AU2019330954B2

AU2019330954B2 - Neuroblastoma treatment with taurolidine hydrolysis products

Info

Publication number: AU2019330954B2
Application number: AU2019330954A
Authority: AU
Inventors: Robert Diluccio; Bruce Reidenberg
Original assignee: Cormedix Inc
Current assignee: Cormedix Inc
Priority date: 2018-08-28
Filing date: 2019-08-28
Publication date: 2025-11-13
Anticipated expiration: 2039-08-28
Also published as: JP2024170590A; JP2021535163A; CN113347976A; EP3843746A4; CA3111057A1; KR20210050544A; WO2020047113A1; AU2019330954A1; EP3843746A1

Abstract

Neuroblastoma is a tumor primarily affecting children. The current standard of care is not curative except in the rare case of a surgically- resectable lesion, although very high survival rates have been documented for low-risk neuroblastoma and moderate-risk neuroblastoma. Taurolidine was developed as an anti-infective, but it has been found to have surprising oncolytic activity in cell cultures and now in a rodent cancer model. The efficacy in rodent model is superior to the efficacy in cell culture. This invention relates to the use of taurolidine hydrolysis products (tarultam and/or taurinamide and/or methylene glycol and/or selected combinations thereof) for the treatment of neuroblastoma in juvenile mammals.

Description

WO wo 2020/047113 PCT/US2019/048592 1

NEUROBLASTOMA TREATMENT WITH TAUROLIDINE HYDROLYSIS PRODUCTS

Reference ToPending Reference To PendingPrior Prior Patent Patent Applications Applications

This patent application:

(i) is a continuation-in-part of pending prior

U.S. Patent Application Serial No. 15/403,876, filed

01/11/2017 by CorMedix Inc. and Robert DiLuccio for

THERAPEUTIC NANOPARTICLES FOR THE TREATMENT OF

NEUROBLASTOMA AND OTHER CANCERS (Attorney's Docket No.

CORMEDIX-14), which patent application claims benefit

of prior U.S. Provisional Patent Application Serial

No. 62/277,243, filed 01/11/2016 by CorMedix Inc. and

Robert DiLuccio for NANOPARTICLE SYSTEM FOR THE

PROV

WO wo 2020/047113 PCT/US2019/048592 2

TREATMENT OF NEUROBLASTOMA (Attorney's Docket No.

CORMEDIX-14 PROV) PROV);;and and

(ii) claims benefit of pending prior U.S.

Provisional Patent Application Serial No. 62/723,618,

filed 08/28/2018 by Cormedix Inc. and Bruce Reidenberg

et et al. al. for forNEUROBLASTOMA NEUROBLASTOMATREATMENT WITHWITH TREATMENT TAUROLIDINE TAUROLIDINE

HYDROLYSIS PRODUCTS (Attorney's Docket No. CORMEDIX-33

PROV). PROV)

The three (3) above-identified patent

applications are hereby incorporated herein by

reference.

Field Of The Invention

This invention relates to therapeutic methods and

compositions in general, and more particularly to

therapeutic methods and compositions for the treatment

of neuroblastoma in a juvenile mammalian body.

Background Of Background OfThe TheInvention Invention

Neuroblastoma (NB) is the most common

extracranial solid cancer in childhood and the most

WO wo 2020/047113 PCT/US2019/048592 3

common cancer in infancy, with an incidence of about

six hundred fifty cases per year in the U.S., and a

hundred cases per year in the UK. Nearly half of

neuroblastoma cases occur in children younger than two

years. It is a neuroendocrine tumor, arising from any

neural crest element of the sympathetic nervous system

(SNS). Neuroblastoma most frequently originates in

one of the adrenal glands, but can also develop in

nerve tissues in the neck, chest, abdomen, or pelvis.

Note Note that that while whileneuroblastoma neuroblastomaarises fromfrom arises nerve nerve

tissues, it is not a tumor of the central nervous

system system (CNS) . (CNS).

