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| Item 8.01 | Other Events. |
On May 3, 2021, AVROBIO, Inc. (the “Company”) issued a press release titled “AVROBIO Provides Regulatory Update on Investigational AVR-RD-01 for Fabry Disease.” A copy of the press release is filed as Exhibit 99.1 to this Current Report on Form 8-K and incorporated into this Item 8.01 by reference.
Also on May 3, 2021, the Company updated its corporate presentation for use in meetings with investors, analysts and others. A copy of the slide presentation is filed as Exhibit 99.2 to this Current Report on Form 8-K and incorporated into this Item 8.01 by reference.
| Item 9.01. | Financial Statements and Exhibits. |
(d) Exhibits
| 99.1 | AVROBIO, Inc. press release, dated May 3, 2021. | |
| 99.2 | AVROBIO, Inc. slide presentation, dated May 2021. | |
| 104 | The cover page from this Current Report on Form 8-K, formatted in Inline XBR | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| AVROBIO, INC. | ||||||
| Date: May 3, 2021 | By: | /s/ Geoff MacKay | ||||
| Geoff MacKay | ||||||
| President and Chief Executive Officer | ||||||
Exhibit 99.1
AVROBIO Provides Regulatory Update on Investigational AVR-RD-01
for Fabry Disease
Anticipates initiating registration trial with kidney biopsy endpoint in mid-2022 to support potential full approval of AVR-RD-01 as first-line therapy, subject to FDA discussion and agreement
Two additional patients dosed in last two months in ongoing FAB-GT Phase 2 trial; plan to enroll a total of up to 14 participants
To support use of AVR-RD-01 in a broad Fabry disease population, company expects to include female patients, eliminate antibody status exclusions and collect additional cardiovascular and CNS data in FAB-GT trial
CAMBRIDGE, Mass., May 3, 2021 — AVROBIO, Inc. (Nasdaq: AVRO), a leading clinical-stage gene therapy company with a mission to free people from a lifetime of genetic disease, today provided an update on its regulatory plans for AVR-RD-01, the first investigational lentiviral gene therapy for Fabry disease. This update follows a recent U.S. regulatory development for Fabry disease therapies, as well as AVROBIO’s receipt of minutes from the company’s Type B (End-of-Phase 1) meeting with the U.S. Food and Drug Administration (FDA) on March 31, 2021.
On March 11, 2021, approximately three weeks before the company’s End-of-Phase 1 meeting, FDA granted full approval of Fabrazyme® (agalsidase beta)1 more than 18 years after the enzyme replacement therapy (ERT) received accelerated approval on the basis of a surrogate endpoint: reduction of GL-3 (also referred to as Gb3) inclusions in biopsied renal peritubular capillaries (PTCs). The conversion of Fabrazyme to full approval opens a new pathway for full approval of ERTs based on this surrogate endpoint, which AVROBIO believes could potentially apply to investigational AVR-RD-01. In addition, the conversion of Fabrazyme to full approval limits the accelerated approval pathways available for new therapies to treat Fabry disease. As a result, AVROBIO can no longer pursue an accelerated approval pathway for AVR-RD-01 with the FAB-GT trial as currently designed, and instead intends to discuss with FDA a registration trial with a primary efficacy endpoint of clearance of GL-3/Gb3 inclusions in biopsied renal PTCs as the basis for full approval.
“We believe we have a potential new path to pursue full approval for investigational AVR-RD-01 as a first-line therapy for Fabry disease by conducting a single, head-to-head registration trial versus Fabrazyme using a kidney biopsy surrogate endpoint similar to our FAB-GT Phase 2 trial, where we have seen 100% and 87% substrate reductions at one year post-gene therapy in the two patients with evaluable kidney biopsies,” said Geoff MacKay, CEO and president of AVROBIO. “We plan to design a registration trial with a scope, size and duration comparable to other gene therapy trials.”
| 1 | Fabrazyme® (agalsidase beta) is a registered trademark owned by Sanofi Genzyme |
In its FDA briefing book, which was submitted to FDA prior to Fabrazyme’s full approval, the company sought an accelerated approval pathway by expanding the FAB-GT Phase 2 clinical trial and conducting an additional confirmatory trial. The revised regulatory plan anticipates retaining the two-study approach with a similar overall requirement in terms of scope, size and duration.
The company plans to engage FDA to discuss and agree upon its revised approach, with the goal of initiating the registration trial in mid-2022. Although FDA guidance provides that a surrogate endpoint in a particular clinical development program should not be assumed to be appropriate for use in a different program, AVROBIO believes this recent development could potentially apply to investigational AVR-RD-01, a gene therapy designed to facilitate the production of functional enzyme by the patient’s own stem cells after a one-time treatment with the therapeutic gene.
AVROBIO also remains on track to request a CMC-oriented Type C meeting in the second half of 2021. Additionally, in parallel the company intends to seek scientific advice from the European Medicines Agency on the planned registration trial.
Two additional patients dosed in two months, with plans to amend the FAB-GT trial protocol
The ongoing FAB-GT trial continues to progress, now with six patients dosed, including two in the past two months, and additional participants are enrolled in the trial.
To help support the use of AVR-RD-01 in a broad Fabry disease population, AVROBIO expects to amend the FAB-GT trial protocol in the second quarter of 2021 by enrolling female participants, eliminating antibody-status exclusions and adding the collection of data on additional parameters that are recognized to be limitations of ERT, such as endpoints to assess the gene therapy’s potential ability to address cardiovascular and central nervous system manifestations. The company plans to enroll a total of up to 14 participants in the FAB-GT trial.
“We look forward to working with FDA and other regulators to design a single registration trial to support full approval that we hope will advance AVR-RD-01 as quickly as possible. We remain fiercely committed to our purpose: to free people living with Fabry disease from a lifetime of painful symptoms, chronic treatment and the unremitting fear of disease progression,” added MacKay.
About AVR-RD-01
AVR-RD-01 is an investigational ex vivo lentiviral gene therapy designed to provide a durable therapeutic benefit for people living with Fabry disease. The therapy starts with the patient’s own hematopoietic stem cells, which are genetically modified to express functional alpha-galactosidase A (AGA). Functional AGA reduces levels of globotriaosylceramide (Gb3 or GL-3), a toxic substrate, which together with its metabolite globotriaosylsphingosine (lyso-Gb3 or lyso-GL1), are associated with the signs and symptoms of Fabry disease. AVR-RD-01 has received orphan drug designations from FDA and the European Commission. AVROBIO is currently evaluating AVR-RD-01 in FAB-GT (NCT03454893), a Phase 2 clinical trial.
