxypropylation.[3] The specific formulation investigated extensively in clinical trials for NPC was designated VTS-270.[3] Other identifiers associated with this substance include Kleptose HPB.[1] The development and nomenclature history reflect its transition from a chemical entity (HPβCD) to a specific investigational drug product (VTS-270) and finally to a formally adopted name (Adrabetadex).

B. Identification and Properties

Precise identification is crucial for tracking and researching this investigational compound. Key identifiers and basic properties are summarized in Table 1.

Table 1: Adrabetadex Key Identifiers and Properties

Property	Value	Source(s)
Generic Name	Adrabetadex	1
Other Names	VTS-270, (2-hydroxypropyl)-β-cyclodextrin, HPβCD, Kleptose HPB	1
DrugBank ID	DB15146	1
CAS Number	128446-35-5	1
UNII	8W6Q67R6NX	1
Type	Small Molecule, Beta-Cyclodextrin, Ether	2
Molecular Formula	C54​H94​O38​ (representative structure)	2
Average Weight	~1351.3 Da	2
Water Solubility	418.0 mg/mL (predicted)	4
logP (predicted)	-2.3 to -12.9	1
Hydrogen Bond Donors	20 (predicted)	4
Hydrogen Bond Acceptors	38 (predicted)	4
Rule of Five Violation	Yes (predicted)	4

Adrabetadex exhibits very high predicted water solubility, consistent with its administration as an aqueous solution via intravenous (IV) and intrathecal (IT) routes in clinical trials.[4] Its hydrophilic nature is reflected in the highly negative predicted logP values. The large number of hydrogen bond donors and acceptors contribute to this solubility but also result in deviations from standard empirical rules for oral drug-likeness, such as Lipinski's Rule of Five.[4]

C. Primary Investigational Indication

The primary focus of Adrabetadex's clinical development has been Niemann-Pick Disease Type C (NPC), particularly the more common Type C1 (NPC1) subtype which accounts for approximately 95% of cases.[1] NPC1 is a rare, autosomal recessive, progressive, and ultimately fatal neurodegenerative lysosomal storage disorder primarily affecting children and adolescents.[7]

II. Mechanism of Action in Niemann-Pick Disease Type C

A. Pathophysiology of NPC

Niemann-Pick Disease Type C arises from mutations in either the NPC1 gene (in ~95% of cases) or the NPC2 gene.[8] Both NPC1 and NPC2 proteins are crucial components of the cellular machinery responsible for exporting cholesterol, particularly low-density lipoprotein (LDL)-derived cholesterol, from the late endosomal/lysosomal (LE/Ly) compartment.[9] NPC2 is thought to bind cholesterol released from LDL within the lysosome and transfer it to the NPC1 protein, a large transmembrane protein, which then facilitates its transport across the lysosomal membrane for cellular use or storage.[27]

Mutations impairing the function of either protein disrupt this egress pathway, leading to the pathological accumulation of unesterified cholesterol within the LE/Ly system.[8] This primary cholesterol storage defect triggers secondary accumulation of other lipids, including glycosphingolipids and, as recently identified, specific alkyl-lysophosphatidylcholine (alkyl-LPC) species.[14] The consequences of this lipid accumulation are widespread, causing cellular dysfunction and damage, most notably in the central nervous system (leading to progressive neurodegeneration) and visceral organs like the liver and spleen.[8]

B. Adrabetadex as a Cholesterol Modulator

Adrabetadex (HPβCD) is categorized pharmacologically as a cholesterol modulator and binding agent.[3] This classification stems from the inherent structure of cyclodextrins, which possess a hydrophilic exterior and a hydrophobic internal cavity. This cavity provides an environment suitable for forming non-covalent inclusion complexes with lipophilic molecules, including cholesterol.[28] Studies using fluorescently labeled β-cyclodextrin have demonstrated that it enters cells via the endocytic pathway, trafficking through early endosomes, late endosomes, and ultimately reaching the lysosomes – the precise subcellular compartment where cholesterol accumulation occurs in NPC.[30]

C. Proposed Mechanism of Cholesterol Mobilization

The therapeutic rationale for using Adrabetadex in NPC hinges on its ability to interact with and mobilize the cholesterol trapped within lysosomes. Once inside the lysosome, the hydrophobic cavity of HPβCD is believed to sequester or form inclusion complexes with the accumulated unesterified cholesterol.[28] This interaction effectively bypasses the dysfunctional NPC1/NPC2 export machinery.[13] By complexing with cholesterol, Adrabetadex may facilitate its release or transport out of the lysosome, acting functionally analogous to the NPC1 protein itself.[28] Preclinical studies in NPC mouse and cat models provided evidence supporting this concept, showing that systemic HPβCD administration could release trapped cholesterol from lysosomes and normalize cholesterol levels in affected tissues like the liver.[13] Once mobilized from the lysosome, the cholesterol can potentially be processed by other cellular pathways or excreted, thereby mitigating the cytotoxicity associated with its accumulation.[13]