Neuroblastoma is one of the few human

malignancies known to demonstrate spontaneous

regression from an undifferentiated state to a

completely benign cellular appearance.

Neuroblastoma Neuroblastomaisisa adisease exhibiting disease extreme exhibiting extreme

heterogeneity, and is stratified into three risk

categories: low-risk, intermediate-risk, and high-

risk. Low-risk neuroblastoma is most common in

infants and good outcomes are common with observation only or surgery, whereas high-risk neuroblastoma is difficult to treat successfully even with the most intensive multi-modal therapies available.

When the neuroblastoma lesion is localized, it is

generally curable. However, long-term survival for

children older than 18 months of age with advanced

disease of age is poor, despite aggressive multimodal

therapy, e.g., intensive chemotherapy, surgery,

radiation therapy, stem cell transplant,

differentiation agent isotrentinoin (also called 13- -

cis-retinoic acid), and frequently immunotherapy with

anti-GD2 immunotherapy with anti-GD2 monoclonal

antibody therapy.

Biologic and genetic characteristics have been

identified which, when added to classic clinical

staging, has allowed patient assignment to risk groups

for planning treatment intensity. These criteria

include age of the patient, extent of disease spread,

microscopic appearance, and genetic features including

DNA ploidy and N-myc oncogene amplification (N-myc

regulate regulate micro microRNAs) . These RNAs). Thesecriteria areare criteria used to to used

WO wo 2020/047113 PCT/US2019/048592 5

classify the neuroblastoma into low-risk,

intermediate-risk, and high-risk disease. A recent

biology study (COG ANBL00B1) analyzed 2,687

neuroblastoma patients and the spectrum of risk

assignment was determined: 37% of neuroblastoma cases

are low-risk, 18% of neuroblastoma cases are

intermediate-risk, and 45% of neuroblastoma cases are

high-risk. Note that there is some evidence that the

high- and low-risk high- and low-risktypes types of of neuroblastoma neuroblastoma are are caused caused

by different mechanisms, and are not merely two

different degrees of expression of the same mechanism.

The therapies for these different risk categories

are very different.

Low-risk neuroblastoma Low-risk neuroblastoma can can frequently frequently be observed be observed

without any treatments at all or cured with surgery

alone.

Intermediate-risk neuroblastoma is generally

treated with surgery and chemotherapy.

High-risk - neuroblastoma neuroblastoma isis generally generally treated treated with with

intensive chemotherapy, surgery, radiation therapy,

bone marrow/hematopoietic stem cell transplantation, biological-based therapy with 13-cis-retinoic acid

(isotretinoin or Accutane) and antibody therapy

(usually administered with the cytokines GM-CSF and

IL-2. IL-2. cytokines). cytokines) .

With current treatments, patients with low-risk

neuroblastoma and intermediate-risk neuroblastoma have

an excellent prognosis, with cure rates above 90% for

low-risk neuroblastoma and 70-90% cure rates for

intermediate-risk neuroblastoma. In contrast, therapy

for high-risk neuroblastoma over the past two decades

has resulted in cures only about 30% of the time. The

addition of antibody therapy has raised survival rates

for high-risk neuroblastoma significantly. In March

2009, an early analysis of a Children's Oncology Group

(COG) study with 226 high-risk neuroblastoma patients

showed that two years after stem cell transplant 66%

of the group randomized to receive ch14.18 antibody

with GM-CSF and IL-2 were alive and disease-free

compared to only 46% in the group that did not receive

the antibody. The randomization was stopped SO so all patients enrolling in the trial could receive the antibody therapy.

Chemotherapy agents used in combination have been

found to be effective against neuroblastoma. Agents

commonly used in induction and for stem cell

transplant conditioning are platinum compounds

(cisplatin, carboplatin), alkylating agents

(cyclophosphamide, ifosfamide, melphalan,

topoisomerase II inhibitor) and vinca alkaloids

(vincristine). (vincristine).. Some Some newer newer regimens regimensinclude include

topoisomerase I inhibitors (topotecan and irinotecan)

in induction which have been found to be effective

against recurrent disease.