About Fabry Disease
Fabry disease is a rare, inherited lysosomal disorder characterized by the accumulation of globotriaosylceramide (Gb3 or GL-3) in the body’s cells. The build-up of Gb3 is due to variations in the GLA gene, which is responsible for the production of alpha-galactosidase A, the enzyme that breaks down Gb3. When Gb3 accumulates in cells and tissues, damage may occur and result in the progressive signs and symptoms of Fabry disease, including chronic pain, gastrointestinal issues such as nausea, vomiting and diarrhea, hearing loss, heart disease, progressive kidney disease and an increased risk of stroke. Even on ERT – the current standard of care – people with Fabry disease typically have a shortened life expectancy and may experience debilitating symptoms that significantly reduce their quality of life. An estimated one in 40,000 to 60,000 males are diagnosed with Fabry disease. Fabry disease also affects females, although the prevalence is unknown.
About AVROBIO
Our vision is to bring personalized gene therapy to the world. We aim to prevent, halt or reverse disease throughout the body with a single dose of gene therapy designed to drive durable expression of therapeutic protein, even in hard-to-reach tissues and organs including brain, muscle and bone. Our ex vivo lentiviral gene therapy pipeline includes clinical programs in Fabry disease, Gaucher disease type 1 and cystinosis, as well as preclinical programs in Hunter syndrome, Gaucher disease type 3 and Pompe disease. AVROBIO is powered by our industry leading plato® gene therapy platform, our foundation designed to deliver gene therapy worldwide. We are headquartered in Cambridge, Mass., with an office in Toronto, Ontario. For additional information, visit avrobio.com, and follow us on Twitter and LinkedIn.
Forward-Looking Statements
This press release contains forward-looking statements, including statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words and phrases such as “aims,” “anticipates,” “believes,” “could,” “designed to,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will,” and variations of these words and phrases or similar expressions that are intended to identify forward-looking statements. These forward-looking statements include, without limitation, statements regarding our business strategy for and the potential therapeutic benefits of our current and prospective product candidates, our plans and expectations with respect to the development of AVR-RD-01, including timing and design of our potential registration trial, the intended use of such trial as our registration trial for this product candidate, anticipated interactions with regulatory agencies and the planned use of surrogate endpoints in future development of AVR-RD-01, results of preclinical studies, the design, commencement, enrollment and timing of ongoing or planned clinical trials, clinical trial results, product approvals and regulatory pathways, the timing of patient recruitment and enrollment activities, and product approvals, anticipated benefits of our gene therapy platform including potential impact on our commercialization activities, timing and likelihood of success, and the expected benefits and results of our implementation of the plato® platform in our clinical trials and gene therapy programs, including the use of a personalized and ultra-precision busulfan conditioning regimen. Any such statements in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Results in preclinical or early-stage clinical trials may not be indicative of results from later stage or larger scale clinical trials and do not ensure regulatory approval. You should not place undue reliance on these statements, or the scientific data presented.
Any forward-looking statements in this press release are based on AVROBIO’s current expectations, estimates and projections about our industry as well as management’s current beliefs and expectations of future events only as of today and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that any one or more of AVROBIO’s product candidates will not be successfully developed or commercialized, the risk of cessation or delay of any ongoing or planned clinical trials of AVROBIO or our collaborators, the risk that AVROBIO may not successfully recruit or enroll a sufficient number of patients for our clinical trials, the risk that AVROBIO may not realize the intended benefits of our gene therapy platform, including the features of our plato® platform, the risk that our product candidates or procedures in connection with the administration thereof will not have the safety or efficacy profile that we anticipate, the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical or clinical trials, will not be replicated or will not continue in ongoing or future studies or trials involving AVROBIO’s product candidates, the risk that regulatory agencies may disagree with our anticipated development approach for our product candidates such as AVR-RD-01, including that we may not be able to utilize our planned registration trial of AVR-RD-01 for full approval but instead be required to conduct additional testing, that we may be required to conduct our planned testing in a more time-consuming, expensive, challenging or otherwise different manner than we envision or have conducted for our existing trials, particularly in light of the FDA’s preference for clinical trials to be double-blinded and potentially include sham controls, the risk that we may not be able to utilize our envisioned surrogate endpoint to support full approval of AVR-RD-01 but instead be required to measure a different endpoint such as a clinical outcome, the risk that we will be unable to obtain and maintain regulatory approval for our product candidates, the risk that the size and growth potential of the market for our product candidates will not materialize as expected, risks associated with our dependence on third-party suppliers and manufacturers, risks regarding the accuracy of our estimates of expenses and future revenue, risks relating to our capital requirements and needs for additional financing, risks relating to clinical trial and business interruptions resulting from the COVID-19 outbreak or similar public health crises, including that such interruptions may materially delay our enrollment and development timelines and/or increase our development costs or that data collection efforts may be impaired or otherwise impacted by such crises, and risks relating to our ability to obtain and maintain intellectual property protection for our product candidates. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause AVROBIO’s actual results to differ materially and adversely from those contained in the forward-looking statements, see the section entitled “Risk Factors” in AVROBIO’s most recent Annual or Quarterly Report, as well as discussions of potential risks, uncertainties and other important factors in AVROBIO’s subsequent filings with the Securities and Exchange Commission. AVROBIO explicitly disclaims any obligation to update any forward-looking statements except to the extent required by law.