While direct cholesterol complexation and facilitation of its transport is the most widely cited mechanism, the full picture may be more complex. Some evidence suggests HPβCD might exert broader effects, potentially involving the regulation of protein expression that contributes to restoring cellular function.[31] Furthermore, treatment with HPβCD in animal models has been shown to reduce the levels of secondary storage metabolites, such as specific alkyl-LPCs, indicating downstream effects beyond simple cholesterol removal.[14] This suggests that Adrabetadex might influence multiple aspects of the complex cellular pathology in NPC, potentially impacting lysosomal homeostasis or triggering compensatory cellular responses in addition to acting as a cholesterol shuttle. Understanding these potential pleiotropic effects is important for fully characterizing its therapeutic profile and potential off-target activities.

III. Clinical Development for Niemann-Pick Disease Type C1

A. Overview of Clinical Program

The clinical development program for Adrabetadex (VTS-270) in NPC1 has been extensive, progressing through Phase 1 to Phase 2/3 trials.[1] A key feature of the program was the exploration of different administration routes to address both the neurological and systemic manifestations of the disease. Intrathecal (IT) administration, involving injection into the cerebrospinal fluid (CSF) via lumbar puncture, was investigated to directly target the progressive neurodegeneration characteristic of NPC1.[3] Intravenous (IV) infusion was also explored, both in expanded access programs and dedicated trials, particularly for addressing systemic aspects like liver disease, and sometimes in combination with IT delivery.[9] Table 2 summarizes key clinical trials conducted for Adrabetadex in NPC1.

Table 2: Summary of Key Adrabetadex (VTS-270/HPβCD) Clinical Trials for NPC1

Trial Identifier(s)	Phase	Title / Purpose	Status	Key Feature(s)	Primary Indication
NCT01747907 (related) / NIH-led	1/2a	Open-label, dose-escalation safety and efficacy study	Completed	Intrathecal (IT) HPβCD (monthly or bi-weekly), compared to historical controls, biomarker analysis	Neurological NPC1
NCT02534844 / EudraCT 2015-002548-15	2b/3	Prospective, randomized, double-blind, sham-controlled trial of IT VTS-270	Terminated	Pivotal trial, IT VTS-270 vs sham control, primary endpoint based on NPC Neurological Severity Scale (NSS) change over 52 weeks	Neurological NPC1
NCT04958642 (formerly Part C of NCT02534844)	2b/3	Open-label extension (OLE) phase for participants from NCT02534844 and other trials	Active?	Long-term safety and efficacy follow-up with open-label IT VTS-270	Neurological NPC1
NCT03887533	1/2 IIT	Combined Intrathecal and Intravenous VTS-270 Therapy for Liver and Neurological Disease	Terminated	Investigator-Initiated Trial (IIT) exploring combined IT and IV administration	NPC1 (Liver & Neuro)
NCT03687476	2	Open-label safety and tolerability study of IT VTS-270 in pediatric subjects < 4 years	Withdrawn	Focused on very young children	Neurological NPC1
NCT03879655	2b/3	Open-label trial of IT VTS-270 in subjects previously treated under protocol VTS-301 (likely NCT02534844 OLE)	Terminated	Follow-on study for participants from the pivotal trial program	Neurological NPC1
NCT03643562	N/A	Open-label evaluation of Adrabetadex (IT)	Active?	Long-term open-label treatment, focus on risk-benefit assessment	Neurological NPC1
Phase 1/2a (WashU-led, NCT not specified)	1/2a	Open-label, multiple ascending dose trial of IV 2HPBCD for infantile liver disease	Completed	Intravenous (IV) administration in infants (0-6 months) with NPC-related liver disease, biomarker focus (TCG)	NPC1/2 Liver Disease
Expanded Access Programs (EAPs)	N/A	Compassionate use programs providing access to HPβCD (IV and/or IT) outside of formal trials	N/A	Provided real-world data on long-term use, tolerability, and perceived clinical benefit/stabilization via different routes, particularly IV for systemic manifestations	NPC1

Status information based on latest available data in snippets, may require verification on clinical trial registries.