However, However, aa need needexists exists for for a new a new method method and and

composition which are effective against neuroblastoma.

Summary Of The Invention

In accordance with the present invention,

selected hydrolysis products of taurolidine are used

to treat neuroblastoma. The selected hydrolysis products of taurolidine may comprise at least one from the group consisting of: taurinamide; taurultam; methylene glycol; taurultam and taurinamide in a ratio of 1 taurultam: taurultam:77 taurinamide; taurinamide; and and taurultam, taurinamide and methylene glycol in a ratio of 1 taurultam: 7 taurinamide:1 taurinamide: 11 methylene methylene glycol. glycol.

The taurinamide is given with a dosage range of

from 5 mg/kg to 280 mg/kg, with optimal range between

5 mg/kg and 60 mg/kg, from once daily through weekly,

for an effective period of time based on individual

patient response.

The taurultam is given with a dosage range of

from 5 mg/kg to 280 mg/kg, with optimal range between

5 mg/kg and 60 mg/kg, from once daily through weekly,

for an effective period of time based on individual

patient response.

The methylene glycol is given with a dosage range

of from 2.5 mg/kg to 160 mg/kg, with optimal range between 2.5 mg/kg between 2.5 mg/kgand and3030 mg/kg, mg/kg, from from onceonce daily daily through weekly,for through weekly, foranan effective effective period period of time of time basedbased on individual patient response.

The taurultam and taurinamide (in a ratio of 1

taurultam: 7 taurinamide) is given with a dosage range

of Taurultam from 5 mg/kg to 280 mg/kg, with optimal

range between 5 mg/kg and 40 mg/kg, combined with

Taurinamide from 5 mg/kg to 280 mg/kg, with optimal

range from 35 mg/kg to 40 mg/kg, from once daily

through weekly, for an effective period of time based

on individual patient response.

The taurultam, taurinamide and methylene glycol

(in a ratio of 1 taurultam: 7 taurinamide: 1 methylene

glycol) is given with a dosage range of Taurultam from

5 mg/kg to 280 mg/kg, with optimal range between 5

mg/kg and 40 mg/kg, combined with Taurinamide with a

dosage range of from 5 mg/kg to 280 mg/kg, with

optimal range from 35 mg/kg to 40 mg/kg, further

combined with methylene glycol with a dosage range of

from 2.5 mg/kg to 160 mg/kg, with optimal range from 5

mg/kg to 40 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.

In one preferred form of the invention, the

selected hydrolysis products (i.e., the active

ingredients) can be delivered systemically in a

"shielded form" SO so that they can reach the site of the

neuroblastoma without premature degradation.

More particularly, in one preferred form of the

invention, the hydrolysis products can be delivered in

the form of a nanoparticle, where the nanoparticle

comprises a core of the hydrolysis product and an

exterior coating which is configured to prevent

premature exposure of the hydrolysis product prior to

the arrival of the nanoparticle to the tumor site.

The exterior coating breaks down as the nanoparticle

travels from the site of the insertion to the site of

the tumor SO so as to release the hydrolysis product

intact at the site of the tumor. In one preferred

form of the invention, the coating comprises an

absorbable polymer or lipid which breaks down as the nanoparticle travels from the site of insertion to the site of the tumor.

In another form of the invention, the hydrolysis

products may be delivered using a polymer system which

is configured to delay degradation of the active

ingredient. By way of example but not limitation, the

hydrolysis products may be "pegylated" using

polyethylene glycols (PEGs) to delay premature of

degradation of the active ingredient.

The selected hydrolysis products of taurolidine

can be given systemically, as either a single agent or

in combination with other oncolytic agents and/or

radiotherapy.

