UNITED STATES
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CURRENT REPORT
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| Item 7.01 | Regulation FD Disclosure. |
On February 8, 2021, AVROBIO, Inc. (the “Company”) issued a press release titled “AVROBIO Announces 100% Kidney Substrate Reduction at 12 Months Post-Gene Therapy in First Patient Dosed with plato® Gene Therapy Platform in Fabry Disease Phase 2 Trial.” A copy of the press release is furnished as Exhibit 99.1 to this Current Report on Form 8-K.
The information in Item 7.01 of this Current Report on Form 8-K, including Exhibit 99.1 attached hereto, shall not be deemed “filed” for purposes of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such a filing.
| Item 8.01 | Other Events. |
On February 8, 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 February 8, 2021. | |
| 99.2 | AVROBIO, Inc. slide presentation, dated February 8, 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: February 8, 2021 | By: | /s/ Geoff MacKay | ||||
| Geoff MacKay | ||||||
| President and Chief Executive Officer | ||||||
Exhibit 99.1
AVROBIO Announces 100% Kidney Substrate Reduction at 12 Months Post-Gene Therapy in First Patient Dosed with plato® Gene Therapy Platform in Fabry Disease Phase 2 Trial
Consistent with the 87% reduction in the first evaluable kidney biopsy, there is complete clearance of Gb3 inclusions in second evaluable kidney biopsy in Fabry disease Phase 2 trial
New Gaucher disease type 1 Phase 1/2 data show plasma chitotriosidase levels decreased 49% and toxic metabolite lyso-Gb1 levels decreased 44% in first patient at six months post-gene therapy, compared to patient’s pre-gene therapy ERT baseline levels
Strong new cystinosis Phase 1/2 data across multiple measures for the three dosed patients, including substantial improvement in photophobia in first patient 12 months post-gene therapy
Investor and analyst presentation today at 8 a.m. ET
CAMBRIDGE, Mass., Feb. 8, 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 announced a 100% reduction, or complete clearance, of toxic substrate in the kidney biopsy of the first patient dosed with the plato® gene therapy platform in the ongoing Phase 2 FAB-GTi clinical trial of AVR-RD-01, an investigational ex vivo lentiviral gene therapy for Fabry disease. Kidney substrate reduction is the trial’s primary efficacy endpoint and has previously been used by the U.S. Food and Drug Administration (FDA) in evaluating and approving treatments for Fabry disease.
The company also announced six-month data from the first patient dosed in the Phase 1/2 trial of AVR-RD-02, an investigational ex vivo lentiviral gene therapy for Gaucher disease type 1, showing plasma chitotriosidase and the toxic metabolite lyso-Gb1 – key biomarkers of Gaucher disease – had both dropped sharply below the patient’s baseline levels achieved on enzyme replacement therapy (ERT) before gene therapy was administered. Additionally, all three cystinosis patients in the investigator-sponsored Phase 1/2 trialii of AVR-RD-04 show strong data across multiple measures and remain off cysteamine pills and eye drops, with trial enrollment completion expected this year.
“We are thrilled to begin the new year with this update, which adds to the breadth of strong clinical data we’ve reported across our leading lysosomal disorder pipeline of single-dose gene therapies,” said Geoff MacKay, president and CEO of AVROBIO. “With 13 patients dosed across three clinical programs, we have observed sustained and potentially transformative
improvements in key biomarkers and functional metrics, with data from our Fabry disease program out 3 1⁄2 years after dosing. Additionally, enrollment activities for our Fabry disease trial are accelerating, giving us added confidence in our efforts to meet our goal of having dosed a cumulative 30 patients across all our clinical programs by the end of the year. With this strong momentum, we look forward to clarifying the regulatory pathway with regulatory agencies.”
The data will be presented this week at the 17th annual WORLDSymposium™, an annual scientific meeting dedicated to lysosomal disorders, held virtually Feb. 8-12, 2021. The presentations and posters are available online for WORLD attendees on the conference website.