B. Detailed Review of Key Trials and Findings

1. Phase 1/2a Intrathecal Trial (NIH-led, related to NCT01747907)

This initial human study provided critical early data on intrathecal (IT) HPβCD administration for neurological NPC1. Conducted primarily at the NIH with additional participants at Rush University Medical Center (RUMC), the trial employed an open-label, dose-escalation design.[15] Fourteen participants at NIH received monthly IT infusions, while three at RUMC received bi-weekly infusions, with doses ranging from 50 mg up to 1200 mg over 12 to 18 months.[16] Efficacy was assessed by comparing changes in the NPC Neurological Severity Score (NSS) to a historical cohort of 21 untreated NPC1 patients of similar age.[16]

The results were encouraging: the mean annual rate of NSS score increase (indicating worsening) was significantly lower in the HPβCD-treated group (1.22 ± 0.34 points/year) compared to the historical controls (2.92 ± 0.27 points/year, p=0.0002).[16] This suggested a slowing of overall neurological disease progression. Specific NSS domains showing improvement or reduced progression included ambulation, cognition, and speech.[16] Biomarker analyses provided evidence of target engagement and potential neuroprotective effects; levels of 24(S)-hydroxycholesterol (24(S)-HC), a marker of brain cholesterol metabolism, increased in CSF and serum following infusions, while levels of proteins associated with neuronal injury (FABP3, Calbindin D) decreased in CSF during treatment.[15] Long-term follow-up (2.5–3 years) data published separately for three participants from this cohort suggested sustained disease stabilization or even improvement in domains like swallowing, cognition, balance, and fine motor skills, a clinical course considered atypical for untreated NPC1.[26]

From a safety perspective, the trial established an acceptable profile overall, with no drug-related serious adverse events (SAEs) reported.[16] However, it confirmed a significant risk associated with IT administration: mid-to-high frequency hearing loss was documented in all participants.[16] This hearing loss was managed with hearing aids and reportedly did not severely impact daily communication, but it became an expected adverse event of IT therapy.[16] Transient post-dose symptoms like tiredness and ataxia were also observed, particularly at higher doses.[26]

2. Phase 2b/3 Intrathecal Trial (VTS-270-301 / NCT02534844)

Based on the promising signals from the Phase 1/2a study, a larger, pivotal Phase 2b/3 trial (NCT02534844) was initiated by Vtesse (later acquired by Sucampo, then Mallinckrodt).[6] This was a prospective, randomized, double-blind, sham-controlled study designed to definitively evaluate the efficacy and safety of IT VTS-270 in approximately 51 participants aged 4 years and older with neurological manifestations of NPC1.[8] Participants were randomized 2:1 to receive either IT VTS-270 (at a dose determined from an initial dose-finding part) or a sham procedure (needle pricks at the lumbar puncture site without drug injection) every other week for 52 weeks.[8] The primary endpoint was the change in the NPC NSS score over the 52-week period.[12] The trial included an open-label extension phase (Part C, later registered as NCT04958642).[8]

In November 2018, Mallinckrodt announced that the trial had failed to meet its primary endpoint.[12] Analysis of the top-line data revealed no statistically significant difference in disease progression, as measured by the NSS, between the VTS-270 group and the sham-control group over 52 weeks.[12] An unexpected finding was that neither the active treatment arm nor the sham arm showed the degree of disease progression anticipated for a neurodegenerative condition over the one-year observation period.[12] The specific safety findings from this trial were not detailed in the outcome announcements beyond the known risk of hearing loss associated with IT administration.[18] Following this outcome and a subsequent review, Mallinckrodt discontinued the development program, and the trial was officially terminated by the subsequent IND sponsor, Mandos, in April 2022.[3]

3. Combined Intrathecal and Intravenous Trial (NCT03887533)

Recognizing that NPC1 affects both the central nervous system and peripheral organs, an investigator-initiated Phase 1/2 trial (NCT03887533) was launched by the NICHD to evaluate the safety and potential efficacy of combining IT and IV administration of VTS-270.[1] The aim was to simultaneously address both neurological and liver disease manifestations.[4] However, this trial was terminated prematurely.[4] While results were reportedly submitted to ClinicalTrials.gov in July 2022 [34], the specific findings are not available in the provided documentation.[35] The termination likely reflects the broader challenges faced by the Adrabetadex program following the pivotal trial results and the subsequent changes in sponsorship. Consequently, the potential benefits or drawbacks of combined IT/IV therapy remain largely unevaluated in a controlled setting.

4. Insights from Expanded Access Programs (EAP) / Compassionate Use

Data gathered from patients receiving HPβCD through EAPs or compassionate use protocols provide additional context, particularly regarding IV administration and long-term use.