Brief Description Of The Drawings

These and other objects and features of the

present invention will be more fully disclosed or

rendered obvious by the following detailed description

of the preferred embodiments of the invention, which

is to be considered together with the accompanying drawings wherein like numbers refer to like parts, and further wherein:

Fig. 1 is a graph showing that leukemia cell

lines appear more sensitive to the effects of

taurolidine compared to healthy lymphocytes in vitro

(not in vivo) ;

Fig. 2 is a graph showing that neuroblastoma cell

lines are more sensitive to a decrease in viability

due to taurolidine when compared to healthy

fibroblasts (BJ on graph) in vitro (not in vivo) ;

Figs. 3-6 are graphs or photographs showing that

taurolidine given to CB57 SCID mice with measurable

tumors from a neuroblastoma cell line implanted

subcutaneously in the CB57 SCID mice has efficacy in

IMR5 tumors and measurable efficacy in SK-N-AS tumors

in vivo (not in vitro) ;

Figs. 7 and 8 are graphs showing that

statistically significant decreases in tumor size were

achieved when taurolidine was administered to treat

mice with a different cell line (SK-N-AS) also derived

WO wo 2020/047113 PCT/US2019/048592 13

from neuroblastoma but overall survival was not

significantly different from control;

Fig. 9 illustrates the mechanism for the

hydrolysis of taurolidine;

Fig. 10 is a chart showing the mean

pharmacokinetic parameters of taurinamide; and

Fig. 11 is a chart showing the mean

pharmacokinetic parameters of taurultam.

Detailed Description Of The Invention

Taurolidine is a well known antimicrobial with a

published mechanism of action and antimicrobial

spectrum. Taurolidine is unstable in circulation and

therefore has not been successfully developed for

systemic infections. Taurolidine has demonstrated

efficacy in local application for peritonitis and for

prevention of infection when infused as a catheter-

lock solution.

Taurolidine has recently been investigated for

oncolytic activity and found to have inhibitory effect

on cell lines in culture, in combination with standard

WO wo 2020/047113 PCT/US2019/048592 14

chemotherapy or alone. Despite claims that in vitro

inhibitory concentrations are clinically achievable,

the only published human pharmacokinetic study showed

NO NO measurable measurableconcentration concentrationof of taurolidine in healthy taurolidine in healthy

volunteers when 5 grams of taurolidine were given

intravenously by 20 minute infusion. This is believed

to be due to the rapid hydrolysis of taurolidine when

administered systemically in a mammalian body.

It has been found that leukemia cell lines appear

more sensitive to the effects of taurolidine compared

to healthy lymphocytes in vitro (not in vivo) vivo).See See

Fig. 1.

It has also been found that neuroblastoma cell

lines are more sensitive to a decrease in viability

due to taurolidine when compared to healthy

fibroblasts in fibroblasts invitro vitro(not in in (not vivo) . See vivo) SeeFig. Fig.2.2.

Furthermore, taurolidine given to CB57 SCID mice

with measurable tumors from a neuroblastoma cell line

implanted subcutaneously in the CB57 SCID mice showed

efficacy in IMR5 tumors and measurable efficacy in SK-

vitro). N-AS tumors in vivo (not in vitro . See Figs. 3-6.

WO wo 2020/047113 PCT/US2019/048592 15

Note that Note that the theininvitro vitroefficacy forfor efficacy neuroblastoma neuroblastoma

cell lines is seen at the highest two concentrations

tested, i.e. i.e.,, above above 40 40 microMolar microMolar [1

[1 Mole/Liter Mole/Liter XX 284 284

gm/Mole X 1Mole/1,000,000 microMoles X 40 microMolar X

1000 mg/gram = 11 mg/ liter = 11 mcg/mL], as seen in

Fig. 2 (where only the SK-N-MC cell line, a

neuroepithelioma cell line, is below 50% cell

viability). The IC50 values are between 80-140

microMolar for neuroblastoma cell lines, and 200

microMolar for normal fibroblasts (see Fig. 2).

