US 20070259031A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0259031 A1 Bankiewicz et al. (43) Pub. Date: Nov. 8, 2007 (54) COMPOSITIONS AND METHODS FOR (22) Filed: Apr. 26, 2007 CONVECTION ENHANCED DELVERY OF HIGH MOLECULAR WEIGHT Related U.S. Application Data NEUROTHERAPEUTICS (60) Provisional application No. 60/795,371, filed on Apr. (75) Inventors: Krystof S. Bankiewicz, Oakland, CA 26, 2006. Provisional application No. 60/900,492, (US); Sandeep Kunwar, Hillsborough, filed on Feb. 9, 2007. CA (US) Publication Classification Correspondence Address: JOHN P. O'BANION (51) Int. C. OBANON & RITCHEY LLP A6II 38/17 (2006.01) 4OO CAPTOL MALL SUTE 15SO A 6LX 9/27 (2006.01) SACRAMENTO, CA 95814 (US) (52) U.S. Cl. ............................... 424/450; 514/2; 977/907 (73) Assignee: THE REGENTS OF THE UNIVER SITY OF CALIFORNIA, Oakland, CA (57) ABSTRACT (US) A method of therapeutic treatment of CNS disorders using (21) Appl. No.: 11/740,508 local convection enhanced delivery. Patent Application Publication Nov. 8, 2007 Sheet 1 of 18 US 2007/0259031A1 : FIG. 1 Patent Application Publication Nov. 8, 2007 Sheet 2 of 18 US 2007/0259031A1 Tota Tuimor Mass: 1.1 cm3 Ls-Gd-CPT-11 (Vd): 0.134 cm3 Tumor MaSS Covered. 12.2% FIG 2 Patent Application Publication Nov. 8, 2007 Sheet 3 of 18 US 2007/0259031A1 Liposones FIG 3 Patent Application Publication Nov. 8, 2007 Sheet 4 of 18 US 2007/0259031A1 FIG. 4 Patent Application Publication Nov. 8, 2007 Sheet 5 of 18 US 2007/0259031A1 Cat ifisic m -is ...rt YYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYu .S. a ... i2 s E. : : ... 3 ... is O. : : i:- Linear Componest of Tirror infision (O-88) FIG. 5 Patent Application Publication Nov. 8, 2007 Sheet 6 of 18 US 2007/0259031A1 Distribution Corona Radiata Edog vs. Tumor Dog O 50 30 15C 2O) 25) 3OO 35 Tunnor & Corona Radiata FIG. 6 Patent Application Publication Nov. 8, 2007 Sheet 7 of 18 US 2007/0259031A1 FIG 7 Patent Application Publication Nov. 8, 2007 Sheet 8 of 18 US 2007/0259031A1 FIG. 8 Patent Application Publication Nov. 8, 2007 Sheet 9 of 18 US 2007/0259031A1 3SS. S. S FIG. 9 Patent Application Publication Nov. 8, 2007 Sheet 10 of 18 US 2007/0259031A1 Frontal-superior view Anterior FIG 10 Patent Application Publication Nov. 8, 2007 Sheet 11 of 18 US 2007/0259031A1 Dog right Gd daily Dog i.eft (Gd+LS-fopo 0.5Engfni) 3. s E. 3. il right - left cabined FIG 11 Patent Application Publication Nov. 8, 2007 Sheet 12 of 18 US 2007/0259031A1 (-3 St. Earlie Stsiatt : -88. Astroytona Grate IEE & O-38 Oligodendrogiornia s SE s s: W FIG. 12 Patent Application Publication Nov. 8, 2007 Sheet 13 of 18 US 2007/0259031A1 is their Efisit te2Sai FIG. 13 Patent Application Publication Nov. 8, 2007 Sheet 14 of 18 US 2007/0259031A1 Base CEB 9W Follow CEO Follow up FIG. 14 Patent Application Publication Nov. 8, 2007 Sheet 15 of 18 US 2007/0259031A1 (sitive pn Patent Application Publication Nov. 8, 2007 Sheet 16 of 18 US 2007/0259031A1 Patent Application Publication Nov. 8, 2007 Sheet 17 of 18 US 2007/0259031A1 Patent Application Publication Nov. 8, 2007 Sheet 18 of 18 US 2007/0259031A1 US 2007/0259031 A1 Nov. 8, 2007 COMPOSITIONS AND METHODS FOR to effectively penetrate target tissue. Further, compounds CONVECTION ENHANCED DELIVERY OF HIGH delivered intraventricularly have also exhibited non-uniform MOLECULAR WEIGHT NEUROTHERAPEUTICS distribution and poor target tissue penetration. Accordingly, the poor efficacy exhibited by therapeutic agents to date in CROSS-REFERENCE TO RELATED APPLICATIONS respect of the treatment of CNS disorders may be due to administration and tissue distribution rather than the activity 0001. This application claims priority to U.S. provisional of agents per se. patent application Ser. No. 60/795.371 filed on Apr. 26, 2006, incorporated herein by reference in its entirety, and to 0009 Local delivery of therapeutics to the CNS is an U.S. provisional patent application Ser. No. 60/900,492 filed alternative route of administration that overcomes many on Feb. 9, 2007, incorporated herein by reference in its problems associated with systemic and intraventricular entirety. delivery in the treatment of CNS disorders. However, there are a number of limitations associated with direct infusion STATEMENT REGARDING FEDERALLY and diffusion-based delivery of therapeutics to target CNS SPONSORED RESEARCH OR DEVELOPMENT regions, the most critical being a low tissue distribution 0002 This invention was made with Government support Volume. Clinical studies involving neurotrophin infusion under Grant No. P50 CA097257 awarded by the National into the brain parenchyma of patients with neurodegenera Institutes of Health (NIH), and under Grant No. U54 tive disease have used continuous infusion and relied on NS045309 awarded by the National Institute of Neurologi diffusion for protein to reach target tissues. Without means cal Disorders and Stroke (NINDS). The Government has for monitoring the distribution of infused neurotrophin, it is certain rights in this invention. difficult to determine the therapeutic efficacy. For example, Gillet al. reported in