Homology Medicines : pheNIX Data Presentation

Phase 1/2 pheNIX Gene Therapy Clinical Trial for Adults with Phenylketonuria (PKU) and Pipeline Review

November 6, 2020

© Copyright 2020 Homology Medicines, Inc. All rights reserved.

Forward-Looking Statements

This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this presentation that do not relate to matters of historical fact should be considered forward-looking statements, including statements regarding expectations about our competitive position, business strategy, prospective products, timing, design, results and likelihood of success of studies and/or clinical trials, including the Phase 1/2 pheNIX trial and Part B expansion part and IND-enabling studies for PKU, MLD and MPS II (Hunter syndrome), timing for regulatory feedback, plans and objectives of management for future operations, manufacturing facility capabilities, and the potential future uses and effects of our product candidates. These forward-looking statements are based on management's current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: the fact that we have incurred significant losses since inception and expect to incur losses for the foreseeable future; our need for additional funding, which may not be available; raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our technologies or drug candidates; our limited operating history; failure to use our novel genetic medicines platform to identify additional product candidates and develop marketable products; adverse public perception of genetic medicine, and gene editing in particular, may negatively impact regulatory approval of, or demand for, our potential products; the early stage of our development efforts with all programs in the research or preclinical stage; our failure or the failure of our collaborators to successfully develop and commercialize drug candidates; the regulatory approval processes of the FDA and comparable foreign authorities are lengthy, time-consuming and inherently unpredictable; delays or difficulties in the enrollment of patients in clinical trials; our product candidates may cause serious adverse events, side effects, toxicities or have other properties that may delay or prevent their regulatory approval; interim, topline and preliminary data may change as more patient data become available, and are subject to audit and verification procedures that could result in material changes in the final data; inability to maintain any of our collaborations, or the failure of these collaborations; our reliance on third parties to conduct our preclinical studies and manufacture our drug candidates; our inability to obtain required regulatory approvals; the fact that a Fast Track or Breakthrough Therapy designation by the FDA for our drug candidates may not actually lead to a faster development or regulatory review or approval process; the inability to obtain orphan drug exclusivity for drug candidates; failure to obtain marketing approval in international jurisdictions; failure to obtain U.S. marketing approval; ongoing regulatory obligations, continued regulatory review and any post-marketing restrictions or withdrawals from the market; effects of recently enacted and future legislation; failure to comply with environmental, health and safety laws and regulations; failure to achieve market acceptance by physicians, patients, or third-party payors; failure to establish sales, marketing and distribution capabilities on our own or in collaboration with third parties with such capabilities; effects of significant competition; unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives; product liability lawsuits; failure to retain key personnel and attract, retain and motivate qualified personnel; difficulties in managing our growth; the possibility of system failures or security breaches; failure to obtain and maintain patent protection for or otherwise protect our technology and products; effects of patent or other intellectual property lawsuits; the price of our common stock may be volatile and fluctuate substantially; significant costs and required management time as a result of operating as a public company; the impact of the COVID-19 pandemic on our business and operations, including our preclinical studies, ongoing and planned clinical trials and ability to access capital; and any securities class action litigation. These and other important factors discussed under the caption "Risk Factors" in our Quarterly Report on Form 10-Q for the quarter ended June 30, 2020 and our other filings with the Securities and Exchange Commission could cause actual results to differ materially from those indicated by the forward-looking statements made in this presentation. Any such forward-looking statements represent management's estimates as of the date of this presentation. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this presentation.

This presentation also includes statistical and other industry and market data that we obtained from industry publications and research, surveys and studies conducted by third parties or us. Industry publications and third-party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information. All of the market data used in this presentation involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. While we believe these industry publications and third-party research, surveys and studies are reliable, we have not independently verified such data. The industry in which we operate is subject to a high degree of uncertainty, change and risk due to a variety of factors, which could cause results to differ materially from those expressed in the estimates made by the independent parties and by us.

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Agenda

• Phase 1/2 pheNIX gene therapy clinical trial for adults with phenylketonuria (PKU)
• Plans for pheNIX dose expansion phase
• Homology pipeline review
• Question and answer period

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Mutations in PAH Gene Result in Disruption of the Normal Phe Metabolic Pathway, Build Up of Phe and Cause PKU

NORMAL BIOCHEMICAL PATHWAY	PKU PATHWAY
Protein		Protein
Phenylalanine (Phe)	Phenylalanine (Phe)
	X
PAH Enzyme	Mutated PAH Enzyme

Tyrosine (Tyr)	X
	Tyrosine (Tyr)
	X

Melanin Neurotransmitters

• No Phe build up
• Phe converts to tyrosine
• Production of melanin
• Production of neurotransmitters