Investor Contact:
Christopher F. Brinzey
Westwicke, an ICR Company
339-970-2843
chris.brinzey@westwicke.com
Media Contact:
Stephanie Simon
Ten Bridge Communications
617-581-9333
stephanie@tenbridgecommunications.com
MAY 2021 Corporate Presentation Exhibit 99.2
Disclaimer This presentation has been prepared by AVROBIO, Inc. (“AVROBIO”) for informational purposes only and not for any other purpose. Certain information contained in this presentation and statements made orally during this presentation relate to or are based on studies, publications, surveys and other data obtained from third-party sources and AVROBIO’s own internal estimates and research. While AVROBIO believes these third-party sources to be reliable as of the date of this presentation, it has not independently verified, and AVROBIO makes no representation as to the adequacy, fairness, accuracy or completeness of any information obtained from third-party sources. While AVROBIO believes its internal research is reliable, such research has not been verified by any independent source. This presentation may contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words and phrases such as “aims,” “anticipates,” “believes,” “could,” “designed to,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will,” and variations of these words and phrases or similar expressions that are intended to identify forward-looking statements. These forward-looking statements include, without limitation, statements regarding our business strategy for and the potential therapeutic benefits of our current and prospective product candidates; the design, commencement, enrollment and timing of ongoing or planned clinical trials and regulatory pathways; our plans and expectations with respect to the development of AVR-RD-01, including timing and design of our potential registration trial, the intended use of such trial as our registration trial for this product candidate, anticipated interactions with regulatory agencies and the planned use of surrogate endpoints in future development of AVR-RD-01; the timing of patient recruitment and enrollment activities, clinical trial results, and product approvals; the timing and results of our ongoing preclinical studies; the anticipated benefits of our gene therapy platform including the potential impact on our commercialization activities, timing and likelihood of success; the anticipated benefits and safety profile of busulfan as a conditioning agent; the expected benefits and results of our manufacturing technology, including the implementation of our plato® platform in our clinical trials and gene therapy programs; the expected safety profile of our investigational gene therapies; the potential impact of the COVID-19 outbreak on our clinical trial programs and business generally; and the market opportunity for and anticipated commercial activities relating to our investigational gene therapies. Any such statements in this presentation that are not statements of historical fact may be deemed to be forward-looking statements. Any forward-looking statements in this presentation are based on our current expectations, estimates and projections about our industry as well as management’s current beliefs and expectations of future events only as of today and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that any one or more of our product candidates will not be successfully developed or commercialized; the risk that regulatory agencies may disagree with our anticipated development approach for our product candidates such as AVR-RD-01, including that we may not be able to utilize our planned registration trial of AVR-RD-01 for full approval but instead be required to conduct additional testing, that we may be required to conduct our planned testing in a more time-consuming, expensive, challenging or otherwise different manner than we envision or have conducted for our existing trials, particularly in light of the FDA’s preference for clinical trials to be double-blinded and potentially include sham controls, and the risk that we may not be able to utilize our envisioned surrogate endpoint to support full approval of AVR-RD-01 but instead be required to measure a different endpoint such as a clinical outcome; the risk of cessation or delay of any ongoing or planned clinical trials of AVROBIO or our collaborators; the risk that we may not successfully recruit or enroll a sufficient number of patients for our clinical trials; the risk that we may not realize the intended benefits of our gene therapy platform, including the features of our plato® platform; the risk that our product candidates or procedures in connection with the administration thereof, including our use of busulfan as a conditioning agent, will not have the safety or efficacy profile that we anticipate; the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical or clinical trials, will not be replicated or will not continue in ongoing or future studies or trials involving our product candidates; the risk that we will be unable to obtain and maintain regulatory approval for our product candidates; the risk that the size and growth potential of the market for our product candidates will not materialize as expected; risks associated with our dependence on third-party suppliers and manufacturers; risks regarding the accuracy of our estimates of expenses and future revenue; risks relating to our capital requirements and needs for additional financing; risks relating to clinical trial and business interruptions resulting from the COVID-19 outbreak or similar public health crises, including that such interruptions may materially delay our development timeline and/or increase our development costs or that data collection efforts may be impaired or otherwise impacted by such crises; and risks relating to our ability to obtain and maintain intellectual property protection for our product candidates. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause AVROBIO’s actual results to differ from those contained in the forward-looking statements, see the section entitled “Risk Factors” in AVROBIO’s most recent Annual or Quarterly Report, as well as discussions of potential risks, uncertainties and other important factors in AVROBIO’s subsequent filings with the Securities and Exchange Commission. AVROBIO explicitly disclaims any obligation to update any forward-looking statements except to the extent required by law. Note regarding trademarks: plato® is a registered trademark of AVROBIO. Other trademarks referenced in this presentation are the property of their respective owners. Copyright© 2021 AVROBIO, Inc. All rights reserved.