Nat. Med. 9:5899-595, 2003 that, when INCORPORATION-BY-REFERENCE OF glial cell line-derived neurotrophic factor (GDNF) was used MATERIAL SUBMITTED ON A COMPACT in clinical studies as a treatment for Parkinson's disease, it DISC was not clear how far GDNF would diffuse away from the 0003) Not Applicable catheter tip and that it is possible more rostral portions of the putamen would continue to degenerate if not reached by NOTICE OF MATERIAL SUBJECT TO diffusion. They also found that, as the dose of GDNF was COPYRIGHT PROTECTION escalated, a high T2 MRI signal intensity was observed 0004. A portion of the material in this patent document is around the tip of the catheter, possibly owing to Vasogenic Subject to copyright protection under the copyright laws of edema or protein buildup, which required dosage reduction the United States and of other countries. The owner of the and potentially further compromised rostral portions of the copyright rights has no objection to the facsimile reproduc putamen. tion by anyone of the patent document or the patent disclo sure, as it appears in the United States Patent and Trademark 0010 Convection-enhanced delivery (CED) is a promis Office publicly available file or records, but otherwise ing technique for local delivery of therapeutics that over reserves all copyright rights whatsoever. The copyright comes some of the limitations inherent in diffusion-based owner does not hereby waive any of its rights to have this delivery. Despite its promise, however, there are difficulties patent document maintained in Secrecy, including without associated with CED. Many therapeutics do not appear limitation its rights pursuant to 37 C.F.R. S.1.14. amenable to convection-based delivery. For example, low molecular weight therapeutics are not readily convectible BACKGROUND OF THE INVENTION and show limited distribution with CED in CNS tissue, and failed attempts with large protein therapeutics have also 0005 1. Field of the Invention been reported. Additionally, retrograde flow (reflux) along 0006 The present invention concerns disorders of the the catheter shaft and unwanted distribution of infusate to central nervous system. The invention relates specifically to secondary sites is a reported problem. Reflux may cause the treatment of central nervous system disorders with high infusate to reach unintended tissue and cause underexposure molecular weight neurotherapeutics delivered locally by of the intended target. An additional factor influencing the convection enhanced delivery. distribution of a CED-delivered agent is the distribution of 0007 2. Description of Related Art agent binding sites. It has been previously demonstrated that 0008 Disorders of the central nervous system (CNS) therapeutic growth factors delivered by CED exhibit limited often result in serious morbidity, death or impairment of distribution in the absence of a facilitating agent Such as mobility because of the lack of effective surgical or medical heparin. The facilitating agent appears to decrease binding therapies. Although potentially therapeutic compounds exist of growth factor to binding sites in the infusate path, thereby for treating many of these disorders, delivering effective increasing the tissue distribution Volume of the growth doses of these agents selectively to target CNS tissue has factor. Finally, many therapeutic agents, particularly cyto remained a challenge. Systemic toxicity and an inability to toxic agents useful for the treatment of CNS tumors, are cross the blood brain barrier frequently compromise the non-specific. The local delivery of such agents by CED or efficacy of compounds that exhibit promising activity in other methods, while providing an effective dose in target vitro. Additionally, many compounds that are capable of tissue and avoiding problems associated with systemic crossing the blood brain barrier exhibit non-uniform, incon delivery, poses a threat to non-tumor CNS tissue exposed to sistent patterns of distribution as well as a frequent inability infusate. US 2007/0259031 A1 Nov. 8, 2007 0011. It will also be appreciated that therapeutics with 25 nm, more preferably greater than about 40 nm, more reduced toxicity in respect of non-target tissue which retain preferably greater than about 50 nm, more preferably greater therapeutic efficacy and the ability to be delivered locally by than about 60 nm, more preferably greater than about 70 nm, CED are highly desirable. more preferably greater than about 80 nm, more preferably greater than about 90 nm, more preferably greater than about SUMMARY OF INVENTION 100 nm, more preferably greater than about 110 nm, and more preferably greater than about 120 nm. In some embodi 0012. The invention is directed to the therapeutic treat ments, a high molecular weight neurotherapeutic of the ment of CNS disorders. The invention overcomes problems invention has a diameter or length greater than about 130 associated with many previous treatment regimens by nm, or greater than about 140 nm, or greater than about 150 employing local convection enhanced delivery.