The efficacy observed with taurolidine treatment

of IMR5 cell implants in vivo (Figs. 3-6), despite

IRM5's relatively high IC50 in vitro (Fig. 2),

supports the conclusion that the hydrolysis products

of taurolidine may have independent anti-neoplastic

activity. In other words, taurolidine treatment of

neuroblastoma cells in vivo appears to be

significantly more effective than taurolidine

treatment of neuroblastoma cells in vitro. Since it

is known that taurolidine metabolizes to taurolidine

hydrolysis products in vivo, this would support the

WO wo 2020/047113 PCT/US2019/048592 16

conclusion that the hydrolysis products of taurolidine

may have significant anti-neoplastic activity against

neuroblastoma cells. In fact, it may be that the

hydrolysis products of taurolidine have higher

efficacy against neuroblastoma cells than taurolidine

which has not been hydrolyzed.

Statistically significant decreases in tumor size

were achieved when taurolidine was administered to

treat mice with a different cell line (SK-N-AS) also

derived from neuroblastoma, though overall survival of

the mice implanted with the tumor was not

statistically different from the control. See Figs. 7

and 8.

It has now been discovered that selected

hydrolysis products of taurolidine may be used to

treat neuroblastoma. The mechanism for the hydrolysis

of taurolidine is shown in Fig. 9. The selected

hydrolysis products of taurolidine that may be used to

treat neuroblastoma may comprise at least one from the

group consisting of:

taurinamide; taurultum; methylene glycol; taurultam and taurinamide in a ratio of 1 taurultam: 7 taurinamide; and taurultam, taurinamide and methylene glycol in a ratio of 1 taurultam: 7 taurinamide: 1 methylene glycol.

The taurinamide is given with a dosage range of

from 5 mg/kg to 280 mg/kg, with optimal range between

5 mg/kg and 60 mg/kg, from once daily through weekly,

for an effective period of time based on individual

patient response. The mean pharmacokinetic parameters

of taurinamide are shown in Fig. 10.

The taurultam is given with a dosage range of

from 5 mg/kg to 280 mg/kg, with optimal range between

5 mg/kg and 60 mg/kg, from once daily through weekly,

for an effective period of time based on individual

patient response. The mean pharmacokinetic parameters

of taurultam are shown in Fig. 11.

The methylene glycol is given with a dosage range

of from 2.5 mg/kg to 160 mg/kg, with optimal range

between 2.5 mg/kg and 30 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.

The taurultam and taurinamide (in a ratio of 1

taurultam:7 taurultam: 7taurinamide) taurinamide)is isgiven givenwith witha adosage dosagerange range

of Taurultam from 5 mg/kg to 280 mg/kg, with optimal

range between 5 mg/kg and 40 mg/kg, combined with

Taurinamide from 5 mg/kg to 280 mg/kg, with optimal

range from 35 mg/kg to 40 mg/kg, from once daily

through weekly, for an effective period of time based

on individual patient response.

The taurultam, taurinamide and methylene glycol

(in a ratio of 1 taurultam: 7 taurinamide: 1 methylene

glycol) is given with a dosage range of Taurultam from

5 mg/kg to 280 mg/kg, with optimal range between 5

mg/kg and 40 mg/kg, combined with Taurinamide with a

dosage range of from 5 mg/kg to 280 mg/kg, with

optimal range from 35 mg/kg to 40 mg/kg, further

combined with methylene glycol with a dosage range

from 2.5 mg/kg to 160 mg/kg, with optimal range from 5

Dose selectionfor Dose selection forthe the hydrolysis hydrolysis products products werewere

calculated as follows:

AUC 0-inf Taurultam/AUC AUC 0-inf Taurultam/AUC 0-inf 0-inf Taurinamide Taurinamide = 42.9/312.7 = 42.9/312.7

= 0.14

Since the molecular weight difference is only a

single methyl group, the use of weight-based AUC does

not need to be corrected. Therefore, the target ratio

when givingTaurultam when giving Taurultamand and Taurinamide Taurinamide in combination in combination

is 0.14 or 1:7. And the target ratio when giving

taurultam and taurinamide and methylene glycol in

combination is 1:7:1.