Vision Bring personalized gene therapy to the world. Purpose Freedom from a lifetime of genetic disease.
Leading lysosomal disorder gene therapy pipeline 15 patients dosed to date across three indications IND: Investigational New Drug Fabry AVR-RD-01 Gaucher type 1 AVR-RD-02 Cystinosis AVR-RD-04 Hunter AVR-RD-05 Gaucher type 3 AVR-RD-06 Pompe AVR-RD-03 Proof-of-Concept IND-Enabling Phase 1/2
Disease Approx. 2020 Global Net Sales† Five-Year SOC Cost per U.S. Patient* Selected Companies w/ Marketed Therapies Fabry $1.4B $1.7M Cystinosis $0.2B $4.3M Gaucher $1.5B $2.3M Hunter $0.6B $2.4M Pompe $1.1B $3.2M Multi-billion dollar market opportunity Over 50,000 patients across target indications Sources: Rombach S et al., Orphanet J Rare Dis, 2013; van Dussen L et al., Orphanet J Rare Dis, 2014 * WAC pricing from Redbook using standard dosing assumptions † 2020 Net Sales from company annual and other reports ‡ Horizon’s Procysbi oral therapy (delayed release cysteamine bitartrate); midpoint between avg. adult and pediatric Note: Shire acquired by Takeda in 2019 SOC: Standard of Care Total: $4.8B ‡
Lifelong treatments vs. potential single-dose therapy Treatment burden Enzyme or protein level DISEASE PROGRESSION CONTINUES COULD HALT, PREVENT OR REVERSE DISEASE Enzyme Replacement Therapy (ERT) Temporary bolus of enzyme, not curative Bi-Weekly ERT Plasma Pharmacokinetics of ERT Life-long infusions Transient, intermittent elevation Bi-weekly IV infusions AVROBIO Gene Therapy Designed for 24/7 expression of protein, curative potential Functional Protein Expression in Transduced HSCs and Their Progeny 24/7 expression One-Time Gene Therapy Long-term, continuous elevation Single IV infusion ERT: Enzyme Replacement Therapy; IV: Intravenous; HSC: Hematopoietic Stem Cells Ability to impact CNS No Yes
PROGRAM PATIENT MONTHS POST-INFUSION Fabry Phase 1 PATIENT 1 PATIENT 2 PATIENT 3 PATIENT 4 PATIENT 5 Fabry Phase 2 PATIENT 1 PATIENT 2 PATIENT 3 PATIENT 4 PATIENT 5 PATIENT 6 Gaucher Type 1 Phase 1/2 PATIENT 1 Cystinosis Phase 1/2 PATIENT 1 PATIENT 2 PATIENT 3 * Data not yet available for patient #5 and #6 in Fabry Phase 2 Durability demonstrated across clinical programs First patient out 3.5 years; 10 patients out 1 year or more
Bu90-TCI conditioning-related side effects have been predictable and transient in first two plato® patients Note: FAB-GT, f-k-a FAB-201, safety data cut-off December 7, 2020; Gaucher safety data cut-off January 4, 2021 * Source: Bartelink IH et al., Lancet Haematol, 2016 Bu90-TCI: Busulfan 90-Target Concentration Intervention; AUC: Area Under the Curve; TCI: Target Concentration Intervention Adverse Event Probability 50 70 90 110 130 Busulfan Cumulative AUC (mg x hr/L) 0.0 0.2 0.4 0.6 0.8 Graft Failure Increased Toxicity Analysis of 465 non-malignant patients identified optimum exposure for busulfan conditioning*: Bu90-TCI target Conditioning-related grade 3-4 AEs in first two plato® patients Days Post Gene Therapy Bu90 TCI Mean Toxicity Grade Day 0 BLOOD GI SYSTEM OTHERS
Unrivaled commercial-scale platform in plato® MOBILIZATION & APHERESIS Patient Consent & Screening Patient Monitoring CONDITIONING & GENE THERAPY ADMINISTRATION CELL SEPARATION & CULTURE TRANSDUCTION CLOSED, AUTOMATED SYSTEM HARVESTING & CRYOPRESERVATION DRUG PRODUCT TESTING
“First Wave” Programs Fabry, Gaucher Type 1, cystinosis
Fabry disease opportunity Standard of care (SOC): ERT Not curative, relentless progression of disease continues Burdensome and expensive – bi-weekly ERT infusions required; 5-year treatment cost of ERT = ~$1.7 million* Caused by mutation in gene encoding for alpha-galactosidase A enzyme Kidney function Proteinuria, polyuria, kidney failure Cardiac function Left ventricular hypertrophy, fibrosis, heart failure Neuropathic pain Pain and burning sensations in hands and feet, pain crises Everyday burden of illness, and life expectancy Not curative, relentless progression of disease, shortened lifespan CNS complications TIA/stroke, depression, executive function deficit, white matter lesions Unmet needs with SOC: Fabry Disease Target Product Profile**: Prevents, halts or reverses disease; extends/normalizes lifespan Addresses all patient segments – all genetic mutations, male and female, all ages Lifelong durability – single infusion; off ERT Impacts hard-to-reach organs – e.g., brain, heart, kidney Well tolerated * WAC pricing from Redbook using standard dosing assumptions ** Note: these are target attributes for a first-line therapy Affects ~ 1:40,000 males and 1:118,000 females in U.S. Tom, living with Fabry disease
OBJECTIVES PATIENTS Safety and tolerability Preliminary efficacy n = 5 patients 18 – 59 year-old males On ERT >6 months prior to enrollment FULLY ENROLLED PHASE 1 * Sponsored by FACTs team (Fabry Disease Clinical Research and Therapeutics) in Canada ** FAB-GT fka FAB-201 *** Plan to increase to up to 14 patients with protocol amendment, including females Two AVR-RD-01 Fabry clinical trials 11 patients dosed across Phase 1 and 2 OBJECTIVES PATIENTS Safety and tolerability Efficacy n = 8-12 patients*** (6 dosed to-date) 16 – 50 year-old males*** Treatment naïve ACTIVELY RECRUITING PHASE 2 Investigator-Sponsored Trial* AVROBIO FAB-GT Trial **
100% substrate reduction 1 Year (48 weeks) Scored by 2 independent, blinded pathologists Patient 4 Clinically meaningful and statistically significant reduction in substrate in first two evaluable kidney biopsies FABRY PHASE 2 Baseline: The last available, non-missing observation prior to AVR-RD-01 infusion Note: With respect to Fabry disease, Gb3 inclusions per PTC is interchangeable with GL-3 inclusions per KIC PTC: Peritubular Capillary; Gb3: Globotriaosylceramide; GL-3: Globotriaosylceramide; KIC: Kidney Interstitial Capillary 87% substrate reduction 1 Year (48 weeks) Scored by 2 independent, blinded pathologists NEW DATA
Plasma AGA Activity (nmol/hr/mL) Leukocyte AGA Activity (nmol/hr/mg protein) Leukocyte AGA Enzyme Activity Plasma AGA Enzyme Activity Plasma AGA Activity Reference Range: 5.1–9.2 nmol/hr/mL; AGA: α-galactosidase A Leukocyte AGA Activity Reference Range: 24–56 nmol/hr/mg protein; AGA: α-galactosidase A Durability demonstrated over multiple measures up to 2.5 years Patient 4 dosed using plato® FABRY PHASE 2 Patient 1 Patient 2 Patient 3 Patient 4 VCN: Vector Copy Number; PBL: Peripheral Blood Leukocytes; dg: Diploid Genome Drug Product VCN/dg Patient 1: 0.7 Patient 2: 0.5 Patient 3: 1.4 Patient 4: 1.6 Vector Copy Number