MelaninX NeurotransmittersX

• Mutations in PAH abolish activity
• Phe builds up in blood and brain, does not convert to Tyr
• Phe-restricteddiet
• Neurocognitive defects

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Effective PKU Treatment Remains a High Unmet Medical Need

Standard of care is onerous low Phe diet with poor compliance

90% of adults in U.S. (10,000 patients) untreated with any therapeutic product

Classical PKU is most severe form (~2/3 of PKU population)

Diet is not sufficient to reduce Phe levels to within ACMG targets (120-360 μmol/L) or EU targets (120-600 μmol/L)

For ~95% of patients, treatments do not reconstitute normal biochemical pathway; all require chronic dosing

16.5K patients in U.S., 50K globally

Newborn screening with 350 new cases a year in U.S., 1-1.5K globally

Untreated population source: PKU population from NORD, NPKUA and sales of two FDA-approved PKU treatments in the U.S.

Target sources: Vockley J et al. Genetics in Medicine 2014; Levy H et al. Molecular Genetics and Metabolism 2019; van Spronsen FJ et al. Lancet Diabetes Endocrinol 2017.

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Preclinical Development Data Led to HMI-102 Gene Therapy Product Candidate for Adults with PKU

Designed to address underlying genetic cause of PKU

Tested extensively in murine model of PKU:

• Preclinical data demonstrated that HMI-102 provided functional
  PAH gene à functional PAH protein
• Reduction in Phe to normal levels for lifetime of model
• Concomitant increase in tyrosine

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HMI-102 Gene Therapy Overview

Liver-Tropic

AAVHSC15

Liver-Specific	PAH Gene
Promoter

HMI-102

Cell

Nucleus

Episome w/

Promoter &

Functional

PAH

Mutated PAH Gene

PAH

Enzyme

mRNA

Mutated mRNA

Mutated PAH

Enzyme

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Design of Dose-Escalation Phase of First-Ever PKU Gene Therapy Trial: pheNIX Phase 1/2 Trial of HMI-102

N=2

Low-Dose

2E13 vg/kg

N = 2

Mid-Dose

6E13 vg/kg

✓

			● Adult patients with classical PKU
	N = 2	✓	● Designed to evaluate:
	● Safety
	High-Dose
	1E14 vg/kg
			● Efficacy (reduction in Phe)

✓

• Goal to select dose for the expansion phase
• Single I.V. administration
• Prophylactic, tapering steroids
• Patients dosed in 3 cohorts

= Safety/efficacy review with Data Monitoring Committee (DMC) and Internal Data Review Team

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Key Learnings of pheNIX Dose-Escalation Phase

Safety

• AE profile supports advancing to the expansion phase of the trial
• Immune response managed with increased steroids when necessary
• ALTs may be associated with reduced efficacy

Efficacy

• Phe reduction with Tyr increase consistent with PAH enzyme activity w Degree of Phe variability in individual patients and among patients
• Optimize treatment protocol (monitoring, steroid regimen)
• Greater understanding of kinetics and durability of response
• No patients failed screening due to pre-existing neutralizing antibodies (Nabs)

Dose-Selection

• Safety and efficacy data support advancing to dose expansion phase (randomized, concurrently controlled, potential registration phase)
• Goal to progress to expansion phase to treat a larger number of patients concurrently (no enrollment stagger in dose expansion phase)
• Apply learnings to dose expansion protocol

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Baseline Characteristics, Follow-Up and Select Co-Morbidities

Cohort				Per Protocol	Wks Post-	Pre-Existing Underlying
(Dose	Patient #	Sex	Age	Baseline Phe
HMI-102	Immune Conditions
Level)				μmol/L
Cohort 1	1	F	36	1140	52	-
(End of Study)
(Low; 2E13					52
vg/kg )	2	M	49	1020	-
					(End of Study)
Cohort 2	3	M	24	1010	48	-
(Mid; 6E13
vg/kg)	4	F	21	1060	44	Asthma, Seasonal Allergies
Cohort 3	5	F	31	1660	28	Asthma, Eczema, Food Allergies,
Environmental Allergies
(High; 1E14
vg/kg)	6	M	33	1060	13	-

No one failed screening due to pre-existing neutralizing antibodies (Nabs)

Baseline = Per protocol, day prior to dosing

As of data cutoff date of Oct 19, 2020

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Key Safety Observations

Generally well-tolerated

• No treatment-related serious adverse events (SAEs)
  wOne non-treatment-related SAE: Herpes zoster (shingles) wNo clinically significant changes in ECGs or vital signs
• No clinical signs of complement activation
• ALT elevations managed with increased steroids in Cohorts 2 and 3 when necessary

wNo AEs reported related to bilirubin levels

wPatients 4 and 5 had one Grade 3 ALT (both patients had pre-existing immune conditions)

