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| Item 7.01 | Regulation FD Disclosure. |
On May 17, 2022, AVROBIO, Inc. (the “Company”) issued a press release titled “AVROBIO Reports Positive Data from Phase 1/2 Clinical Trial of Investigational Gene Therapy for Cystinosis, including New Interim Data on Neurocognitive Measures.” A copy of the press release is furnished as Exhibit 99.1 to this Current Report on Form 8-K.
On May 17, 2022, 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.
The information in Item 7.01 of this Current Report on Form 8-K, including Exhibits 99.1 and 99.2 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 9.01. | Financial Statements and Exhibits. |
(d) Exhibits
| 99.1 | AVROBIO, Inc. press release, dated May 17, 2022. | |
| 99.2 | AVROBIO, Inc. slide presentation, dated May 17, 2022. | |
| 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 17, 2022 | By: | /s/ Geoff MacKay | ||||
| Geoff MacKay | ||||||
| President and Chief Executive Officer | ||||||
Exhibit 99.1
AVROBIO Reports Positive Data from Phase 1/2 Clinical Trial of Investigational
Gene Therapy for Cystinosis, including New Interim Data on Neurocognitive Measures
New early data show key visual motor integration, visual perception and motor coordination measures impacted by cystinosis stabilized or improved post gene therapy
Systemic reach of AVR-RD-04 observed across multiple other measures
All five dosed patients remain off oral cysteamine post gene therapy
Continued favorable safety profile with no adverse events related to drug product to date
Clinical proof-of-concept in adult patients lays groundwork for AVROBIO-sponsored clinical trial planned to begin in 2023
CAMBRIDGE, Mass.—(BUSINESS WIRE)—May 17, 2022—AVROBIO, Inc. (Nasdaq: AVRO), a leading clinical-stage gene therapy company with a shared purpose to free people from a lifetime of genetic disease, today reported new interim data, including on new visual motor integration, motor coordination and visual perception measures, from a collaborator-sponsored, ongoing Phase 1/2 gene therapy clinical triali of AVR-RD-04, an investigational gene therapy for cystinosis, at the 25th Annual Meeting of American Society for Gene and Cell Therapy (ASGCT) in Washington D.C., May 16-19, 2022.
The collaborator-sponsored Phase 1/2 clinical trial is evaluating the safety and efficacy of AVR-RD-04 in adult patients diagnosed with the infantile form of cystinosis who previously had been treated with the current standard of care (SOC) cysteamine. AVR-RD-04 genetically modifies patients’ own hematopoietic stem cells (HSC) to express a functional version of cystinosin, the protein that is deficient in people living with cystinosis. Preliminary data suggest that post gene therapy, functional cystinosin has been produced throughout the body as evidenced by clinical measures in multiple tissues, including the eyes, skin, gastrointestinal mucosa and neurocognitive system. No adverse events (AEs) related to the drug product have been reported to date.
“We’re thrilled with our progress in this first and only gene therapy trial for cystinosis, a devastating genetic disease with unmet medical needs that impact the daily lives of patients and their families,” said Stephanie Cherqui, Ph.D., lead investigator of the clinical trial and associate professor of Pediatrics at the University of California San Diego (UCSD). “Now with data from up to five patients, we have observed a strong safety and tolerability profile, as well as a reduction in the harmful accumulation of cystine crystals in cells across multiple tissues.
“All five patients dosed to date remain off oral cysteamine. We believe the results to date for this investigational gene therapy show its potential to stabilize or reduce impact of cystinosis on different tissues with a single dose,” she added.
| i | 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). |
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The 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).
“We believe the interim data from this ongoing clinical trial demonstrate the potential of gene therapy using patient’s own hematopoietic stem cells to impact the body head-to-toe by restoring functional cystinosin and reducing the accumulation of cystine crystals systemically,” said AVROBIO Chief Medical Officer, Essra Ridha, M.D., MRCP, FFPM. “Cystinosis is a devastating disease that currently carries a 5-year treatment cost in excess of $4 million per patient in the U.S. and impacts approximately 1,600 patients in the U.S., Europe and Japan alone. With proof-of-concept demonstrated, we continue to lay the groundwork for an AVROBIO-sponsored clinical trial planned to begin in 2023 and look forward to our interactions with regulators on our clinical and Chemistry Manufacturing and Controls (CMC) strategy later this year.”