FAB-GT biopsy data: 100% reduction of kidney substrate at 12 months in first patient dosed with plato® gene therapy platform
Gb3 is a fatty substrate that accumulates in the cells of Fabry disease patients and can result in damage to multiple organs, including the kidneys, heart and CNS. The kidney biopsy for Patient 4 in the Phase 2 trial showed a reduction from an average of 4.0 globotriaosylceramide (Gb3) inclusions per peritubular capillary (PTC) at baseline to zero inclusions per PTC one year after dosing, a 100% reduction (p<0.0001). This assessment was made by two blinded pathologists who independently scored 99 digital images of the sectioned kidney from the 12-month biopsy. Every image scored zero inclusions.
Patient 4 is the first in the trial treated using AVROBIO’s proprietary plato® gene therapy platform, which includes a state-of-the-art lentiviral vector, a personalized conditioning regimen with precision dosing and an automated, closed manufacturing process intended to deliver potent and consistent drug product from manufacturing sites worldwide at commercial scale.
“The complete clearance of Gb3 substrate in kidney tissue, coming on top of strong results from the first evaluable kidney biopsy in this trial, is very exciting,” said Mark Thomas, M.D., the lead investigator in the FAB-GT trial, a clinician in the department of nephrology at Royal Perth Hospital and a clinical professor at the University of Western Australia Medical School. “Along with the reduction in plasma lyso-Gb3 observed across patients in this trial, which has been sustained up to 2.5 years so far, a massive drop in kidney substrate has the potential to substantially improve outcomes over ERT – the current standard of care. Fabry disease is a serious and life-shortening condition for many patients that requires lifelong fortnightly ERT infusions, with life-limiting symptoms manifesting throughout the body and brain, and we urgently need options to halt, prevent or reverse progression of the disease.”
Two of four FAB-GT trial participants had evaluable kidney biopsies. As previously reported, the kidney biopsy for Patient 1 showed an 87% reduction, effective clearance of Gb3 inclusions per PTC compared to baseline.
Additional Fabry disease clinical data: Continued durability across multiple biomarkers and functional cardiac measurements
In addition to the kidney biopsy, AVROBIO reported updated data suggesting generally stable and sustained plasma and leukocyte alpha-galactosidase A (AGA) enzyme activity and a corresponding reduction in toxic plasma lyso-Gb3 in patients across the Phase 1 and FAB-GT trials of AVR-RD-01. To date, four patients have been dosed in the Phase 2 FAB-GT trial and five patients have been dosed in the fully enrolled Phase 1 trial.
New aggregated data across all cardiac measures for the FAB-GT patients show patients continue to exhibit stable cardiac structure and function at 12 months post-gene therapy, which is notable given that people living with Fabry disease often experience progressive left ventricular hypertrophy and fibrosis, leading to reduced cardiac function.
Additionally, the company is leveraging existing trial sites to potentially expand the pool of patients globally, with four Fabry disease patients from Brazil currently moving through the travel, screening, consent and enrollment process for potential treatment at AVROBIO’s global center of excellence in Australia.
No unexpected safety events have been identified in the AVR-RD-01 Phase 1 and Phase 2 trials as of the safety data cut-off date of Nov. 26, 2020 and Dec. 7, 2020, respectively. Eight serious adverse events (SAEs) reported in the two Fabry disease trials have been consistent with the conditioning regimen, stem cell mobilization, underlying disease or pre-existing conditions. All SAEs have been resolved without clinical sequelae.
Enrollment in the FAB-GT trial (NCT03454893) is ongoing, and further details are available on clinicaltrials.gov.
Gaucher disease type 1: Preliminary clinical data in first patient show improvement in relevant biomarkers, plasma chitotriosidase and lyso-Gb1, over patient’s ERT baseline
The first patient dosed in the Phase 1/2 Guard1 trial of AVR-RD-02 shows substantial improvement over pre-gene therapy ERT baseline in key biomarkers at six months post-gene therapy. This patient, who was previously ERT-stable, discontinued ERT use prior to gene therapy and remains off ERT. She was treated using AVROBIO’s proprietary plato® gene therapy platform.
The patient’s plasma chitotriosidase levels dropped 49% from her pre-gene therapy ERT baseline levels. Plasma chitotriosidase is a biomarker of activated macrophages, which lead to chronic inflammation and severe organ damage. Six-month data show continued reduction in plasma chitotriosidase since the patient’s three-month exam, suggesting that healthy macrophages carrying the therapeutic gene may be replacing the diseased Gaucher cells.
