PBOO1: potential to
reduce hearing aid
dependence for
ARHL.
Navigating early phase drug development of
PB001
• Form partnerships with healthcare stakeholders for ensuring market access.
• Review of target product profile (TPP) goals and objectives throughout
development. 
Navigating early phase drug development of
PB001
• Form partnerships with healthcare stakeholders for ensuring market access and
commercial feasibility.
• Review of target product profile (TPP) goals and objectives throughout
development and to ensure commercial feasibility.
- Ongoing 
market 
access 
research. 
- IP strategy
Navigating early phase drug development of
PB001
• Form partnerships with healthcare stakeholders for ensuring market access and
commercial feasibility.
• Review of target product profile (TPP) goals and objectives throughout
development to ensure commercial feasibility.
Favourable 
side effect 
and 
efficacy 
profile
Navigating early phase drug development of
PB001
• Form partnerships with healthcare stakeholders for ensuring market access and
commercial feasibility.
• Review of target product profile (TPP) goals and objectives throughout
development to ensure commercial feasibility.
 
CMC Nonclinical Clinical
CMC development plan
Proposed DP CQA Specification:
• Drug loading: 90%
• Particle size: approximately 230 nm
• Polydispesry index (PDI): 0.09
• Zeta potential: +16 mV
Examples of process components:
mRNA Manufacturing Method (DS):
• In vitro transcription (IVT)
PLGA NPs Manufacturing Method (DP):
• Double emulsification method (W/O/W)
PLGA NPs Purification Method (DP):
• Tangential Flow Filtration (TFF)
Proposed formulation components:
• API (mRNA)
• PLGA
• DOTMA
• PEG
• Ligand
Question:
• Is the proposed QbD approach (see section 2.1) for PB001s process development appropriate?
Non-clinical development plan
Examples of extra considerations for PB001:
• Biodistribution throughout cells neighboring the cochlear.
• Translation machinery and ligand binding affinity in species selection.
• Animals that can adequately represent an elderly target population
Examples of bioanalytical methods for in vivo
studies:
• qPCR/RNA-seq (for the DS).
• Immunohistochemistry.
• Flow cytometry
Question: Are the proposed biodistribution studies within the neighbouring cochlear cells appropriate
(see section 2.2.5) within selected species (see section 2.2.1)? 
Clinical development plan
• Question: Is the proposed plan for participant recruitment and proposed method of
measuring mRNA translation through a biopsy for the FIH clinical trial ethically and scientifically
acceptable (see section 2.3.1.1)?
Study design
Proposed
patient
population
55-65 health volunteer
Proposed
sample size
40
Administrati
on
Local injection
AE's Inflammation, infection
PK/PDs e.g biopsy for
measuring mRNA/protein
Clinical development plan
• Question: Is the proposed plan for participant recruitment and proposed method of measuring mRNA 
translation through a biopsy for the FIH clinical trial ethically and scientifically acceptable?
Study design
Proposed patient population
55-65 health volunteer 
(who use hearing aids) 
Proposed sample size 40
Administration Local injection
AE's  Inflammation, infection 
PK/PDs 
e.g biopsy for 
measuring mRNA/protein
Reference list
Overall strategy
• Cheng, Y., Chen, W., Xu, J., Liu, H., Chen, T. and Hu, J. 2023. Genetic analysis of potential biomarkers and therapeutic targets in age-related hearing loss. Hear Res. 439, p108894.
• Green, M.R. and Sambrook, J. 2020. In Vitro Transcription Systems. Cold Spring Harb Protoc. 2020(1), p100750. 
• Huang, Y., Furuno, M., Arakawa, T., Takizawa, S., de Hoon, M., Suzuki, H. and Arner, E. 2019. A framework for identification of on- and off-target transcriptional responses to drug 
treatment. Scientific reports. 9(1). 
• Wang, J. and Puel, J.-L. 2020. Presbycusis: An Update on Cochlear Mechanisms and Therapies. Journal of clinical medicine. 9(1), pp.218 
• Wells, H.R.R., Newman, T.A. and Williams, F.M.K. 2020. Genetics of age-related hearing loss. Journal of neuroscience research. 98(9), pp.1698–1704. 
• Xie, R., Wang, M. and Zhang, C. 2024. Mechanisms of age-related hearing loss at the auditory nerve central synapses and postsynaptic neurons in the cochlear nucleus. Hearing 
research. 442, pp.108935–108935. 
Manufacturing
• Dalwadi, G. and Sunderland, V.B. 2007. Purification of PEGylated nanoparticles using tangential flow filtration (TFF). Drug development and industrial pharmacy. 33(9), pp.1030–1039.
• Kang, D.D., Li, H. and Dong, Y. 2023. Advancements of in vitro transcribed mRNA (IVT mRNA) to enable translation into the clinics. Advanced drug delivery reviews. 199(114961), 
p.114961.
• Priwitaningrum, D.L., Jentsch, J., Bansal, R., Rahimian, S., Storm, G., Hennink, W.E. and Prakash, J. 2020. Apoptosis-inducing peptide loaded in PLGA nanoparticles induces anti-tumor 
effects in vivo. International journal of pharmaceutics. 585(119535), p.119535.
• Wang, L., Griffel, B. and Xu, X. 2017. Synthesis of PLGA–lipid hybrid nanoparticles for siRNA delivery using the emulsion method PLGA-PEG–lipid nanoparticles for siRNA 
delivery In: RNA Nanostructures. New York, NY: Springer New York, pp.231–240.
• Yasar, H., Biehl, A., De Rossi, C., Koch, M., Murgia, X., Loretz, B. and Lehr, C.-M. 2018. Kinetics of mRNA delivery and protein translation in dendritic cells using lipid-coated PLGA 
nanoparticles. Journal of nanobiotechnology. 16(1).
Nonclinical
• ICH S3A  Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies 1994 
• ICH S3B Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies 1994
• ICH S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals guideline 2011.
Clinical
• Xie, R., Wang, M. and Zhang, C. 2024. Mechanisms of age-related hearing loss at the auditory nerve central synapses and postsynaptic neurons in the cochlear nucleus. Hearing 
research. 442, pp.108935–108935.