ReNeuron : Preliminary Results Presentation for the year ended 31 March 2019

Preliminary Results Presentation

For the year ended 31 March 2019

Olav Hellebø - Chief Executive Officer

Michael Hunt - Chief Financial Officer

Disclaimer

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Global Leader in Cell-Based Therapeutics

Leading clinical stage stem cell company

Proprietary allogeneic stem cell technology

platforms

Two clinical stage therapeutic candidates

targeting unmet medical needs

Significant clinical validation milestones over the

next 18 months

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Proprietary Platform Technology

hRPC

CTX

Cells

CTX-

Derived

Exosomes

• Human retinal progenitor stem cell line
• Cryopreserved formulation allows globalship-and-store
• Positive early Phase 2a data in retinitis pigmentosa
• Partnered with Fosun Pharma for China
• Immortalised neural progenitor stem cell line
• 12 month shelf life (cryopreserved)
• Positive Phase 2a results in stroke disability
• Partnered with Fosun Pharma for China
• Nano-sizedvesicles from CTX cells
• Potential as drug load/delivery vehicle and as a therapeutic

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Pipeline with Near Term Catalysts

Programme	Indication	Pre-clinical Phase 1	Phase 2	Next Milestone
hRPC	Retinitis			Top line Phase 1/2a data
Pigmentosa			read out expected Q4 2019

PISCES III, pivotal, multi-centre

CTX cellsStroke DisabilityU.S. Phase 2b study, data read out expected Q4 2020

Exosomes	Drug Delivery	Collaboration / Partnering
deals targeted

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Prelim Results - Operational Highlights

hRPC

CTX

Cells

CTX-Derived

Exosomes

Business

Development

• Positive preliminary efficacy data from first three Phase 2a patients in ongoing US Phase 1/2a clinical trial in retinitis pigmentosa
• Top line data from all treated Phase 2a patients to be presented at the American Academy of Ophthalmology Annual Meeting in October 2019
• Patient dosing commenced inplacebo-controlled US Phase 2b clinical trial
• Top line data from Phase 2b study expected in late 2020
• Programme primarily focused on use of exosome technology as a drug delivery vehicle
• First collaboration agreement signed with US company to explore use of exosome technology as a delivery vehicle in gene therapy
• Exclusiveout-licence agreement signed post-year end with Fosun Pharma to commercialise hRPC and CTX programmes in China
• • ReNeuron to receive upfront, future near term and estimatedsuccess-based milestone payments of £80.0 million plus double-digit royalties on sales
• Discussions ongoing with other commercial third parties regarding potentialout-licence deals

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Prelim Results - Financial Highlights

	Year ended 31	Year ended 31
	March 2019	March 2018
(£'m)	(Audited)	(Audited)
Revenues and other income	2.7	0.9
Research and development costs	(16.3)	(16.7)
General and administrative costs	(4.7)	(4.6)
	(18.3)	(20.4)
Net finance income/(costs)	1.1	(0.6)
Tax credit	2.9	3.4
Loss for the year	(14.3)	(17.6)
Net decrease in cash and deposits	(11.0)	(15.7)
Cash and deposits at start of period	37.4	53.1
Cash and deposits at period end	26.4	37.4

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Human

Retinal

Progenitor

Cells

(hRPC)

Human Retinal Progenitor Cell Therapy

hRPC: unique, allogeneic cell-based therapeutic approach to retinal disease

• hRPCs differentiate into functional photoreceptors and integrate into retinal layers inpre-clinical models; integration may also enable durable trophic support
• Broad therapeutic potential across a range of retinal diseases
• Initially targeting inherited retinal degenerative diseases

Proprietary manufacturing process and controls allow for stable and high quantity GMP production

• Collaborations with Schepens Eye Research Institute and University College London
• Proprietary technology enabled development of GMP manufacturing process to support clinical application
• Cryopreserved formulation provides for commercially viable shelf life and allows for worldwide shipment on demand

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Retinitis Pigmentosa: An Unmet Need

• RP is an inherited, degenerative eye disease1,2,3
• • Primary loss of rod photoreceptors; secondary loss of cones
  • Onset varies from early childhood to 20s/30s
  • Early stage main symptom is night blindness
  • Progressive loss of peripheral vision, then central vision
  • Incidence of 1:4,000 in U.S. and worldwide
• >100 genes identified containing mutations leading to RP4
• Orphan Drug Designation in EU and U.S.
• FDA Fast Track Designation

Therapeutic benefit of hRPC approach not dependent on

genetic causes of IRD

No approved treatment for the vast majority of patients with RP

1Hamel (2006) Orphanet J Rare Disease 1, 40;

2https://nei.nih.gov/health/pigmentosa/pigmentosa_facts;