At six months post-gene therapy, the patient’s glucosylsphingosine (lyso-Gb1) metabolite levels were down 44% from her pre-gene therapy ERT baseline levels. As with chitotriosidase, the lyso-Gb1 levels were lower at six months than three months, suggesting continued improvement since dosing. Lyso-Gb1 is a toxic metabolite and a highly sensitive and specific biomarker for Gaucher disease. Elevated Lyso-Gb1 levels contribute to the severe organ damage commonly seen in Gaucher disease.
Hemoglobin and platelet counts, which are typically low in patients with Gaucher disease, remained in the normal range for the first patient at six months post-gene therapy.
“The early data from the first patient dosed with AVR-RD-02, our investigational gene therapy for Gaucher disease type 1, are consistent with what we have seen in our Fabry disease trials with lyso-Gb3,” said MacKay. “Based on the data observed to date, we believe lentiviral gene therapy drives down toxic metabolites below levels of ERT, supporting our view that gene therapy has the potential to prevent, halt or even reverse progression of these devastating diseases with a single infusion.”
No unexpected safety events have been identified in this first patient. There have been no SAEs related to AVR-RD-02 as of the safety data cut-off date of Jan. 4, 2021. Adverse events (AEs) reported have been consistent with the conditioning regimen, stem cell mobilization, underlying disease or pre-existing conditions.
Enrollment in the Phase 1/2 Guard1 trial (NCT04145037) is ongoing, and further details are available on clinicaltrials.gov.
Cystinosis: Continued positive data across multiple measures; all three patients remain cysteamine-independent post-gene therapy
All three cystinosis patients in the investigator-sponsored Phase 1/2 trial of AVR-RD-04 show strong data across multiple measures. Vector copy number (VCN/dg) data for all three patients continue to perform as expected. The first patient has potentially reached a VCN plateau, similar
to the pattern seen in AVROBIO’s Fabry trials. The second patient had a VCN of 1.7/dg at six months and the third patient had a VCN of 2.6/dg at one month. All three patients remain off cysteamine pills and eye drops at 16, six and two months post-gene therapy respectively.
The renal function data for the first patient dosed in the trial, who has established, progressive kidney disease, suggest continued stabilization post-gene therapy. Additionally, imaging scans show a marked reduction in crystal density in both corneas, as well as a two-grade clinically meaningful improvement (from grade 3 to grade 1) in his photophobia, one of the more debilitating effects of cystinosis. Photophobia can be extremely painful for patients exposed to any level of light, requiring some patients to wear dark glasses all the time, even at night.
The investigator-sponsored Phase 1/2 trial (NCT03897361) of AVR-RD-04 is expected to be fully enrolled this year. Further details are available on clinicaltrials.gov.
No unexpected safety events have been identified in the trial, with no SAEs reported as of the Jan. 27, 2021, safety data cut-off date. AEs reported have been consistent with the conditioning regimen, stem cell mobilization, underlying disease or pre-existing conditions.
Investor and analyst presentation today at 8 a.m. ET
The conference call and presentation will begin at 8:00 a.m. ET and can be accessed under “Events and Presentations” in the Investors section of the company’s website at avrobio.com or by dialing (866) 353-0165 from locations in the U.S. and (409) 217-8080 from outside the U.S. The conference ID number is 3287052. An archived webcast recording of the event will be available on the website for approximately 30 days.
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 Statement
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 prospective product candidates, 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 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 Quarterly Report on Form 10-Q, 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
| i | Formerly known as the FAB-201 trial |
| ii | Collaborator-sponsored Phase 1/2 clinical trial of AVR-RD-04 is funded in part by grants to UCSD from the California Institute for Regenerative Medicine (CIRM), Cystinosis Research Foundation (CRF) and National Institutes of Health (NIH). |
WORLD 2021 Data Update FEBRUARY 8, 2021 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; 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, as well as our plans and expectations with respect to the timing and resumption of any development activities that may be temporarily paused as a result of the COVID-19 outbreak; the market opportunity for and anticipated commercial activities relating to our investigational gene therapies; and statements regarding our financial and cash position and expected cash reserves. 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 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 Quarterly Report on Form 10-Q, 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. Note regarding future updates: The statements contained in this presentation reflect our current views with respect to future events, which may change significantly as the global consequences of the COVID-19 pandemic rapidly develop. Accordingly, we do not undertake and specifically disclaim any obligation to update any forward-looking statements. Copyright© 2021 AVROBIO, Inc. All rights reserved.
