Applicability of Existing Regulations to the Development of a Dendrimer Nanotechnology-Based Pharmaceutical Presentation to Advisory Committee for Pharmaceutical Sciences Jeremy Paull, PhD October 6, 2006

2 Key Messages Nanotechnologies are enabling technologies Dendrimer-based API developed as a preventive product Developed in context of existing regulatory framework Possible challenges now and in the future?

3 Defining Regulation and Nanotechnology Regulation aims to set standards that ensure balance between risk and benefit Specific regulations for nanotechnology? Nanotechnology is: Research and technology development at the atomic, molecular or macromolecular levels, in the length scale of approximately nanometer range. Creating and using structures, devices and systems that have novel properties and functions because of their small and/or intermediate size. Ability to control or manipulate on the atomic scale. Isn’t it? But! Specific regulation of non-specific technology challenging, inappropriate? i-Pod NanoNano Cash

4 Dendrimers: Nanoscale Chemical Diversity Core molecule Surface molecules Branching molecules Dendrimer Synthesis 1 nm Approximate size range: 10 nm100 nm Dendrimers –Precise, defined nanostructures, with significant potential for structural diversity –It is difficult to generalize about properties and applications of dendrimers because of the extreme diversity possible It is difficult to generalize about properties and applications of dendrimers because of the extreme diversity possible

5 Dendrimer Nanotechnology: Applications Pharmaceuticals –Polyvalent presentation of surface molecules covalently bound to the underlying dendrimer architecture, resulting in unique properties compared with single presentation. Drug Delivery –Small molecules bound on the surface or carried within dendrimer architecture, not bound to the dendrimer, then released. In vitro Diagnostics –Detection of biomarkers in assays. In vivo Diagnostics –Imaging agents bound to the surface of dendrimers, with improved resolution, targeting. Combinations?

6 Dendrimer Synthesis: Small Molecule Techniques Amide bond formation Deprotection of reactive groups

7 Dendrimer Synthesis: Large Molecule Techniques Ultrafiltration: a technique used in the purification of biopharmaceuticals Purification and analytical techniques vary with dendrimer generation (size) and surface polarity

8 Dendrimer Synthesis: Surface Group

9 Dendrimers: a Platform for Polyvalent Interactions

10 Dendrimers: Controlled Topologies Precise, controlled placement of surface groups to provide specific properties Quality by design

11 Dendrimers: Drug Delivery Capability Dendrimers as ‘functional excipients’ Delivery of covalently bound or encapsulated drug direct to a target Adapted from: Dendrimers & Dendrons: Facets of Pharmaceutical Nanotechnology: Sakthivel and Florence, Drug Delivery Technology, accessed 10/02/2006

12 Regulatory Challenge All forms of nanotechnology carry unique properties because of their size Particles of a finished drug product or other material may provide better or more favorable solubility or function if they are nanoscale Dendrimers are not different because they are small, they are different because the individual molecules are big compared with small molecules Can you regulate such different types of nanotechnology as a single technology?

13 Classification of Dendrimer Products ‘Star R x ’: Existing regulatory framework allows for proper classification and oversight of development Cosmetic, Drug, Device, Biologic? NOT Cosmetic, NOT Biologic Drug? Device? Drug-Device Combination? Claims made and primary mode of action? Prevention of HIV / HSV-2, ‘pharmaceutical’ / antiviral mode of action – potential clinical utility as vaginal microbicide. Opportunity / Challenge: Topical administration, not absorbed, barrier to virus – possibility of device classification? Drug delivery? Regulation of a molecule as device?

14 Manufacturing and Characterization of Dendrimers ‘Star R x ’: Existing industry manufacturing norms and expectations apply: ICH Q7A, 21 CFR Parts 210 / 211 Identity, strength, purity, quality Quality by design Risk management Control of inputs Monitoring of reaction Opportunity / Challenge: Combination of small molecule and large molecule processes required Lack of commercial availability of API starting materials and intermediates – does strict cGMP compliance apply?

15 Manufacturing and Characterization of Dendrimers ‘Star R x ’: Characterization of dendrimers in order to monitor and confirm identity, strength, purity, and quality provides the biggest challenge How much characterization required if QbD, process understanding (PAT)?

16 Manufacturing and Characterization of Dendrimers ‘Star R x ’: Achieving purities expected of small molecule synthesis? Minor impurity in dendrimer capping material can lead to significantly undercapped or miscapped, related API Characterize related species in terms of identity as well as qualify in terms of safety and efficacy – adequate characterization of impurities?

17 ADME of Dendrimers ‘Star R x ’: Topical (vaginal) administration Due to size and polarity of molecule, not expected to be absorbed Not detected systemically following repeated vaginal administration in animals and humans Bioanalytical assay limit of quantitation – 0.5µg/mL = 30nM Opportunity / Challenge: Application of small molecule expectations in terms of bioanalytical assay limits to large molecules? Absorption below 0.5µg/mL qualified? Full characterization of metabolites, degradation required? Opportunity for analytical lab!

18 Safety and Efficacy of Dendrimers ‘Star R x ’: Intensive battery of toxicology studies conducted, as required for development of a topical, vaginal product: Genotoxicity Hypersensitivity (topical) Acute, Single-Dose (oral, intravenous, vaginal) Sub-Chronic, Repeat-Dose (vaginal) Reproductive and Developmental Intensive battery of toxicology studies ongoing or planned: Chronic, Repeat-Dose (vaginal) Further Reproductive and Developmental Carcinogenicity Intensive battery of in vitro and in vivo pharmacology studies: In vitro HIV and HSV anti-viral activity / mode of action In vivo HIV and HSV anti-viral activity

19 Safety and Efficacy of Dendrimers ‘Star R x ’: Nonclinical safety and efficacy profile acceptable for use in human clinical studies Phase 1 study: Confinement to a Phase 1 unit for intensive monitoring of volunteers Escalating doses Intensive monitoring of safety endpoints Ongoing assessment of safety Safety profile acceptable for use in further human clinical studies No special safety or efficacy study considerations for dendrimer- based ‘Star R x ’

20 Regulatory Interaction on Dendrimer Development ‘Star R x ’: Human studies conducted under US IND Fast Track designation Opportunities for frequent (more frequent!) informal and formal interaction on most advanced dendrimer nanotech product Engagement of industry by regulator, and of regulator by industry important to ensure efficient development of new products based on novel technologies

21 Environmental Considerations ‘Star R x ’: Exempt at this stage of development under 21 CFR Part 25.24(c)(4) Ongoing nonclinical and clinical safety assessment in controlled environment Environmental impact of lysine-based dendrimer molecule? Case-by-case consideration required

22 Occupational Health and Safety Considerations ‘Star R x ’: Treated as an uncertain risk Suitable precautions taken during manufacturing, analysis, transportation and handling No special ‘nanotechnology’ requirements

23 Other Nanotechnology-Based Products Can other products be consistently manufactured? Are other products well characterized? Does the safety profile of other products support intended use? Do other products perform as required and expected? FDA regulation should be applied to new materials as they are incorporated into products regulated by FDA Consumer products containing nanotech materials should be overseen by FDA if they present public health issues

24 Summary Existing regulations have adequately addressed development of a dendrimer nanotechnology-based pharmaceutical Development challenges come from science, not from regulation Starpharma is developing dendrimer employing risk-based approach and quality-by-design

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