3NORD	10
4https://www.genome.gov/13514348/learning-about-retinitis-pigmentosa/

Pre-clinical Studies Support RPC Potential in Degenerative Retinal Disease

hRPC in RCS Dystrophic Rats

12 Weeks Post-Injection

hRPC Survival

Vision (via OKR)

hRPC (red)/photoreceptors (blue); white arrows indicate hRPC cells within retinal layers

OKR = optokinetic response; OS = oculus sinister (left eye); OD = oculus dextrus (right eye)

pRPC in Pigs

4 Weeks Post-Injection

IS

ONL

INL

Transplanted donor cells (green); transplanted donor cells becoming

photoreceptor cells (yellow) in the host retina (blue)

IS = inner segments; ONL = outer nuclear layer; INL = inner nuclear layer

• Evidence that hRPC:
• • Integrated into host retina
  • Provided trophic support of host cells
  • Preserved vision based on OKR

• Evidence that pRPC:
• • Differentiated into retinal cells
  • Integrated into host retina
  • Required no immunosuppression

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Pre-Clinical Data Support a Durable Response

Time after

Species	Treatment	Incidence of Survival
Dystrophic RCS &	28 weeks	77%; 23/30 dystrophic RCS rats
Normal Rats		70%; 7/10 normal control rats
NIH-III Nude Mice	39 weeks	33%; 15/45
Mini Pigs	12 weeks	81%; 21/26
(allogeneic study mimicking		At 12 weeks a number of surviving pRPCs appeared to have
the clinical scenario)
	migrated into the photoreceptor layer up to a depth of 2-3
		layers, indicating cell integration.

RPC cells survive for long periods in all species and survival is

unaffected by the presence of disease

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Clinical Development - Phase 1 / 2a

Phase 1

• FIH, single ascending dose in subjects with established RP
• • Subjects with very poor visual potential
  • Four cohorts, three subjects each
  • Cohorts1-2: 250K, 500K fresh cells
  • Cohort3-4: 1 MM cryopreserved cells
• Reformulation into commercial, cryopreserved formula with 6+ month shelf life

Phase 2a

• 6-12additional subjects with established RP
• • Subjects with better visual potential
  • Cohort 5: three subjects, 1 MM commercial, cryopreserved cells
• Primary endpoint: safety
• Secondary safety/efficacy measures: visual acuity, visual field, retinal sensitivity and retinal structure

U.S. Clinical Sites

• Massachusetts Eye & Ear Infirmary, Boston, Jason Comander, MD, PhD
• Retinal Research Institute, Phoenix, Pravin Dugel, MD

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Cohort 5 Efficacy Results*

Changes in Letters Read (ETDRS chart)

Subject 1 treated at Mass Eye & Ear (OS), Subjects 2 and 3 treated at Retinal Consultants of Arizona (OD)

+23 from BL

+25 from BL

+21 from BL

Subject 1	Subject 2	Subject 3
* Sixth annual Retinal Cell and Gene Therapy Innovation Summit, Vancouver, Canada - April 2019	14

Cohort 5 Efficacy Results

• Strongly positive visual acuity data
• 4-linegain on ETDRS chart
• FDA guidance considers a3-line improvement as clinically significant (responder)

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hRPC Platform Next Steps

• Build further safety data in RP using commercial formulation
• Treating patients with more intact retinas in order to further assess efficacy potential -
• • further Phase 1/2a readout at AAO meeting in Oct 2019
• Conduct controlledmulti-centre Phase 2b trial in RP
• Assess other indications

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CTX

Cells

CTX Cell Therapy

CTX: allogeneic, cryopreserved, human neural stem cell product

• Promotes anatomical plasticity in the brain
• Excellent safety profile - no immunogenicity issuespost-administration
• Manufactured under cGMP with a 12 month shelf life

Commercially Attractive

• Product to be readily ordered, shipped and stored at the hospital
• Delivered incryo-shipper, controlled thawing at hospital site
• Administer to patient 'on demand'
• Commercial scale manufacturing at attractive COGs

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CTX Promotes Anatomical Plasticity in the Brain

Cells

stereotaxically implanted in the putamen - modulate immune response to promote repair

Potential Mechanism(s) of Action1,2

	Stimulate	Cell trans-
	differentiation
	neurogenesis
Stimulate/
restore		Modulate
synaptic
	inflammation	Release of
activity
		paracrine
	Stimulate		factors

angiogenesis

Symptomatic

relief of

disability

Tissue

restoration

and/or repair

1Pollock et al (2006) Exp Neurol 199, 143-155;
2Sinden et al.(2017) Stem Cells Dev 26, 1078-1085	19