Day 0 70% average plasma lyso-Gb3 reduction FABRY PHASE 2 Patient 1 Patient 2 Patient 3 Patient 4 Reduction from Baseline to Last Observation Patient 1 86% Patient 2 N/A Patient 3 55% Patient 4 69% Lyso-Gb3 Plasma Reference Value: 2.4 nM; Lyso-Gb3: Globotriaosylsphingosine Note: Patient 2 has normal substrate, consistent with late-onset cardiac variant phenotype
ERT No ERT Gene Rx 25.3 26.1 58.5 29.1 15.8 Day 0 25% average plasma lyso-Gb3 reduction below baseline ERT All patients who have discontinued ERT remain off ERT* FABRY PHASE 1 * As of January 11, 2021 Lyso-Gb3: Globotriaosylsphingosine; ERT: Enzyme Replacement Therapy; Rx: Therapy Gene Rx + Off ERT Gene Rx + ERT Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 25% reduction from baseline ERT OFF ERT 19.0 14.7 33.4 8.2 39.2 43% reduction from baseline ERT OFF ERT 48% reduction from baseline ERT ON ERT 44% reduction from baseline ERT ON ERT 35% increase from baseline ERT OFF ERT
Day 0 Kidney function (eGFR) stable up to 3.5 years* Normal Kidney Function Severe CKD Moderate CKD Mild CKD FABRY PHASE 1 & 2 * Eight of nine patients stable; other patient entered trial with more advanced kidney disease and a baseline eGFR level <50 mL/min/1.73m2; as expected, this patient has not stabilized, and the patient remains on ERT Note: eGFR was calculated using the CKD-EPI formula eGFR: Estimated Glomerular Filtration Rate; CKD: Chronic Kidney Disease; CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration Fabry Phase 2 Fabry Phase 1
Cardiac function and mass stable across multiple measures up to 1 year FABRY PHASE 2 Source: *Alfakih K et al, J Magn Reson Imaging, 2003 ; **Maceira AM et al, J of Cardiovascular Magnetic Resonance, 2006 *Reference Range Mean Values Male 20-39 yrs; EF: 64.3 ± 4.2%; EDV: 178.6 ± 30.1 mL; CO: 4-8 L/min; LV Mass Index: 67.8 ± 10.7 g/m2 **Reference Range Mean Values Male 40-49 yrs; EF: 58-75 %; EDV: 117-200 mL; CO: 4-8 L/min; LV Mass Index: 58-91 g/m2
No unexpected safety events identified Conditioning-related side effects have been manageable and transient (n=1 Bu) (n=3 Mel) No AEs or SAEs related to AVR-RD-01 drug product AEs across trials generally consistent with myeloablative conditioning, underlying disease or pre-existing conditions Phase 1 AEs (n=94) Grade 3 or 4 (n=14) Phase 1 SAEs (n=2) resolved without clinical sequelae Post-AVR-RD-01 treatment: febrile neutropenia; thrombophlebitis Phase 2 AEs (n=111) Grade 3 or 4 (n=22) Phase 2 SAEs (n=6) resolved without clinical sequelae Post-AVR-RD-01 treatment: dehydration; nausea; vomiting; febrile neutropenia Phase 2 conditioning-related grade 3/4 AEs Phase 1 & 2 AEs and SAEs Note: Phase 2 safety data cut-off December 7, 2020; Phase 1 safety data cut-off November 26, 2020 AE: Adverse Event; Bu: Busulfan; Mel: Melphalan Day 0 Day 0 Gastrointestinal System Blood FABRY PHASE 1 & 2
Accelerating enrollment by adding international referrals Global patient recruitment Expands pool of potential patients Helps navigate COVID-19 issues First global center of excellence established in Australia Long-term follow-up expected to take place in Brazil TWO Fabry patients from Brazil have been dosed and TWO additional patients enrolled in Australia
Regulatory update on AVR-RD-01 Just prior to our End-of-Phase 1 meeting with the FDA, Fabrazyme® was converted from accelerated to full approval based upon a kidney biopsy surrogate endpoint We believe this development opens a new pathway for the potential full, traditional approval of AVR-RD-01 We plan to design a single head-to-head registration trial versus Fabrazyme with a scope, size and duration comparable to other gene therapy trials, using a kidney biopsy surrogate endpoint similar to our FAB-GT Phase 2 trial Our briefing book submitted to FDA (prior to Fabrazyme full approval) proposed an expanded Phase 2 clinical trial and an additional confirmatory trial Revised regulatory plan similarly anticipates a two study approach with a similar overall requirement in terms of scope, size and duration PLANNED NEXT STEPS: Request clinically-oriented Type C meeting with FDA to discuss and seek agreement on revised approach Request CMC-oriented Type C meeting with FDA in second half of 2021 Amend FAB-GT Phase 2 protocol to collect data on additional parameters that are recognized to be limitations of ERT and cap enrollment at up to 14 patients Initiate registration trial in mid-2022 FDA: Food and Drug Administration
FDA conversion of Fabrazyme to traditional approval impacts approval pathways for future Fabry treatments Fabrazyme receives accelerated approval Fabrazyme receives traditional/full approval March 11, 2021 FDA releases updated surrogate endpoints table March 31, 2021 200320102020 FDA: Food and Drug Administration
Updated FDA table of surrogate endpoints (as of 3/31/21) Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure | FDA FDA: Food and Drug Administration Note: FDA guidance provides that the acceptability of a surrogate endpoint in a particular clinical development program should not be assumed to be appropriate for use in a different program.
Cystinosis opportunity Standard of care (SOC): Cysteamine pills & eye drops Not curative, relentless progression of disease continues; significantly shortened lifespan; kidney transplant often required Burdensome and expensive – high pill burden and hourly eye drops; 5-year treatment cost with SOC ~$4.3 million* Caused by CTNS gene defect, resulting in cystine buildup in lysosomes Cystinosis Target Product Profile**: Prevents, halts or reverses disease; extends/normalizes lifespan Addresses all patient segments – male & female; kidney transplant independent; all ages Lifelong durability – single infusion; off cysteamine pills and eye drops Impacts hard-to-reach organs – e.g., eye, endocrine organs, brain Well tolerated Unmet needs with SOC: Vision Corneal cystine accumulation, photophobia, involuntary eyelid closure Endocrine disorders Softening & deformation of bones, hypothyroidism, diabetes, infertility Everyday burden of illness, reduced life expectancy High pill burden causes GI discomfort; sulfur body odor and breath CNS complications Myopathy, hypotonia, tremors, swallowing, neurodevelopmental issues Kidney function Renal Fanconi syndrome, proteinuria, CKD, kidney failure Jaxon, living with cystinosis Affects ~ 1:170,000 people * WAC pricing from Redbook using standard dosing assumptions ** Note: these are target attributes for a first-line therapy