Reports on patients receiving IV HPβCD, sometimes preceding or concurrent with IT therapy, indicated potential benefits beyond neurological aspects.9 These included improvements or resolution of systemic manifestations like liver disease (reduced hepatomegaly, improved liver function tests) and interstitial lung disease.13 Caregivers and physicians also reported improvements in neurocognitive function (alertness, communication), behavior, and overall quality of life in patients receiving IV therapy.13 Importantly, IV administration appeared well-tolerated, with only mild infusion reactions reported, and notably, no associated hearing loss was observed.13 A dedicated Phase 1/2a trial evaluating IV 2HPBCD (VTS-270 formulation) in three infants (0-6 months) with NPC-related liver disease found the treatment was tolerated and led to improvements in liver enzymes and relevant plasma biomarkers (e.g., TCG).9

Reviews summarizing outcomes from patients receiving IT HPβCD (often in combination with IV) via expanded access generally echoed the findings from the Phase 1/2a trial, suggesting clinical stabilization or benefit in the majority of reported cases.[26] However, these reviews also noted that efficacy seemed partial and potentially influenced by factors like disease severity at treatment initiation and timing of administration.[32] Hearing loss was consistently reported as an adverse event in patients receiving IT HPβCD under these programs.[32]

C. Summary of Efficacy Findings

The efficacy profile of Adrabetadex for NPC1 presents a complex picture.

• Neurological Progression: Early-phase and open-label studies utilizing the IT route consistently suggested a slowing of neurological decline compared to historical data, primarily measured by the NSS.[16] However, the more rigorous, sham-controlled Phase 2b/3 trial failed to confirm this benefit, showing no significant difference between IT Adrabetadex and the sham procedure over 52 weeks.[12] Data from EAPs hinted at potential neurocognitive benefits with IV administration.[13]
• Biomarkers: Multiple biomarker studies provided evidence of biological activity. IT administration led to increased CSF and serum levels of 24(S)-HC (indicating improved brain cholesterol turnover) and decreased levels of CSF neuronal injury markers like FABP3 and Calbindin D in the Phase 1/2a study.[15] IV administration in infants effectively reduced plasma TCG, a biomarker linked to lysosomal cholesterol sequestration.[9] Treatment with HPβCD also reduced elevated levels of secondary storage lipids (alkyl-LPCs) in preclinical models.[14] Furthermore, levels of several CSF proteins (e.g., CALB2, CHI3L1, CCL18, PARK7, MIF, ENO2) were found to be altered in NPC1 patients compared to controls, correlated with disease severity or progression metrics (NSS, ASIS, age of onset), and some showed changes following IT HPβCD treatment, suggesting potential utility as disease or response markers.[14]
• Clinical Observations: Uncontrolled EAP reports described improvements in specific functions like swallowing and motor skills, as well as enhanced quality of life, with both IV and IT administration.[13]

The divergence between the positive signals from early-phase/uncontrolled studies (NSS slowing vs historical controls, biomarker changes, EAP reports) and the negative outcome of the pivotal, controlled Phase 2b/3 trial (no difference vs sham on NSS) remains the central conundrum in evaluating Adrabetadex's efficacy via the IT route. While the biomarker data confirm that the drug engages its target and modulates relevant biological pathways in the CNS, this did not translate into a demonstrable clinical benefit over sham control using the NSS endpoint within the one-year timeframe of the pivotal trial. This discrepancy highlights the inherent difficulties in conducting trials for slowly progressive, heterogeneous rare neurological disorders, potentially stemming from limitations of historical controls, the sensitivity of the chosen clinical endpoint over the study duration, unexpected effects of the sham procedure, or a complex relationship between measurable biological activity and functional clinical improvement.

D. Summary of Safety Profile

The safety profile of Adrabetadex is markedly dependent on the route of administration.

• Intrathecal (IT) Administration: The most significant and consistently reported adverse event associated with IT Adrabetadex is ototoxicity, manifesting as mid-to-high frequency sensorineural hearing loss.[15] This adverse event occurred in virtually all participants receiving IT therapy in the Phase 1/2a trial, appeared dose-dependent, and often required management with hearing aids.[15] The risk of hearing loss was a key safety consideration that required explicit discussion and risk-benefit assessment for patients continuing on IT therapy in later open-label studies.[18] Other IT-related adverse events included transient post-dose symptoms like tiredness and ataxia (more common at higher doses) and procedural complications like post-lumbar puncture headache and nausea, which were largely mitigated by using specialized needles.[26]
• Intravenous (IV) Administration: In contrast, IV administration of HPβCD appears to be better tolerated. Data from EAPs and the dedicated infant trial did not report hearing loss associated with the IV route.[13] Adverse events were generally mild, including manageable infusion reactions (nausea, headache).[13] No drug-related SAEs were reported in the infant IV study or linked to IV use in EAP reports.[9]

Overall, aside from the significant issue of IT-induced hearing loss, Adrabetadex seems relatively well-tolerated. The stark difference in the ototoxicity risk between the two routes is a critical factor. This suggests that the high local concentrations achieved in the CSF and potentially the inner ear environment following IT injection are responsible for the hearing damage, a threshold likely not reached with systemic IV administration. This route-dependent toxicity profile heavily influences the risk-benefit assessment for using Adrabetadex, particularly for targeting neurological symptoms via the IT route where the primary safety concern directly impacts neurological function (hearing).