●Normal cortisol levels were observed in Patient 4 during planned high-dose, prophylactic steroid therapy, raising question of adherence

As of data cutoff date of Oct 19, 2020

ALT = Alanine aminotransferase / ALT Grades based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5

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Key Efficacy Observations in Cohorts 2 and 3 (Mid- and High-Dose)

• Significant reductions in plasma Phe levels observed in Cohorts 2 and 3, compared to low-dose Cohort 1*
• Achieved plasma Phe levels below 360 μmol/L (ACMG target Phe levels):

w Cohort 2: Five values out to 48 weeks post-administration for Patient 3

w Cohort 3: One value out to 13 weeks post-administration for Patient 6

• Majority of patients self-liberalized (increased) dietary intact (natural) protein and/or Phe intake, and decreased Tyr intake
• Greater plasma Phe reductions observed in patients with lower ALT elevations
  (Grade 1)
• Concomitant Phe reduction and Tyr increase consistent with PAH enzymatic

activity

As of data cutoff date of Oct 19, 2020

ALT = Alanine aminotransferase / ALT Grades based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5 Mid-dose: n=2 patients; High-dose: n=2 patients

*P<0.004; Post-hoc comparison of Cohort 1 vs Cohorts 2&3 using repeated measures MANOVA/regression analysis

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Cohort 1: No Meaningful Phe Reduction

Patient 1		Patient 2

Baseline

Mean % CFB

Phe: +16.5

Tyr: -0.1

P/T: +20.9

Diet Mean % CFB

Intact Protein: +14.2

Total Protein: +4.5

Phe Intake: +0.4

Tyr Intake: -10.8

Peak ALT Grade: WNL (within normal limit)

Peak ALT Grade: 1 (1.4xULN)

As of data cutoff date of Oct 19, 2020

CFB = Change from baseline for last value prior to data cutoff; P/T = Phe/Tyr ratio; ALT = Alanine aminotransferase / ULN = Upper limit of normal ALT Grades based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5 / Patient 2 missed Week 32 measurements

Baseline

Mean % CFB

Phe: +35.4

Tyr: +16.1

P/T: +22.0

Diet Mean % CFB

Intact Protein: +66.0

Total Protein: -3.9

Phe Intake: +78.5

Tyr Intake: -14.7

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Cohort 2: Marked Phe Reductions Observed with Grade 1 ALT but not Grade 3 ALT

Patient 3

Baseline

Mean % CFB

Phe: -48.6

Tyr: +81.1

P/T: -70.8

Diet Mean % CFB

Intact Protein: -30.0

Total Protein: -4.8

Phe Intake: +100.6

Tyr Intake: -1.9

Peak ALT Grade: 1 (1.73xULN)

Patient 4

**

Peak ALT Grade: 3* (11.02xULN)

Baseline

Mean % CFB

Phe: +13.0

Tyr: +131.1

P/T: -45.5

Diet Mean % CFB

Intact Protein:+140.5

Total Protein: -9.6

Phe Intake: +289.0

Tyr Intake:-75.6

As of data cutoff date of Oct 19, 2020

CFB = Change from baseline for last value prior to data cutoff; P/T = Phe/Tyr ratio; ALT = Alanine aminotransferase / ULN = Upper limit of normal ALT Grades based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5

*Pre-existing immune conditions / **Began additional PKU medication after Week 36 / Patient 3 missed Week 20 and Patient 4 missed Weeks 16 and 20 measurements

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Cohort 3: Marked Phe Reductions with Grade 1 ALT but not Grade 3 ALT

Patient 5		Patient 6
Baseline
		Baseline
	Mean % CFB	Mean % CFB
•	Phe: -10.8	Phe: -31.4
•	Tyr: +22.6	Tyr: +40.3
•	P/T: -25.4	P/T: -52.4
	Diet Mean % CFB	Diet Mean % CFB
Intact Protein: -16.9	Intact Protein: +45.4
Total Protein: -16.9	Total Protein: +8.8
Phe Intake: -18.5	Phe Intake: +41.8
Tyr Intake: -21.0	Tyr Intake:+ 3.4
Peak ALT Grade: 3* (5.1xULN)		Peak ALT Grade: 1 (3.2xULN)**
As of data cutoff date of Oct 19, 2020
CFB = Change from baseline for last value prior to data cutoff; P/T = Phe/Tyr ratio; ALT = Alanine aminotransferase / ULN = Upper limit of normal
ALT Grades based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5 / *Pre-existing immune conditions
**Patient 6 Grade 1 based on baseline ALT value above ULN
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Patients 3 and 6 Showed Similar Trajectory in Plasma Phe Reductions