Steady enrollment in AVR-RD-04 IST trial in cystinosis AVR-RD-04 trial sponsored by University of California, San Diego; IST does not use plato® platform Note: AVR-RD-04 aka CTNS-RD-04 IST: Investigator Sponsored Trial OBJECTIVES PATIENTS Safety and tolerability Hypothesis generation of endpoints Up to 6 patients (3 patients enrolled to-date) Adults and adolescents Cohorts 1-2 >18 years; Cohort 3 >14 years Male and female Oral and ophthalmic cysteamine ACTIVELY RECRUITING: PHASE 1/2 AVR-RD-04
CYSTINOSIS PATIENT MONTHS OFF CYSTEAMINE PILLS AND EYE DROPS POST AVR-RD-04 INFUSION OFF cysteamine pills PATIENT 1 PATIENT 2 PATIENT 3 OFF cysteamine eye drops PATIENT 1 PATIENT 2 PATIENT 3 All patients continue to be cysteamine-independent CYSTINOSIS PHASE 1/2 Note: All 3 subjects remain off cysteamine pills and eye drops. Subjects 2 and 3 stopped cysteamine eye drops 1-month post-transplant (per protocol). Subject 1 stopped cysteamine eye drops prior to baseline. Data as of January 20, 2021
Day 0 Annualized slope: -1.8 Annualized slope: -7.2 CYSTEAMINE GENE THERAPY eGFR data at 16 months suggest renal function stabilization post-gene therapy after years of pathological decline Note: These results are for a single patient only and may vary in the study population; eGFR calculated using CKD-EPI formula; eGFR: Estimated Glomerular Filtration Rate; CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration CYSTINOSIS PHASE 1/2: PATIENT 1
Trial designed to demonstrate broad applicability across cystinosis patient population Positive eGFR trends independent of kidney transplant status CYSTINOSIS PHASE 1/2: PATIENTS 1 & 2 Note: eGFR calculated using CKD-EPI formula Patient 2 is post two kidney transplants eGFR: Estimated Glomerular Filtration Rate; CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration Day 0 eGFR (mL/min/1.73 m2) Patient 1 Patient 2 (post-kidney transplants)
Sharp drop in the number and size of cystine crystals in skin and rectal biopsies CYSTINOSIS PHASE 1/2: PATIENT 1 RECTAL BIOPSY SKIN BIOPSY Average intracytoplasmic crystals per cell Occupancy of cytoplasmic volume Average intracytoplasmic crystals per cell Occupancy of cytoplasmic volume Baseline 12 months Baseline 12 months 90% 25% 75% 10% 44% reduction 4.6 2.6 76% reduction 11.3 2.7 Note: These results are for a single patient only and may vary in the study population Baseline 12 months Baseline 12 months
Substantial decline in corneal crystals observed at 1 year CYSTINOSIS PHASE 1/2: PATIENT 1 Note: These results are for a single patient only and may vary in the study population; IVCM: In Vivo Confocal Microscopy; OD: Oculus Dexter (right eye); HRT3: Heidelberg Retina Tomograph 3 111 µm, OD 174 µm, OD 330 µm, OD 515 µm, OD 724 µm, OD Baseline IVCM images from Nidek Confoscan 12 months post-gene therapy IVCM images from Heidelberg HRT3 w/ Rostock Corneal Module 51 µm, OD 331 µm, OD 513 µm, OD 176 µm, OD Back of cornea CORNEAL CRYSTALS Front of cornea
Photophobia improved meaningfully at 1 year Photophobia, or extreme sensitivity to light, is a hallmark of cystinosis CYSTINOSIS PHASE 1/2: PATIENT 1 Liang, H. IONS May 2015 Cystinosis photophobia intensity associated with: Crystal density (light scattering) Inflammatory cell infiltration Corneal nerve damage Clinician-Assessed Photophobia Grade (Patient 1) No photophobia under maximum slit-lamp beam Unable to bear blue slit-lamp beam Unable to bear minimum slit-lamp beam Unable to bear moderate slit-lamp beam Unable to open eyes even inside dark room Unable to open eyes inside illuminated consultation room, need dark glasses
Blond hair and pale skin typical for cystinosis patients 4 months 6 months 9 months Post-Infusion Patient 1 appears to exhibit progressively darkening skin, eyebrows and hair color post-infusion, suggesting a possible impact of cystinosin protein on melanin Note: These results are for a single patient only and may vary in the study population; Background removed for clarity Source: Chiaverini et al., FESEB, 2012 Darker pigmentation may be a sign of multi-functional cystinosin activity post-gene therapy CYSTINOSIS PHASE 1/2: PATIENT 1 Cystinosin is located in melanosomes and regulates melanin synthesis Pre-Infusion
Day 0 VCN trending as expected across patients Patient 1 reached VCN therapeutic plateau DRUG PRODUCT VCN/dg Patient 1 2.1 Patient 2 1.3* Patient 3 1.6 * From second apheresis VCN: Vector Copy Number; PBCs: Peripheral Blood Cells; dg: Diploid Genome CYSTINOSIS PHASE 1/2 Patient 1 Patient 2 Patient 3
Note: Safety database cut as of January 27, 2021 AE: Adverse Event; SAE: Serious Adverse Event AEs are generally consistent with myeloablative conditioning or underlying disease: Pre-AVR-RD-04 treatment and prior to conditioning (not all events listed) Diarrhea, hypokalemia, dizziness Dehydration, vomiting Post-AVR-RD-04 treatment (not all events listed) Alopecia, intermittent diarrhea, vomiting, loss of appetite Mucositis, intermittent febrile neutropenia, intermittent epistaxis Intermittent blurry vision, intermittent hypokalemia, mucoceles Thrombocytopenia AEs & SAEs reported CYSTINOSIS PHASE 1/2 AEs (n=48) Majority of AEs are mild or moderate and resolved SAE (n=1) Post AVR-RD-04 treatment: appendicitis unrelated to study treatment or procedures No unexpected safety events Conditioning-related side effects have been manageable and transient No SAEs or AEs related to AVR-RD-04 drug product
Planned global regulatory strategy for cystinosis Planned 50% Enrolled POTENTIAL REGISTRATION Adults and pediatrics, males and females Mutation-independent, kidney transplant-independent Efficacy, durability, safety Ophthalmology, kidney, and other undisclosed Multiple crystal measures Quality of life PHASE 1/2 – INVESTIGATOR SPONSORED TRIAL n ≤6 Adults and adolescents, males and females Mutation-independent, kidney transplant-independent Safety, durability, preliminary efficacy Biomarker data, kidney function, vision Quality of life Anticipated Next Steps: Engage with FDA on registration trial design Identify global sites for registration trial Prepare plato® CMC / analytics requirements FDA: Food and Drug Administration; CMC: Chemistry, Manufacturing, and Controls