Table 3: Summary of Key Efficacy and Safety Findings for Adrabetadex in NPC1

Domain	Finding	Route	Key Evidence Source(s)
Efficacy
Neurological Progression (NSS)	Slowing of progression vs historical controls	IT	Phase 1/2a (NCT01747907 related) 16
	No significant difference vs sham control over 52 weeks	IT	Phase 2b/3 (NCT02534844) 12
	Stabilization/improvement in long-term open-label/EAP	IT/IV	Phase 1/2a Follow-up, EAP reports 13
Biomarkers (CNS Target Engagement/Neuroprotection)	↑ CSF/Serum 24(S)-HC; ↓ CSF FABP3, Calbindin D	IT	Phase 1/2a (NCT01747907 related) 15
	Altered CSF levels of CALB2, CHI3L1, CCL18, etc., correlated with disease severity/progression	IT	Natural History / Phase 1/2a 17
Biomarkers (Systemic/Other)	↓ Plasma TCG (infants)	IV	Infant Phase 1/2a 9
	↓ Alkyl-LPC levels (preclinical)	N/A	Preclinical studies 14
Clinical Functions	Improvements in swallowing, motor skills, QoL reported	IT/IV	EAP reports, Phase 1/2a Follow-up 13
Systemic Disease	Improvement/resolution of liver disease, lung disease reported	IV	EAP reports 13
Safety
Hearing Loss	Mid-to-high frequency hearing loss (common, dose-dependent)	IT	Phase 1/2a, EAP reports, Phase 2b/3 (expected), OLE risk assessment 15
	Not reported as an adverse event	IV	EAP reports, Infant Phase 1/2a 13
Other IT AEs	Transient post-dose ataxia/tiredness (esp. high doses); Post-LP headache/nausea (manageable)	IT	Phase 1/2a, EAP reports 26
IV AEs	Generally well-tolerated; Mild infusion reactions (nausea, headache)	IV	EAP reports, Infant Phase 1/2a 9
Serious Adverse Events	No drug-related SAEs reported in Phase 1/2a IT trial or IV studies/EAPs; SAEs in EAPs related to devices (ports, reservoirs)	IT/IV	9

IV. Development History and Regulatory Status

A. Developer Timeline and Transitions

The development path of Adrabetadex has been marked by several transitions between research institutions and pharmaceutical companies:

1. NIH Initiation: Initial research and development, including preclinical work and the first-in-human Phase 1/2a IT trial, were conducted under the auspices of the U.S. National Institutes of Health (NIH), specifically the National Center for Advancing Translational Sciences (NCATS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).[3]
2. Vtesse, Inc.: To advance clinical development towards registration, Vtesse, Inc., a venture capital-backed startup (including funding from Pfizer Ventures and NEA), was formed. Vtesse licensed the technology and initiated the pivotal Phase 2b/3 trial (NCT02534844).[6]
3. Sucampo Acquisition: In April 2017, Sucampo Pharmaceuticals acquired Vtesse for $200 million, gaining control of the VTS-270 program.[6]
4. Mallinckrodt Acquisition: Shortly thereafter, in early 2018, Mallinckrodt plc acquired Sucampo Pharmaceuticals for approximately $1.2 billion, with VTS-270 highlighted as a key pipeline asset.[12]
5. Pivotal Trial Failure & Program Discontinuation: In November 2018, Mallinckrodt announced that the Phase 2b/3 trial failed to meet its primary endpoint.[12] Following a comprehensive review, Mallinckrodt announced in January 2021 its decision to discontinue the development program for Adrabetadex.[33]
6. Transfer to Mandos, LLC: In June 2021, Mallinckrodt entered into an agreement to divest the asset and transfer the Investigational New Drug (IND) application for Adrabetadex to Mandos, LLC. This transfer was subject to approval within Mallinckrodt's Chapter 11 bankruptcy proceedings. Mallinckrodt also committed to working with Mandos to secure additional drug supply for continued patient access through EAPs or potential future development.[3]

This complex history, involving multiple corporate acquisitions and culminating in the discontinuation of the program by a major pharmaceutical company following a pivotal trial failure, highlights the substantial risks and challenges inherent in developing treatments for ultra-rare, complex neurological diseases like NPC1. Even with promising early data and significant investment, the path to approval can be fraught with difficulty. The transfer to Mandos suggests the asset retains perceived value, potentially requiring a more focused or specialized development approach.