Vision Bring personalized gene therapy to the world. Purpose Freedom from a lifetime of genetic disease.
Ex vivo lentiviral gene therapy has emerged as a leading modality across multiple genetic diseases Industry-wide data demonstrate proven record, broad utility TOLERABILITY DURABILITY EFFICACY WIDE REACH BROAD UTILITY Approved Beta thalassemia MLD Investigational ALD (in registration) Fanconi anemia Hurler syndrome Sanfilippo A Sanfilippo B SCID-ADA SCID-X Sickle cell disease Wiskott-Aldrich syndrome X-CGD >350 patients >1,000 patient years Pediatrics and adults All mutations No exclusions due to pre-existing antibodies >12 years post-infusion Head-to-toe, including: Brain Muscle Bone ALD: Adrenoleukodystrophy; SCID-ADA: Severe Combined Immunodeficiency-Adenosine Deaminase Deficiency; SCID-X: X-Linked Severe Combined Immunodeficiency; MLD: Metachromatic Leukodystrophy; X-CGD: X-Linked Chronic Granulomatous Disease
Leading lysosomal disorder gene therapy pipeline 13 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. 2019 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 $1.4B $2.3M Hunter $0.6B $2.4M Pompe $1.0B $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 † 2019 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: $4.6B ‡
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 Gaucher Type 1 Phase 1/2 PATIENT 1 Cystinosis Phase 1/2 PATIENT 1 PATIENT 2 PATIENT 3 Note: Based on data cut-off date of January 11, 2021 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 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
100% substrate clearance in kidney biopsy of first plato® patient Durability sustained across Fabry Phase 1 & 2 patients up to 3.5 years Positive data across multiple measures in cystinosis patients Engaging with FDA on regulatory approval pathway for Fabry >40% reduction in plasma chitotriosidase and lyso-Gb1 vs. ERT baseline in first Gaucher type 1 patient Today’s update: Strong, consistent data across programs
Fabry Disease
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 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 f-k-a FAB-201 Two AVR-RD-01 Fabry clinical trials 9 patients dosed across Phase 1 and 2 OBJECTIVES PATIENTS Safety and tolerability Efficacy n = 8-12 patients (4 dosed to-date) 16 – 50 year-old males Treatment naïve ACTIVELY RECRUITING PHASE 2 Investigator-Sponsored Trial* AVRO FAB-GT Trial **
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 NEW DATA
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) NEW DATA
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 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
FDA guidance cites kidney biopsy as surrogate endpoint for accelerated approval Fabry Disease: Developing Drugs for Treatment Guidance for Industry (fda.gov) “The purpose of this guidance is to provide recommendations to sponsors regarding clinical trial design features that can support approval of drugs and biological products intended for the treatment of Fabry disease” “Sponsors can use histological reduction of GL-3 inclusion burden in biopsied kidney interstitial capillaries (KIC) as a surrogate endpoint reasonably likely to predict clinical benefit to support accelerated approval” “When assessing (counting) KIC GL-3 inclusions in histology specimens, the sponsor should use validated and standardized assay methodologies, and scoring of KIC GL-3 inclusions should be conducted by experienced pathologists in a blinded and systematic fashion” Complete guidance available at fda.gov
Precedent for use of kidney biopsy data for FDA approval of drug candidate for Fabry disease Sources: Galafold (Migalastat), Multi-Discipline FDA Review; Germain 2019, Genet Med 21, 1987–1997 (2019) 12.1% -54.1% -42.6% -64.1% -36.3% -45.6% -27.3%
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 NEW DATA POINT
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 NEW DATA POINT
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 NEW DATA POINT
ERT No ERT Gene Tx 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; Tx: Therapy Gene Tx + Off ERT Gene Tx + 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 NEW DATA POINT
Natural history annualized eGFR slopes of treatment-naïve patients1 eGFR declines in natural history and on ERT Classic Fabry male literature eGFR data Sources: 1Schiffmann R et al., Nephrol Dial Transplant, 2009 (Table 4); 2Rombach SM et al., Orphanet J Rare Dis, 2013 (Table 2) eGFR: Estimated Glomerular Filtration Rate; UP: Urinary Protein; ERT: Enzyme Replacement Therapy FABRY PHASE 1 slope:-3.4; n=30 Annualized eGFR slope of ERT-treated patients2 slope:-6.9; n=22 slope:-3.3; n=21 slope:-1.6; n=18 Baseline UP: <0.1 g/24hr 0.1-1.0 g/24hr >1.0 g/24hr