Gaucher disease type 1 opportunity Standard of care (SOC): ERT Not curative, relentless progression of disease continues, including bone crisis and fatigue Burdensome and expensive – bi-weekly infusions required; 5-year treatment cost with ERT = ~$2.3 million* Caused by mutation in the gene encoding for glucocerebrosidase (GCase) enzyme Gaucher Disease Type 1 Target Product Profile**: Prevents, halts or reverses disease; extends/normalizes lifespan Addresses all patient segments – all GD1 genetic mutations, all ages, male & female Lifelong durability – single infusion; off ERT/chaperone therapy Impacts hard-to-reach organs – e.g., brain, bone and bone marrow Well tolerated Unmet needs with SOC: Bone-related manifestations Skeletal abnormalities, avascular necrosis, osteoporosis Hemoglobin levels and platelet counts Anemia, thrombocytopenia, easy bruising, bleeding Hepatosplenomegaly Enlarged liver, enlarged spleen Everyday burden of illness, and life expectancy Fatigue, pain, lung disease, biweekly infusions, shortened lifespan CNS complications Increased risk of GBA-Parkinson’s disease Adrianna, living with Gaucher disease type 1 Affects ~ 1:44,000 people worldwide * WAC pricing from Redbook using standard dosing assumptions ** Note: these are target attributes for a first-line therapy
Guard1: Phase 1/2 study in Gaucher disease type 1 OBJECTIVES PATIENTS Safety Efficacy Engraftment Enrollment goal 8-16 patients 18-45-year-old males and females Have a confirmed diagnosis of GD1 based on: Deficient glucocerebrosidase enzyme activity Clinical features consistent with GD1 An adaptive, open-label, multinational phase 1/2 study of the safety and efficacy of ex vivo, lentiviral vector-mediated gene therapy AVR-RD-02 for patients with Gaucher disease type 1 ACTIVELY RECRUITING: RECRUITING PLANNED 2021: PHASE 1/2 AVR-RD-02 Gaucher disease type 1 patients who are: ERT-stable for >24 months or Treatment-naïve or Have not received ERT or SRT in the last 12 months GD1: Gaucher Disease Type 1; ERT: Enzyme Replacement Therapy; SRT: Substrate Reduction Therapy
First patient’s plasma chitotriosidase levels spike off ERT Personal history documents response to intermittent and halted ERT use GUARD1: PATIENT 1 Chitotriosidase Plasma Activity Normal Range: 0.0–44.2 μmoL/L/h ERT: Enzyme Replacement Therapy Chitotriosidase is a marker of inappropriately activated macrophages (Gaucher cells) Chitotriosidase Plasma Activity (µmol/L/h)
Plasma Chitotriosidase Activity (μmol/L/h) Baseline (ON ERT) 3 months (OFF ERT) 6 months (OFF ERT) 151 125 GUARD1: PATIENT 1 Baseline taken one month prior to gene therapy which is when ERT is discontinued Lyso-Gb1 Plasma Normal Range: 0.5 – 1.2 ng/mL Plasma chitotriosidase activity normal range: 0.0 – 44.2 μmoL/L/h ERT: Enzyme Replacement Therapy Key biomarkers below ERT baseline at 6 months 77 Chitotriosidase is a marker of inappropriately activated macrophages (Gaucher cells) NEW DATA 49% reduction 18 25 32 Plasma Lyso-Gb1 (ng/mL) Baseline (ON ERT) 3 months (OFF ERT) 6 months (OFF ERT) 44% reduction Lyso-Gb1 is a sensitive and specific marker of toxic metabolite accumulation in Gaucher disease
Platelet counts and hemoglobin in normal range at 6 months, despite being off ERT GUARD1: PATIENT 1 Platelet Count Reference Value Adult: 130-400x109/L; Hemoglobin Reference Value: Males: 13.5-17.5 g/dL; Females: 11.5-16.0 g/dL; grey line: local (safety) lab values; pink dots: central (efficacy) lab values; ERT: Enzyme Replacement Therapy Platelet Count (x109 /L) Platelet Count Normal range Hemoglobin Concentration Normal range
GUARD1: PATIENT 1 VCN trending as expected at 6 months VCN, vector copy number; PBL, peripheral blood leukocytes; dg, diploid genome Drug Product VCN/dg Patient 1 3.7 Day 0
Bu90-TCI: Busulfan 90-Target Concentration Intervention; GI: Gastrointestinal No unexpected safety events identified in first patient Conditioning-related side effects have been predictable and transient Conditioning-related grade 3/4 AEs Note: Safety database cut as of January 04, 2021 AE: Adverse Event; SAE: Serious Adverse Event; G-CSF: Granulocyte Colony Stimulating Factor G-CSF 5 µg/kg @ Days 5, 6, 7, 10, 11, and 14 post-infusion of AVR-RD-02 BLOOD GI SYSTEM OTHERS Days Post Gene Therapy Bu90 TCI Mean Toxicity Grade No AEs or SAEs related to AVR-RD-02 drug product AEs generally consistent with myeloablative conditioning, underlying disease or pre-existing conditions AEs n=29 Grade 3 (n=7) Eye pain, decreased appetite, dehydration, headache, hypophosphatemia, neutropenia, thrombocytopenia Grade 4 (n=2) Leukopenia and neutropenia AEs resolved without clinical sequelae AEs (no SAEs reported) GUARD1: PATIENT 1
Planned global development strategy for Gaucher disease type 1 Planned Enrolling POTENTIAL REGISTRATION PATH Phase 1/2 expansion Safety, efficacy, durability Organ volumes, hematologic measures, bone assessments, pain, and QOL PHASE 1/2 n=8-16 Adults, males and females, ages 18-45 years old ERT-switch and ERT-naïve Safety, efficacy, durability Biomarker data, organ volumes, hematologic measures, bone assessments, pain, and QOL QOL: Quality Of Life; ERT: Enzyme Replacement Therapy Anticipated Next Steps: Advance patient enrollment Advance regulatory dialogue on registration pathway
“Second Wave” Programs Hunter, Gaucher Type 3 and Pompe
Bold expansion of our leadership in lysosomal disorders Fabry AVR-RD-01 Gaucher type 1 AVR-RD-02 Cystinosis AVR-RD-04 Hunter AVR-RD-05 Gaucher type 3 AVR-RD-06 Pompe AVR-RD-03 Proof-of-Concept IND-Enabling Phase 1/2 IND: Investigational New Drug
Lentiviral gene therapy enables global distribution of functional enzyme to brain and bone in preclinical studies Widespread distribution of GFP+ cells in the brain Colocalization with microglia marker Striatum Cortex Hippocampus Cerebellum Midbrain Olfactory Bulb IV-dosed animal DAPI GFP+ Engrafted Cells Iba1 GFP: Green Fluorescent Protein; DAPI: 4′,6-diamidino-2-phenylindole; Iba1: Ionized Calcium-Binding Adapter Molecule 1; IV: Intravenous PRECLINICAL DATA PRECLINICAL DATA
Proprietary tags deliver therapeutic protein into hard-to-reach organs Figure adapted from Gleitz H et al., EMBO Mol Med, 2018 Fig 3A; *P<0.05, ***P<0.001, ****P<0.0001; LV GT: Lentiviral Gene Therapy Tag normalizes heparan sulfate in brain Tag normalizes glycogen substrate in brain * * * * * * * * * * * * 0 5 10 Normal Mouse Hunter Mouse LV GT LV GT w/ Tag Fold Total Heparan Sulfate over Normal Mouse Hunter syndrome Pompe disease PRECLINICAL DATA LV GT w/ Tag LV GT Pompe Mouse Normal Mouse * * * *
plato® –– AVROBIO’s platform for global gene therapy commercialization Solves key industry challenges Redefines manufacturing best practices
Designed to be fully scalable Common components and automation leveraged across manufacturing DRUG PRODUCT Closed system automated platform Scale out of manufacturing suites and automation units to meet patient demand PLASMID 3 of 4 component plasmids used in every vector Each plasmid can be mass produced and stored for use VECTOR State of the art, largest scale, 200L vector production Expansion through simple installation of additional units, mass produced, frozen, and stored for use Note: This diagram is for illustrative purposes only