CTX for Stroke Disability: Unmet Medical Need

• Stroke is the leading cause of morbidity andlong-term disability in the U.S.1
• • 1 in 6 people will have a stroke in their lifetime
• Financial burden
• • $34 billion annually instroke-related costs in the U.S1
  • Direct medicalstroke-related costs projected to triple from 2012 to 20301
• Limited treatment options
• • Only one drug available, for use within 4.5 hours of stroke onset2
  • Rehabilitation provides most benefit in first month, very little beyond six months3

CTX administration promotes repair in the damaged brain

1Benjamin et al (2017) Circulation 135, e146-e603;	20
2Otwell et al (2010) Am J Health Pharm 67, 1070-1074;

3Hatem et al (2016) Front Hum Neurosci 10, 442

Severity of Functional Disability Measured by Modified Rankin Scale (mRS)

mRS 5: Bedridden, requires constant help from others

mRS 4: Needing help to walk, use toilet, bathe

mRS 3: Can walk with appliance, needs some help at home

mRS 0-2: Slight to no disability

Reductions in disability result in substantial reductions in patient care costs

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CTX in Stroke Disability: PISCES II Study Results

Phase 2a, single arm, open label study

• 23 disabled, stable stroke patients,
  2 to 12 mos post-stroke
• 20 MM CTX cell dose
• Clinically meaningful improvements in disability scales measured out to 12 monthspost-implantation
• Nocell-related safety issues identified

Very promising results for chronic stroke disability, supportive of a larger, randomised, placebo- controlled Phase 2b study

					Patients with NIHSS
Time	Total subjects	upper limb score < 4 at
						baseline
Month	N		Responders* (%)	N	Responders* (%)
Baseline	23			-	14		-
3	23		7	(30.4%)	14	6	(42.9%)
6	22		6	(27.3%)	13	5	(38.5%)
12	20		7	(35.0%)	12	6	(50.0%)

*number of subjects with >1 point improvement in mRS (% of N observed at day of visit)

Greatest mRS improvements in subjects with residual

movement of the affected arm (NIHSS UL <4)

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PISCES III Study Design and Status

Phase 2b, Randomised, Placebo-Controlled Study

110 subjects - 1:1 randomization to placebo (sham) surgery

1. Age35-75 inclusive

1. Ischemic stroke that includes supratentorial region (CT/MRI confirmed)

1. 6-12mos post-strokeomRS 3 and 4
   oSome residual arm movement

Primary Endpoint*

1. >1 pt improvement from baseline in mRS at 6 mospost-treatment

Secondary Endpoints* (1, 3, 6, 9, 12 mos post-tx)

1. Barthel Index (ADL independence)

1. Timed Up and Go test (lower limb and trunk function)

1. Chedoke Arm/Hand Activity Inventory (upper limb function)

1. NIHSS (impairment scale - neurological outcome and recovery)oFugl-Meyer Assessment (performance-based impairment index) oEQ-5D-5L (QoL)

	❍15 surgical sites and 22 patient assessment sites identified and approved
Current Status	❍Initial sites activated and patient dosing in progress
❍CTX Drug Product batches in stock or scheduled for manufacture
	❍Top-line readout expected in Q4 2020

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CTX-

Derived

Exosomes

CTX-Derived Exosomes: Biological Nanoparticles

• Nano-scalevesicles released by most cell types as a means of intercellular communication
• Naturally-occurringliposomal delivery system
• Contain and transport bio- active lipids, proteins and nucleic acids

Lipid bilayer

Surface proteins (tetraspanins CD63, CD81)

Internal proteins (Hsp70, Tsg101)

Specific nucleic acids (miRNAs)

ExoPr0	❍First CTX-derived exosome candidate
❍Potential as a drug delivery vehicle and as a therapeutic

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ReNeuron's CTX-Derived Exosome Technology

Advantages of exosomes as a

delivery vehicle

• Natural carrier of nucleic acids and proteins, amenable for loading complex,hard-to- deliver therapeutic agents
• Ease of bioengineering
• Low immunogenicity
• Intrinsically durable, membrane texture order of magnitude harder than synthetic liposomes

Advantages of ReNeuron's ExoPr0 exosome technology

• Stable, consistent,high-yield,clinical-grade product
• Fully qualifiedxeno-free, optimised, scalable GMP process
• Established analytics
• Proven ability to load miRNA and proteins
• Modifiable to carry siRNA/mRNA, CRISPR/Cas9 proteins,small-molecule inhibitors
• Favourable distribution across the blood brain barrier
• Engineered to target particular tissues

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Summary

Summary

• Global leader incell-based therapeutics - sites in UK and Boston, US
• Allogeneic stem cell technology platforms - patented, scalable & cost effective
• Targeting diseases with large unmet medical needs
• Significant clinical milestones in stroke and retinal programmes over the next 18 months
• Near/medium term opportunities forvalue-generating partnering/collaboration deals

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www.reneuron.com

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