B. Key Regulatory Milestones

Despite the clinical setbacks, Adrabetadex received significant recognition and support from regulatory agencies during its development:

• Orphan Drug Designation: Granted by both the U.S. Food and Drug Administration (FDA) (Designation 386412) and the European Medicines Agency (EMA) for the treatment of Niemann-Pick Disease Type C.[2] This designation provides incentives for developing drugs for rare diseases.
• Breakthrough Therapy Designation: Granted by the FDA for VTS-270 in NPC1.[7] This designation is intended to expedite the development and review of drugs for serious conditions where preliminary clinical evidence indicates substantial improvement over available therapy.
• Rare Pediatric Disease Designation: Granted by the FDA.[12] This can lead to a priority review voucher upon marketing approval.
• Clinical Trial Approvals: The protocol for the pivotal Phase 2b/3 trial (NCT02534844) received approval from both the FDA and EMA, allowing the trial to proceed in multiple regions.[15]
• FDA Guidance on Approval Pathway: Following the announcement of the Phase 2b/3 trial failure, Mallinckrodt reported that the FDA indicated a willingness to consider the "totality of the data" for potential approval, rather than relying solely on the outcome of the single pivotal trial endpoint.[12] This acknowledgment of the complexities of rare disease drug development offered a potential, though challenging, path forward.

C. Current Status

As of the latest information available in the provided sources (up to late 2023/early 2024):

• The Adrabetadex development program, as previously pursued by Mallinckrodt, has been formally discontinued.[33]
• Sponsorship of the IND has been transferred, or is in the process of being transferred, to Mandos, LLC.[3]
• Major clinical trials investigating Adrabetadex, including the pivotal Phase 2b/3 IT trial (NCT02534844), the combined IT/IV trial (NCT03887533), and a related open-label follow-on study (NCT03879655), have been terminated.[3] A planned pediatric safety study (NCT03687476) was withdrawn before enrollment.[5]
• The status of ongoing open-label evaluation or extension studies (e.g., NCT03643562, NCT04958642) under Mandos' sponsorship is less clear but likely involves continued emphasis on risk-benefit assessment for participating patients, particularly regarding IT-associated hearing loss.[8]
• Adrabetadex remains an investigational agent and is not approved for marketing in any major jurisdiction.

The transfer of the IND to Mandos, coupled with the FDA's indication of considering the totality of evidence, suggests that development efforts may continue, albeit potentially with a revised strategy. Given the efficacy challenges and significant safety concerns (ototoxicity) associated with the IT route demonstrated in the pivotal trial, future efforts might pivot towards leveraging the more favorable tolerability profile of the IV route, focusing on systemic disease manifestations or exploring its potential neurocognitive benefits observed in EAPs. Alternatively, a more targeted approach using the IT route in specific patient subgroups, perhaps utilizing different endpoints (including biomarkers) or longer study durations, might be considered. The path forward remains uncertain but underscores the persistent unmet need for effective NPC1 therapies.

V. Conclusion and Future Perspective

A. Summary of Adrabetadex Profile for NPC1

Adrabetadex (VTS-270), a formulation of (2-hydroxypropyl)-β-cyclodextrin, emerged as a potential therapy for Niemann-Pick Disease Type C1 by targeting the fundamental defect of lysosomal cholesterol accumulation. Its proposed mechanism involves entering affected cells and facilitating the removal of trapped cholesterol, effectively bypassing the deficient NPC1/NPC2 pathway.

The clinical development journey yielded mixed results. Initial Phase 1/2a studies using intrathecal (IT) administration showed promising signs of slowed neurological progression compared to historical controls and favorable changes in CNS biomarkers, offering hope for this devastating neurodegenerative disease. However, this potential was tempered by the consistent observation of IT-induced hearing loss, a significant safety concern. The subsequent, pivotal Phase 2b/3 randomized, sham-controlled trial failed to demonstrate a statistically significant clinical benefit of IT Adrabetadex over the sham procedure based on the primary NSS endpoint, despite the earlier positive signals. This outcome led to the discontinuation of the development program by Mallinckrodt.