Patients 3 & 6

Plasma PHE (μmol/L)

Patient 3

Patient 6

Patient 6 Baseline

Patient 3 Baseline

As of data cutoff date of Oct 19, 2020

Patient 3 missed Week 20 measurements

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Significant Plasma Phe Reductions were Observed at the Higher HMI-102 Doses*

		Cohorts 2 and 3 Patients
Cohort 1 Patients
Plasma PHE % CFB		Plasma PHE % CFB

Patient 1

Patient 2

As of data cutoff date of Oct 19, 2020

%CFB = Percent change from baseline at each timepoint

*P<0.004; Post-hoc comparison of Cohort 1 vs Cohorts 2&3 using repeated measures MANOVA/regression analysis

Patient 3

Patient 4

Patient 5 Patient 6

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Phe Reductions in Patient 6 Trending Similarly to Patient 3

Patients 3 & 6

Plasma PHE (μmol/L)

Patient 3

Patient 6

Patient 6 Baseline

Patient 3 Baseline

As of data cutoff date of Oct 19, 2020

Participant 3 missed Week 20 measurements

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Results of Dose-Escalation Phase of First-Ever PKU Gene Therapy Trial

SAFETY

• Generally well-tolerated with no treatment-related SAEs

• • ALT elevations observed in Cohorts 2 and 3 managed with increased steroids when necessary
  • Degree of ALT increase was associated with pre-existing immune conditions
• No clinical signs of complement activation and no AEs related to bilirubin

EFFICACY

• Significant plasma Phe reductions observed in Cohorts 2 and 3, compared to Cohort 1*
  w Patient 3 achieved five Phe levels <360 μmol/L w Patient 6 achieved one Phe level <360 μmol/L
• Tyr increases and Phe/Tyr ratio decreases consistent with PAH enzymatic activity
• ALT elevations may be associated with reduced efficacy

• At mid- and high-doses, Phe reductions were greater in patients with Grade 1 ALTs compared to patients with Grade 3 ALT**

As of data cutoff date of Oct 19, 2020

ALT = Alanine aminotransferase / ALT Grades based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5 *P<0.004; Post-hoc comparison of Cohort 1 vs Cohorts 2&3 using repeated measures MANOVA/regression analysis **P<0.05; Post-hoc comparison of Patients 3&6 vs Patients 4&5 using repeated measures MANOVA/regression analysis

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Randomized, Concurrently Controlled Dose Expansion Phase to Begin Early 2021

• Efficacy results observed in dose-escalation phase support initiating randomized, concurrently controlled, dose expansion phase with two doses

• • Advancing two doses in parallel provides potential to convert to registrational trial quickly (no stagger between dosing)
  • 6E13 vg/kg
  • 8E13 vg/kg has potential to improve Phe reductions while reducing steroid exposure
• Key learnings from dose-escalation being applied to expansion, including:
• • Patient selection
  • Immunosuppressive regimen
  • Patient monitoring
  • Endpoints
• Drug supply on-hand for expansion phase
• • Manufactured in Homology's 25,000 sq. ft. GMP facility
  • Using the Homology manufacturing platform commercial process

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Homology's In Vivo Genetic Medicines Pipeline

			Stage of Development
Our Programs	Target	Discovery	Lead Optimization IND-Enabling	Phase 1/2	Phase 3
Gene Therapy
Adult Phenylketonuria (PKU): HMI-102	Liver
U.S. and E.U. Orphan Drug Designation
Metachromatic Leukodystrophy (MLD): HMI-202	CNS
U.S. and E.U. Orphan Drug Designation
MPS II (Hunter syndrome): HMI-203	CNS
Gene Editing
Pediatric PKU: HMI-103	Liver
Sickle Cell Disease	Human Stem Cells
Hemoglobinopathy	Human Stem Cells
Ophthalmic Target	Eye
has worldwide commercial rights

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High Unmet Need for MPS II (Hunter Syndrome) Treatment that Addresses Peripheral and Cognitive Effects

Lysosomal storage disorder leading to toxic lysosomal accumulation of glycosaminoglycans (GAGs)

Severe form includes progressive debilitation and intellectual decline followed by death in 10-20 years

No treatments currently available to address both cognitive and peripheral organ manifestations

Prevalence is 1 in 100,000 to 1 in 170,000; primarily males

Preclinical Studies

Homology's HMI-203

crossed the blood-brain- barrier, blood-nerve barrier and reach other peripheral organs involved in MPS II

HMI-203 resulted in high levels of active I2S protein expression, systemic reductions in GAG accumulation, and improvements in phenotype in disease model

Prevalence: National MPS Society

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