Effective dosage was computed by computing the

human equivalent dosage from the effective mouse dose

using the formula:

[Human equivalent dose = mouse mg/kg dose X 1 adult

human/12 mice X 25 child BSA ratio/37 adult BSA ratio

= child dose in mg/kg

(https://www.fda.gov/downloads/drugs/guidances/ucm0789 (https://www.fda.gov/downloads/drugs/guidances/ucm0789

32.pdf).

In one preferred form of the invention, the

selected hydrolysis products (active ingredient) can

be delivered systemically in a "shielded form" SO so that

they can reach the site of the neuroblastoma to avoid

premature degradation.

More particularly, More particularly,ininone preferred one formform preferred of the of the

invention, the hydrolysis products can be delivered in

the form of a nanoparticle, where the nanoparticle

comprises a core of the hydrolysis product and an

exterior coating which is configured to prevent

premature exposure of the hydrolysis product prior to

the arrival of the nanoparticle to the tumor site.

The exterior coating breaks down as the nanoparticle

travels from the site of insertion to the site of the tumor SO so as to release the hydrolysis product intact at the site of the tumor. In one preferred form of the invention, the coating comprises an absorbable polymer or lipid which breaks down as the nanoparticle travels from the site of insertion to the site of the tumor. By way of example but not limitation, the coating can be created from combinations of copolymers and multimers derived from polymers structured from l- 1- - lactide, glycolide, e-caprolactone, p-dioxanone, and trimethylene carbonate. The coating may also be associated with glycols such as polyethylene glycols

(PEGs), which can either be linear or multi-arm

structures.

If desired, the nanoparticle may comprise an

excipient (e.g., a buffer for providing enhanced

hydrolytic stability of the hydrolysis product within

the nanoparticle) the nanoparticle).

Additionally, if desired, the nanoparticle can

further comprise a coating, wherein the coating is

configured to target the nanoparticle to the site of a

SO as to improve the efficacy of the neuroblastoma so

WO wo 2020/047113 PCT/US2019/048592 22

hydrolysis product for treatment of the neuroblastoma.

In one preferred form of the invention, the coating

comprises binding molecules which are configured to

target delivery of the nanoparticle to specific

tissue. By way of example but not limitation, the

coating for the nanoparticle comprises a monoclonal

antibody against N-type calcium channels (e.g., an

anti-N-type calcium channel exofacial Fab fragment)

for causing the nanoparticle to bind to neural tissue

(e.g. (e.g.,to toaaneuroblastoma neuroblastomatumor) tumor).

In another form of the invention, the hydrolysis

products may be delivered using a polymer system which

is configured to delay degradation of the active

ingredient and/or optimize the release properties of

the active ingredient. By way of example but not

limitation, the hydrolysis products may be "pegylated"

using polyethylene glycols (PEGs) to delay premature

of degradation of the active ingredient and/or

optimize the release properties of the active

ingredient.

30 Apr 2021 2019330954 30 Apr 2021

- 23

The selected hydrolysis products of taurolidine

can be given systemically, as either a single agent or

in combination with other oncolytic agents and/or

radiotherapy. Examples of oncolytic agents that can 2019330954

be combined with the hydrolysis products of

taurolidine for systemic delivery are platinum

compounds (cisplatin, carboplatin), alkylating agents

(cyclophosphamide, ifosfamide, melphalan,

topoisomerase II inhibitor), vinca alkaloids

(vincristine), and topoisomerase I inhibitors

(topotecan and irinotecan).

Modifications Modifications

While the present invention has been described in

terms of certain exemplary preferred embodiments, it

will be readily understood and appreciated by those

skilled in the art that it is not so limited, and that

many additions, deletions and modifications may be

made to the preferred embodiments discussed above

while remaining within the scope of the present

invention. invention.