DRUG PRODUCT Poised to manufacture at scale Global infrastructure already in place VECTOR (200L scale bioreactor runs (109 titer)) 4 production suites 12 runs per year per suite >50 patients per run 2,400 PATIENTS ANNUALLY 3+ global production suites 8 automated units per suite 100 patients per unit per year 2,400 PATIENTS ANNUALLY Note: This diagram is for illustrative purposes only Scale
CMC achievements have defined the plato® story X Strategic investment in technology laid the foundation for our manufacturing leadership Robust production platform Best-in-class LV manufacturing Scalable from plasmid to drug product Global footprint In the clinic in multiple jurisdictions Cost effective Intended to address key COGs issues Manufacturing Analytics Robust platform analytics Best-in-class VCN assay First-in-class transduction assay Deep product characterization First-in-class single cell analytics Potency assay matrix Intended to accelerate regulatory approvals CMC: Chemistry, Manufacturing, and Controls; VCN: Vector Copy Number; LV: Lentiviral; COGs: Cost Of Goods
Key anticipated 2021 milestones FDA: Food and Drug Administration Fabry AVR-RD-01 Gaucher type 1 AVR-RD-02 Cystinosis AVR-RD-04 Hunter AVR-RD-05 Gaucher type 3 AVR-RD-06 Pompe AVR-RD-03 Seek agreement with regulators on approval pathway in one or more major markets Execute on global phase 1/2 trial Conduct Phase 1/2 trial initiation activities Engage w/ FDA on pivotal trial design FDA dialogue on path to clinic Prepare for classic infantile-onset study Goal: 30 patients dosed cumulatively by end of 2021
Thank you
Appendix
PHASE 2: Treatment-naïve Fabry patients PATIENT 1 PATIENT 2 PATIENT 3 PATIENT 4 Age of symptom onset/diagnosis 10 / 19 years 36 / 37 years 13 / 13 years 9 / 9 years Age dosed with AVR-RD-01 21 years 46 years 40 years 26 years Mutation c.1021G>A (p.E341K) c.644A>G (p.N215S) c.639+1G>T c.833dupA Leukocyte AGA enzyme activity at baseline (nmol/hr/mg protein) 0.10* 2.38** 0.58** 0.46** Plasma lyso-Gb3 at baseline (nM)*** 202 8 147 92 eGFR (mL/min/1.73m2) at baseline**** 128 106 98 129 Comment Few IgA deposits in kidney biopsy, no mesangial proliferation Cardiac variant, not a classic Fabry male * Mayo Lab, ref range ≥23.1 nmol/hr/mg protein; ** Rupar Lab, ref range 24-56 nmol/hr/mg protein; *** Reference value ≤ 2.4 nM; **** eGFR: Estimated Glomerular Filtration Rate; calculated using CKD-EPI formula AGA: α‑galactosidase A; Lyso-Gb3: Globotriaosylsphingosine; Fabry Phase 1 & 2 Patient Characteristics PHASE 1: ERT-Treated Fabry Patients PATIENT 1 PATIENT 2 PATIENT 3 PATIENT 4 PATIENT 5 Age of symptom onset / diagnosis 18 / 37 years 9 / 29 years 10 / 0 years 7 / 4 years 10 / 14 years Years on ERT 11 years 6 years 4 years 11 years 2 years Age dosed with AVR-RD-01 48 years 39 years 40 years 37 years 30 years Mutation c.962A>G (p.Q321R) c.1033T>C (p.S345P) c.427G>C (p.A143P) c.427G>C (p.A143P) (p.Y134S) Leukocyte AGA activity at baseline (nmol/hr/mg protein)** 2.1 1.1 0.6 2.2 1.0 Plasma lyso-Gb3 at baseline (nM)*** 25 26 59 29 16 eGFR (mL/min/1.73m2) at baseline**** 83 49 112 124 121 ERT discontinuation status 18 months after gene therapy dose Did not resume ERT after gene therapy dose 6 months after gene therapy dose FABRY PHASE 1 & 2 FABRY PHASE 1 & 2
FABRY PHASE 2 Patient #4 is first Fabry patient dosed with plato® FAB-GT 12 month data for patient #4 with plato® vs. patients #1-3 4.2x Increase vs. Mean (nmol/hr/mL) Plasma Enzyme Activity Mean = 1.4 1.8 1.0 1.4 5.9 6.3x Increase vs. Mean (nmol/hr/mg protein) Leukocyte Enzyme Activity Mean = 14.6 17.9 11.4 14.6 92.0
100% clearance of substrate in kidney biopsy at 1 year Patient dosed using plato® FABRY PHASE 2 Two-sample t-test for difference between average PTCs at Baseline vs. 48 weeks; p < 0.0001; Error bar represents the standard error at Baseline (n=103 PTCs) and 48 weeks (n=99 PTCs); scored by 2 independent, blinded pathologists Baseline: The last available, non-missing observation prior to AVR-RD-01 infusion Note: With respect to Fabry disease, Gb3 inclusions per PTC is interchangeable with GL-3 inclusions per KIC PTC: Peritubular Capillary; Gb3: Globotriaosylceramide; GL-3: Globotriaosylceramide; KIC: Kidney Interstitial Capillary 100% substrate reduction 1 Year (48 weeks) Patient 4 Average number of Gb3 inclusions per peritubular capillary (PTC)
Durability demonstrated over multiple measures up to 3.5 years FABRY PHASE 1 VCN: Vector Copy Number; PBL: Peripheral Blood Leukocytes; dg: Diploid Genome Vector Copy Number Leukocyte AGA Activity (nmol/hr/mg protein) Leukocyte AGA Enzyme Activity Plasma AGA Activity Reference Range: 5.1–9.2 nmol/hr/mL; AGA: α-galactosidase A Plasma AGA Activity (nmol/hr/mL) Leukocyte AGA Activity Reference Range: 24–56 nmol/hr/mg protein; AGA: α-galactosidase A Drug Product VCN/dg Patient 1: 0.7 Patient 2: 1.4 Patient 3: 0.8 Patient 4: 1.4 Patient 5: 1.2 Plasma AGA Enzyme Activity Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
Reduction of pre-existing anti-ERT drug IgG antibodies Suggests potential as a therapeutic option independent of pre-existing antibodies San Raffaele Telethon Institute for Gene Therapy (SR-TIGET) Change in pre-existing antibodies reported for Hurler disease (MPS-1) Ex vivo LV gene therapy with conditioning n=6 Evaluable patients (5/6) demonstrated sustained, supraphysiologic blood IDUA activity 4/5 prior ERT (rhIDUA) exposure (5-28 months) 4/5 pre-existing ERT-induced IgG antibodies 6/6 anti-rhIDUA IgGs undetectable 2 months post-gene therapy Fabry Disease Phase 1 IgG Antibody Titer Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 IgG Antibody Titer Negative Control Positive Control ~ ~ FABRY PHASE 1 Source: Gentner B et al., Blood, 2019 ERT: Enzyme Replacement Therapy; IgG: Immunoglobulin G; MPS-1: Mucopolysaccharidosis Type 1; IDUA: Iduronidase: SR-TIGET: San Raffaele Telethon Institute for Gene Therapy; LV: Lentiviral; rhIDUA: Recombinant Human alpha-L-Iduronidase Day 0 Similar results observed in other studies
Crystal buildup in eye clearly visible before gene therapy Patient 1 at baseline CYSTINOSIS PHASE 1/2: PATIENT 1
Impact of cysteamine independence (max per day) OFF cysteamine pills 0 pills / day ON cysteamine pills 30 pills / day After AVR-RD-04 X (16 months post-gene therapy) Before AVR-RD-04 Daily cysteamine regimen ON cysteamine eye drops Prescribed 8 drops / day OFF cysteamine eye drops 0 drops / day CYSTINOSIS PHASE 1/2: PATIENT 1 Note: These results are for a single patient only and may vary in the study population; does not include supplements and other medications Data as of January 20, 2021