In contrast, data from expanded access programs and a small trial in infants suggested that intravenous (IV) administration was better tolerated, notably lacking the ototoxicity seen with the IT route, and might offer benefits for systemic disease aspects and potentially neurocognitive function. Following Mallinckrodt's exit, the IND was transferred to Mandos, LLC.

B. Challenges and Future Directions

The primary challenge for Adrabetadex is the discrepancy between the encouraging results from early-phase/uncontrolled studies and the negative outcome of the large, controlled pivotal trial for the IT route. Reconciling these findings and establishing definitive clinical efficacy remains crucial. The significant risk of hearing loss associated with IT administration presents a major safety hurdle that complicates its use for treating neurological symptoms.

Under the stewardship of Mandos, future development strategies will likely need to address these challenges directly. Potential avenues could include:

1. Focusing on IV Administration: Leveraging the better safety profile (absence of ototoxicity) and potential systemic/neurocognitive benefits observed in EAPs and infant studies. This might target specific aspects of NPC1 or be explored in combination with other approaches.
2. Refining IT Administration: If pursued, this would likely require identifying patient subgroups most likely to benefit, utilizing more sensitive or domain-specific endpoints beyond the overall NSS, exploring different dosing regimens, or developing strategies to mitigate hearing loss.
3. Biomarker-Guided Development: Utilizing the established biomarkers (e.g., 24(S)-HC, TCG, CSF proteins, alkyl-LPCs) more centrally in trial design, potentially as surrogate endpoints or for patient stratification, subject to regulatory acceptance.
4. Longer-Term Studies: Designing trials with longer durations might be necessary to capture the slow modification of disease progression in NPC1.

The FDA's willingness to consider the "totality of data" provides a framework, but demonstrating a favorable risk-benefit profile acceptable for regulatory approval will require robust evidence, likely from newly designed studies. Despite the setbacks, the high unmet medical need in NPC1 ensures continued interest in finding effective treatments, and Adrabetadex, particularly via the IV route or through a refined strategy, may still hold therapeutic potential.

