ND0701: A Safer and More Tolerable Apomorphine Formulation For Continuous Subcutaneous Administration – MRI-Based Quantitative AnalysesRonit Shaltiel-Karyo1, Yonit Tsarfati1, Anna Rubinski1, Eduardo Zawoznik1, Irena Weinstock1, Mara Nemas1, Yael S. Schiffenbauer2, Abraham Nyska3, Oron Yacoby-Zeevi1

1. NeuroDerm Ltd., Rehovot, Israel 2. Aspect Imaging, Shoham, Israel 3. Consultant in Toxicologic Pathology, Timrat and Tel Aviv University, Israel

■ Subcutaneous apomorphine is currently used for the management of sudden, unexpected and refractory oral LD-induced 'off' states in fluctuating PD patients either as intermittent rescue injections or continuous infusions [1].

■ Apomorphine hydrochloride provides a similar level of motor benefit to LD as well as a possible anti-dyskinetic effect [2]. There have also been sporadic reports of its possible beneficial effect on non-motor symptoms, commonly appearing in PD patients and affecting their quality of life. Nevertheless, its long-term use is limited by compliance and injection site skin reactions, resulting in the formation of nodules that can cause discomfort and may impact the effectiveness of the drug therapy [2-3].

■ Neuroderm Ltd (Rehovot, Israel) has developed a novel apomorphine formulation, ND0701, for continuous subcutaneous delivery that contains apomorphine-base. In preclinical studies we detected superior local safety and tolerability with equivalent PK of up to 5 fold concentrated apomorphine in comparison to a commercially available apomorphine-HCl.

■ Domestic Landrace × large White pigs, 3 males and 3 females, weighting 45±5kg were administered a single continuous SC infusion of 50mg apomorphine for 20 - 24 hours. ApoGo® 10mg/ml apomorphine-HCl (Britannia Pharmaceuticals, UK), was used as a reference. In all experiments, 4 formulations were compared: 1% ND0701, 2.5% ND0701, 0.5% apomorphine-HCl or 1% apomorphine-HCl.

The following analyses were made:■ PK analysis Was quantified using LC-MS/MS.

■ In vivo MRI MRI scans of infusion site were performed using a 0.35 Tesla Magnetom-C Siemens MRI

machine.

■ Ex-Vivo MRI MRI scans of fixed tissue samples (i.e., injection sites) were performed, from using a 1 Tesla

M2TM Aspect imaging MRI machine.

■ Histopathological evaluation The histological evaluation consisted of a subjective description of the observed tissue reaction.

The scoring of the lesions was done using a semi quantitative system based on the criteria explained by Shackelford et al [4].

The aim of this study was to investigate the local safety and PK of a newly developed, concentrated, formulation of apomorphine-base, ND0701-2.5%, as compared to a commercially available apomorphine-HCl, in pigs.

Introduction

Methods

Objective

ResultsThe pharmacokinetic (PK) profile of apomorphine following continuous SC administration was similar among all 4 tested formulations

Figure 1:

Plasma concentrations of apomorphine following 20h infusion: Pigs (n=6) were continuously administered on different occasions with 1% and 2.5% ND0701 and 0.5% and 1% apomorphine-HCl formulations, for a period of 20h, corresponding to a total dose of 50 mg apomorphine. Plasma samples were collected for 24h from the start of infusion. (A) Mean apomorphine plasma concentration-time profiles, expressed in ng/ml. (B) PK parameters, described as Mean (±SD) values (median for Tmax).

Figure 2:

The intensity of the lesion was demonstrated in 3D representative images (A) 2 weeks and (B) 4 weeks following a single 20h infusion of apomorphine formulations: blue color indicates normal fat tissue; orange-red indicates affected tissue. (C) The mean volume of SC lesions (n=6).

The SC inflammation seen in the ND0701 infused sites exhibited only a minimal, chronic inflammatory reaction characterized by the presence of mixed inflammatory cell infiltration, with no multinucleated giant cells.

Figure 4:

Macroscopic and Microscopic evaluation of infusion sites: Macroscopic (A-D) and microscopic (E-L) evaluation of the SC tissue was performed 4 weeks post 24h-continuous SC administration of the test formulations. (E-H) are presented at low magnification view (×40), and (I-L) at high magnification (x100) view. Representative photos.

Conclusions

References ■ [1]. Olanow, C.W., J.A. Obeso, and F. Stocchi, Continuous dopamine-receptor treatment of

Parkinson’s disease: scientific rationale and clinical implications. Lancet Neurol, 2006. 5(8): p. 677-87.

■ [2]. Katzenschlager, R., et al., Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson’s disease: a prospective study using single-dose challenges. Mov Disord, 2005. 20(2): p. 151-7.

■ [3]. Deleu, D., Y. Hanssens, and M.G. Northway, Subcutaneous apomorphine: an evidence-based review of its use in Parkinson’s disease. Drugs Aging, 2004. 21(11): p. 687-709.

■ [4]. Shackelford, C., et al., Qualitative and quantitative analysis of nonneoplastic lesions in toxicology studies. Toxicol Pathol, 2002. 30(1): p. 93-6.

Figure 5: Patch Pump

24-hour, subcutaneous administration via a convenient, discreet patch pump.

■ Results suggest that even at concentrations 2.5-5 times higher than apomorphine-HCl, ND0701 causes a considerably milder infusion site reaction when compared to apomorphine-HCl.

■ MRI may provide a quantitative tool for the assessment of subcutaneous reactions and for monitoring the progression and recovery of lesions following infusion of newly developed drug products.

■ The findings set forth the development of a new apomorphine product that could provide a safer, more tolerable and convenient alternative to current apomorphine commercial preparations, that could be delivered by a small volume, discrete patch pump for the treatment of motor complications in advanced PD.

Disclosures: Nir Giladi, Yoseph Caraco, Tanya Gurevitch and Ruth Djaldetti report personal compensation for speaking and/or consultative services from Neuroderm.Yael Cohen, Oron Yacobi-Zeevi and Sheila Oren are employed by Neuroderm

2.5% ND0701

2.5% ND0701

1% ND0701

1% ND0701

1% Apo-Go

1% Apo-Go

0.5% Apo-Go

0.5% Apo-Go

Active Granulomatous Inflammatory Reaction

Necrosis Mild inflammation

A

E

B

F

C

G

D

H

I J K L

Lesions’ volume was significantly smaller following administration of ND0701 as compared to apomorphine-HCl. Size of the lesions was reduced by 5-5.5 fold 4 weeks following ND0701 versus only 3-3.2 fold following apomorphine-HCl administration.

B

A

25

100.00

Con

cent

ratio

n (n

g/m

l)

10.00

1.000 6 13 19

Time (Hours)

C 2

1.5

1

0.5

0

2.5% ND07011% ND07011% Apo-Go0.5% Apo-Go

The mean lesion volume of 1% ND0701 was 5 times smaller than 1% apomorphine HCl and the mean lesion volume of 2.5% ND0701 was half the size of 0.5% apomorphine HCl.

A. 2 Weeks Recovery B. 4 Weeks Recovery

2.5% ND0701 2.5% ND07011% ND0701 1% ND07011% Apo-Go 1% Apo-Go0.5% Apo-Go 0.5% Apo-Go

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