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 NEW DATA POINT
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 NEW DATA
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 FOUR Fabry patients from Brazil are moving through travel, screening, consent and enrollment process for treatment in Australia* * 3 patients currently in Australia; 4th patient scheduled to arrive early February
Planned global regulatory strategy for Fabry disease Planned ERT-switch Phase 2 Partially Enrolled ERT-naïve CONFIRMATORY TRIAL Males, mutation-independent Efficacy, durability, safety Cardiac and kidney function Cognition scoring and CNS imaging Biomarker data Quality of life EXPANDED FOR POTENTIAL ACCELERATED APPROVAL n=8-12 Treatment-naïve classic males Efficacy, durability, and safety Biomarker data, kidney and cardiac function, Gb3 in kidney biopsy Expand n, including adding females Fully Enrolled ERT-switch PHASE 1 – INVESTIGATOR SPONSORED TRIAL n=5, fully enrolled ERT-switch in classic males Safety, preliminary efficacy, durability Biomarker data, kidney function ERT: Enzyme Replacement Therapy; CNS: Central Nervous System; Gb3: Globotriaosylceramide Anticipated Next Steps: Discuss accelerated approval approach with FDA in Q1 ‘21 Expand Phase 2 study and complete enrollment Initiate confirmatory ERT-switch trial activities in 2021 Seek early FDA agreement on potency assay matrix Advance commercial readiness activities including payors / HTA interactions
Cystinosis
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 * WAC pricing from Redbook using standard dosing assumptions Affects ~ 1:170,000 people
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 NEW DATA
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
Day 0 eGFR change per year: -0.9 eGFR change per year: -8.0 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 NEW DATA POINT
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) NEW DATA
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
Crystal buildup in eye clearly visible before gene therapy Patient 1 at baseline CYSTINOSIS PHASE 1/2: PATIENT 1
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 NEW DATA 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 NEW DATA POINT
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: Complete Phase 1/2 enrollment in 2021 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
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 * WAC pricing from Redbook using standard dosing assumptions Adrianna, living with Gaucher disease type 1 Affects ~ 1:44,000 people worldwide
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 1H ’21: 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 Plasma chitotriosidase activity normal range: 0.0 – 44.2 μmoL/L/h ERT: Enzyme Replacement Therapy Plasma chitotriosidase reduced below ERT baseline at 6 months 77 Chitotriosidase is a marker of inappropriately activated macrophages (Gaucher cells) NEW DATA 49% reduction
Toxic metabolite lyso-Gb1 reduced below ERT baseline at 6 months 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 ERT: Enzyme Replacement Therapy; Lyso-Gb1: Glucosylsphingosine; 18 25 32 Plasma Lyso-Gb1 (ng/mL) Baseline (ON ERT) 3 months (OFF ERT) 6 months (OFF ERT) Lyso-Gb1 is a sensitive and specific marker of toxic metabolite accumulation in Gaucher disease NEW DATA 44% reduction
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 NEW DATA POINT
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 NEW DATA POINT
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
Key takeaways for today 100% substrate clearance in kidney biopsy of first plato® patient Strong results across first two kidney biopsies; approvable endpoint per FDA guidance Durability sustained across Fabry Phase 1 & 2 patients up to 3.5 years Functional measurements and biomarkers sustained Positive data across multiple measures in cystinosis patients Photophobia significantly improved in first patient; all three patients remain off cysteamine Engaging with FDA on regulatory pathway for Fabry End of Phase 1 meeting requested, patient enrollment activities accelerating Key Gaucher clinical biomarkers over 40% lower than ERT baseline Continued reductions in plasma chitotriosidase and lyso-Gb1 at six months in first patient
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
Key anticipated 2021 milestones FDA: Food and Drug Administration; 2H: Second Half 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 Dose first patient in 2H of 2021 Complete phase 1/2 enrollment 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