Works cited

1. Adrabetadex | C54H94O38 | CID 138059665 - PubChem, accessed May 12, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Adrabetadex
2. ADRABETADEX - GSRS, accessed May 12, 2025, https://gsrs.ncats.nih.gov/ginas/app/beta/substances/8W6Q67R6NX
3. Adrabetadex - Mandos/National Institutes of Health - AdisInsight - Springer, accessed May 12, 2025, https://adisinsight.springer.com/drugs/800040266
4. Adrabetadex: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed May 12, 2025, https://go.drugbank.com/drugs/DB15146
5. Adrabetadex - Drug Targets, Indications, Patents - PatSnap Synapse, accessed May 12, 2025, https://synapse.patsnap.com/drug/b8dd8015f26a4b3e94ecb36e2c0539ea
6. Fledgling biotech Vtesse in $200M buyout from struggling Sucampo, accessed May 12, 2025, https://www.fiercebiotech.com/biotech/fledgling-biotech-vtesse-200m-buyout-from-struggling-sucampo
7. Vtesse, Inc. Announces FDA's Granting of Breakthrough Therapy Designation for VTS-270 in Niemann-Pick Type C1 Disease - WXPress - WuXi AppTec's, accessed May 12, 2025, https://wxpress.wuxiapptec.com/detail/617/Vtesse-Inc-Announces-FDA-s-Granting-of-Breakthrough-Therapy-Designation-for-VTS-270-in-Niemann-Pick-Type-C1-Disease
8. VTS-270 to Treat Niemann-Pick Type C1 (NPC1) Disease - Boston Children's Hospital, accessed May 12, 2025, https://www.childrenshospital.org/clinical-trials/nct02534844
9. A phase 1/2 open label nonrandomized clinical trial of intravenous 2-hydroxypropyl-β-cyclodextrin for acute liver disease in infants with Niemann-Pick C1 - PubMed Central, accessed May 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8170172/
10. Adrabetadex by Mandos for Coronary Artery Disease (CAD) (Ischemic Heart Disease): Likelihood of Approval - Pharmaceutical Technology, accessed May 12, 2025, https://www.pharmaceutical-technology.com/data-insights/adrabetadex-mandos-coronary-artery-disease-cad-ischemic-heart-disease-likelihood-of-approval/
11. Hydroxypropyl betadex [NF] - PubChem, accessed May 12, 2025, https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=135264406
12. Mallinckrodt discloses failure of pivotal trial of VTS-270 for the treatment of Niemann-Pick Type C - FirstWord Pharma, accessed May 12, 2025, https://firstwordpharma.com/story/4682647
13. Expanded access with intravenous hydroxypropyl-β-cyclodextrin to ..., accessed May 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6805667/
14. Accumulation of alkyl-lysophosphatidylcholines in Niemann-Pick disease type C1 - PMC, accessed May 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11367646/
15. Experimental treatment for Niemann-Pick disease type C1 appears safe, effective, accessed May 12, 2025, https://www.nih.gov/news-events/news-releases/experimental-treatment-niemann-pick-disease-type-c1-appears-safe-effective
16. Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick Disease, type C1: an ad-hoc analysis of a non-randomized, open-label, phase 1/2 trial - PubMed Central, accessed May 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6176479/
17. Identification of cerebral spinal fluid protein biomarkers in Niemann-Pick disease, type C1, accessed May 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9887810/
18. CLINICAL STUDY PROTOCOL Open-label Evaluation of Adrabetadex in Patients with Neurologic Manifestations of Niemann-Pick Type C Disease (NPC) - ClinicalTrials.gov, accessed May 12, 2025, https://cdn.clinicaltrials.gov/large-docs/62/NCT03643562/Prot_SAP_001.pdf
19. Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial - PubMed, accessed May 12, 2025, https://pubmed.ncbi.nlm.nih.gov/28803710/
20. Mallinckrodt's Niemann-Pick Type C drug fails to hit trial target - PharmaTimes, accessed May 12, 2025, https://pharmatimes.com/news/mallinckrodts_niemann-pick_type_c_drug_fails_to_hit_trial_target_1259268/
21. Niemann-Pick Disease Type C Market Expected to Exhibit a CAGR of 17.05% During 2025-2035, Impelled by Rising Awareness and Early Diagnosis - BioSpace, accessed May 12, 2025, https://www.biospace.com/press-releases/niemann-pick-disease-type-c-market-expected-to-exhibit-a-cagr-of-17-05-during-2025-2035-impelled-by-rising-awareness-and-early-diagnosis
22. VTS270 in Subjects with Niemann-Pick Type C1 Disease. - NHS Health Research Authority, accessed May 12, 2025, https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/vts270-in-subjects-with-niemann-pick-type-c1-disease/
23. Adrabetadex Withdrawn Phase 2 Trials for Niemann-Pick Disease, Type C Treatment, accessed May 12, 2025, https://go.drugbank.com/drugs/DB15146/clinical_trials?conditions=DBCOND0001494&phase=2&purpose=treatment&status=withdrawn
24. Experimental treatment for Niemann-Pick disease appears safe, accessed May 12, 2025, https://www.europeanpharmaceuticalreview.com/news/65610/experimental-treatment-niemann-pick/
25. Study of IV VTS-270 for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C - ClinicalTrials.Veeva, accessed May 12, 2025, https://ctv.veeva.com/study/study-of-iv-vts-270-for-infantile-liver-disease-associated-with-niemann-pick-disease-type-c
26. Long-Term Treatment of Niemann-Pick Type C1 Disease with ..., accessed May 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5857219/
27. NPC intracellular cholesterol transporter 1 (NPC1)-mediated cholesterol export from lysosomes - PMC, accessed May 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6364775/
28. Mechanism of Action of Hydroxypropyl Betacyclodextrin to Treat Niemann-Pick Disease, accessed May 12, 2025, https://www.youtube.com/watch?v=5XLIZQf3cZU
29. Investigating the Mechanism of Cyclodextrins in the Treatment of Niemann-Pick Disease Type C Using Crosslinked 2-Hydroxypropyl-β-cyclodextrin - PubMed, accessed May 12, 2025, https://pubmed.ncbi.nlm.nih.gov/33079457/
30. Methyl-β-cyclodextrin restores impaired autophagy flux in Niemann-Pick C1-deficient cells through activation of AMPK - PubMed Central, accessed May 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5584846/
31. Molecular Mind Games: The Medicinal Action of Cyclodextrins in Neurodegenerative Diseases - PMC - PubMed Central, accessed May 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10136110/
32. Early experience with compassionate use of 2 hydroxypropyl-beta-cyclodextrin for Niemann-Pick type C disease: review of initial published cases - PubMed, accessed May 12, 2025, https://pubmed.ncbi.nlm.nih.gov/28155026/
33. Mallinckrodt gave up further development of adrabetadex (VTS-270; HPBCD), accessed May 12, 2025, https://cyclodextrinnews.com/2021/06/21/mallinckrodt-gave-up-further-development-of-adrabetadex-vts-270-hpbcd/
34. NCT03887533: A reported trial by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), accessed May 12, 2025, https://fdaaa.trialstracker.net/trial/NCT03887533/
35. accessed January 1, 1970, https://clinicaltrials.gov/study/NCT03887533