30 Apr 2021 2019330954 30 Apr 2021

- 24

Throughout this specification and the claims

which follow, unless the context requires otherwise,

the word "comprise", and variations such as

"comprises" and "comprising", will be understood to 2019330954

imply the inclusion of a stated integer or step or

group of integers or steps but not the exclusion of

any other integer or step or group of integers or

steps.

The reference to any prior art in this

specification is not, and should not be taken as, an

acknowledgement or any form of suggestion that the

prior art forms part of the common general knowledge

in Australia. in Australia.

Claims

13 Oct 2025 What Is Claimed Is:

1. A method for treating neuroblastoma, the method comprising: administering a composition to a patient, wherein 2019330954

the composition comprises taurultam and taurinamide in a weight ratio of 1 taurultam:7 taurinamide.

2. A method according to claim 1 wherein the composition is administered in conjunction with an oncolytic agent and/or radiotherapy.

3. A method according to claim 1 wherein the composition consists of taurultam and taurinamide in a weight ratio of 1 taurultam:7 taurinamide.

4. A method according to claim 3 wherein the taurultam and taurinamide (in a weight ratio of 1 taurultam:7 taurinamide) is given with a dosage range of Taurultam from 5 mg/kg to 280 mg/kg, with optimal range between 5 mg/kg and 40 mg/kg, combined with Taurinamide from 5 mg/kg to 280 mg/kg, with optimal range from 35 mg/kg to 40 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.

13 Oct 2025

5. A method according to claim 3 wherein the composition is administered in conjunction with an oncolytic agent and/or radiotherapy.

6. A method according to claim 1 wherein the 2019330954

composition consists of taurultam, taurinamide and methylene glycol in a weight ratio of 1 taurultam:7 taurinamide:1 methylene glycol.

7. A method according to claim 6 wherein the taurultam, taurinamide and methylene glycol (in a weight ratio of 1 taurultam:7 taurinamide:1 methylene glycol) is given with a dosage range of Taurultam from 5 mg/kg to 280 mg/kg, with optimal range between 5 mg/kg and 40 mg/kg, combined with a dosage range of Taurinamide from 5 mg/kg to 280 mg/kg, with optimal range from 35 mg/kg to 40 mg/kg, further combined with methylene glycol with a dosage range of from 2.5 mg/kg to 160 mg/kg, with optimal range from 5 mg/kg to 40 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.

8. A method according to claim 6 wherein the composition is administered in conjunction with an oncolytic agent and/or radiotherapy.

13 Oct 2025

9. A method according to claim 1 wherein the composition is delivered to the patient using one from the group consisting of parenteral delivery, intramuscular delivery and intravenous delivery. 2019330954

10. A method according to claim 1 wherein the composition is included in a nanoparticle, and further wherein the nanoparticle is configured to delay hydrolysis of the composition until the nanoparticle reaches the site of a tumor.

11. A method according to claim 10 wherein the nanoparticle comprises a core of the composition and an exterior coating, wherein the exterior coating is configured to prevent exposure of the composition prior to arrival of the nanoparticle at the site of the tumor.

12. A method according to claim 11 wherein the exterior coating comprises an absorbable polymer or lipid which breaks down as the nanoparticle travels from the site of insertion to the site of the tumor.

13. A method according to claim 1 wherein the composition is delivered using a polymer system which is configured to delay hydrolysis of the composition.

13 Oct 2025

14. A method according to claim 13 wherein the composition is “pegylated” using polyethylene glycols (PEGs) to delay premature of hydrolysis of the composition. 2019330954

15. A method according to claim 1 wherein the composition further comprises methylene glycol.

16. Use of a composition in the manufacture of a medicament for the treatment of neuroblastoma, wherein the composition comprises taurultam and taurinamide in a weight ratio of 1 taurultam:7 taurinamide.

17. A composition for treating neuroblastoma, the composition comprising taurultam and taurinamide in a weight ratio of 1 taurultam:7 taurinamide.