ReNeuron : Corporate Presentation – January 2020

Corporate Presentation

January 2020

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2

A Leader in Cell-Based Therapeutics

Leading clinical stage cell therapy company

Sites in the UK and Boston, US

Proprietary allogeneic stem cell technology platforms

Two clinical stage therapeutic candidates targeting

unmet medical needs

Significant clinical validation milestones over the next

24 months

3

Proprietary Platform Technology

hRPC

CTX

Cells

CTX-

Derived

Exosomes & iPS cells

• 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
• High-yieldinghuman neural stem cell-derived exosomes
• Proven ability to load exosomes with siRNA, miRNA and proteins
• Favourable distribution of exosomes across the Blood Brain Barrier
• Potential as drug load/delivery vehicle and as a therapeutic
• CTX-derivedinduced pluripotent stem cells (iPSCs) offer further licensing potential

4

Clinical Programme Pipeline

Programme	Indication	Pre-clinical	Phase 1	Phase 2	Next Milestone
hRPC	Retinitis				Further data read-outs from
			expanded Phase 2a study in
Pigmentosa
				2020
					PISCES III, pivotal, multi-centre
CTX cells	Stroke Disability				U.S. Phase 2b study, data read-
					out expected mid-2021

5

Human

Retinal

Progenitor

Cells

(hRPC)

Human Retinal Progenitor Cells (hRPC)

hRPC: 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, high quality and high quantity GMP production

• Collaborations with Schepens Eye Research Institute and University College London
• Proprietary technology enabled development of GMP manufacturing process
• Cryopreserved formulation provides 9 month shelf life and enables local treatment worldwide

7

Retinitis Pigmentosa: An Unmet Need

• RP is an inherited, degenerative eye disease1,2,3
  ❍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 cause

1	Hamel (2006) Orphanet J Rare Disease 1, 40;
2https://nei.nih.gov/health/pigmentosa/pigmentosa_facts;
3	NORD
4https://www.genome.gov/13514348/learning-about-retinitis-pigmentosa/	8

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

9

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

10

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
  • Dose escalated to 1m cells
  • Formulation changed from fresh to cryopreserved cells

• Established safety in 1m cell dose in cryopreserved formulation

Phase 2a

• 6-12additional subjects with established RP
• • Patients with better visual potential
  • 10 subjects treated
• Primary endpoint: safety
• Secondary 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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Phase 1/2a Recent Summary Results*

• Patient recruitment status:
• • 12 Phase 1 patients treated (>12 months follow up)
  • Phase 2a (ongoing)
  • • 10 patients treated, follow up period:
      1 month: n=8; 3 months: n=6; 6 months: n=4; 9 months: n=1
• Good safety profile (n= 22):
• • Noimmune-related adverse events
  • No drug product related serious adverse events
  • 2 patients with surgical procedure related vision loss (one AE, one SAE):
  • • Consistent with nature ofsub-retinal injection procedure; one moderate and likely permanent, the other severe, but improving
• Clinically meaningful efficacy signals consistently seen:
• • Rapid and profound in some patients, more gradual in others

* American Academy of Ophthalmology Annual Meeting (AAO) in San Francisco - October 2019

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Phase 2a Recent Efficacy Results*

Months post-	Mean improvement	Mean improvement in	Mean change in
treatment	in visual acuity in	visual acuity in	visual acuity in
	treated eye	treated eye (excluding	untreated eye
		two patients with
		procedure-related
		vision loss)
1	+8.3 letters (n=8)	+14.5 letters (n=6)	+ 1.6 letters (n=8)
2	+5.4 letters (n=8)	+13.0 letters (n=6)	+ 2.8 letters (n=8)
3	+6.1 letters (n=8)	+17.8 letters (n=6)	+ 6.8 letters (n=8)
6	+18.5 letters (n=4)	+28.7 letters (n=3)	+ 7.8 letters (n=4)
9	+12.0 letters (n=1)	+12.0 letters (n=1)	- 1.0 letter (n=1)

"We're excited by the progress of ReNeuron's hRPC therapy. From the Foundation's perspective, any gain in vision, or even stabilisation, is a major step forward for patients with RP as currently it is a condition where progressive loss of vision leads to blindness."

Benjamin R. Yerxa PhD, Chief Executive Officer -- Foundation Fighting Blindness (14 Oct 2019)

* American Academy of Ophthalmology Annual Meeting (AAO) in San Francisco - October 2019

13

Phase 2a Recent Efficacy Results*

*excluding 2 patients with surgery-related vision loss

* American Academy of Ophthalmology Annual Meeting (AAO) in San Francisco - October 2019

14

hRPC Platform Next Steps

• Expand ongoing Phase 2a study to generate further andlonger-term follow up efficacy data in a larger group of RP patients:
• • Potential modifications in patient selection and surgical strategy to enhance safety and amplify current efficacy signal
  • Subsequent potential singlepre-approval clinical study, allowing shorter time to market
• Furthertop-line efficacy data from expanded Phase 2a study expected to be presented during 2020
• Assess other indications alongside RP (e.g. Cone Rod Dystrophy)

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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 can be easily 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

17

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	18

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;	19
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

20

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

130 subjects - 2:1 randomisation to therapy v. placebo (sham) surgery

1. Age35-75 inclusive

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

1. 6-24mos 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)

	❍12 surgical sites and 21 patient assessment sites now activated across US
Current Status	❍Clinical trial protocol amendments and other initiatives in place to enhance
patient recruitment and enlarge data set for CTX-treated patients in study
	❍Top-lineread-out expected in mid-2021

22

CTX-

Derived

Exosomes

and iPS

cells

CTX-Derived Exosomes: Biological Nanoparticles

• Nano-scalevesicles released by most cell types as a means of intercellular communication
• Naturally occurring liposomal delivery system
• Contain and transport bio- active lipids, proteins and nucleic acids
• • FirstCTX-derived exosome candidate derived
  • Potential as a drug delivery vehicle and as a therapeutic

Lipid bilayer

Surface proteins (tetraspanins CD63, CD81)

Internal proteins (Hsp70, Tsg101)

Specific nucleic acids (miRNAs)

24

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 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

25

CTX-derived induced pluripotent stem cells (iPSCs)

Pluripotency	Conditionally immortalised derivatives
(MSCs) from CTX-iPSCs

• CTX cells can be rapidly and efficiently reprogrammed into a pluripotent state
• CTX-derivediPSCs retained immortalisation technology: key for consistency and scale up
• Potential:
• • New therapeutic candidates for subsequentout-licensing
  • Production of exosomes withtissue-specific targeting

26

Summary

Summary

• A 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 retinal and stroke programmes in 2020 and 2021
• Near/medium term opportunities forvalue-generating partnering/collaboration deals

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www.reneuron.com

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