Key motor coordination and visual perception measures stabilize or show positive trends post gene therapy
Visual motor integration (VMI) measured with the Beery – Buktenica Developmental Test of VMI, a standardized test evaluating the ability of the brain to interpret and translate visual information into an exact motor response, has been shown to be a consistent indicator of visual spatial and visual motor dysfunction in patients with cystinosis. These measures do not generally improve over time in this population.
Early data indicate that post gene therapy the two patients with data to date show stabilization of scores on the Beery – Buktenica Developmental Test of VMI and importantly, improvement in the subtests of motor coordination and visual perception, suggesting a potential impact on the neuropathology of the disease. In patient #1, an approximate 20-point improvement was evident in both visual perception and motor coordination, and in patient #3 a 5-point increase in visual perception was detected, with motor coordination rising by 45 points in the first 6 months post treatment and a more modest rise thereafter.
In addition, following discontinuation of cysteamine, average hand grip strength remained stable up to 27 months after dosing.
Systemic reach of AVR-RD-04 also seen across measurements of blood, eye, skin and gastrointestinal mucosa
Early data indicate that post gene therapy, patients have been able to produce and distribute functional cystinosin protein throughout the body, which prevents the pathological accumulation of cystine crystals. In blood, the leukocyte cystine levels decreased measurably, with the three patients out more than 12 months post gene therapy stabilizing near 1.0 nmol/mg protein.
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Photophobia, or extreme visual sensitivity to light, is a hallmark of cystinosis. In a patient-reported outcome scale of photophobia severity, the first three patients for which data are available, reported improved or stable photophobia scores. Patient #1, who entered the trial with a higher level of cystine crystal accumulation in the eye, reported a two-point photophobia score improvement 24 months post gene therapy. Patients #2 and #3, who both entered the trial with relatively lower cystine crystal accumulation in the eye, reported stable photophobia scores, both at 12 months post gene therapy. Patients #1, #3, #4 and #5 remain off cysteamine eye drops.
A decline in cystine crystals was observed in skin and gastrointestinal mucosa biopsies from the first three patients. Patients with cystinosis accumulate cystine crystals in cells, which leads to tissue and organ damage and results in debilitating co-morbidities. In the skin, reductions in average intracytoplasmic crystals per cell ranged from 8% in patient #1, 64% in patient #2 and 81% in patient #3 below the patients’ own standard-of-care baseline measures at 12-27 months post gene therapy. In the intestinal mucosa, a measurable reduction below patients’ own standard-of-care baseline measures was observed post gene therapy, including for patient #1 a 73% reduction after 27 months, for patient #2 a 28% reduction after 12 months and for patient #3 an 83% reduction after 18 months. These data suggest the systemic distribution of functional cystinosis protein is impacting a variety of measures throughout the body. Biopsies have not yet been conducted for patient #4 and #5, who have been more recently infused.
Darker pigmentation observed may be a sign of multi-functional cystinosin activity post gene therapy
Patients with cystinosis frequently exhibit blond or lighter-colored hair and fair complexion because of reduced levels of melanin in their skin. In vitro studies have demonstrated that cystinosin is located in melanosomes of melanocytes and when functional cystinosin is absent or reduced, melanin pigment synthesis is inhibited.
New early quantitative data suggest that gene therapy-derived cystinosin may restore melanin production. Twelve months after infusion, two patients exhibited progressively darkening hair color, as measured by a 25% and 37% reduction in red, green, blue (RGB) mean intensity for patient #1 and patient #3, respectively, further indicating cystinosin protein throughout the body. In this case, a microscope was used to obtain high resolution images of hair strands. The images were taken using transmitted light at 20x magnification and analyzed for RGB intensity with numerical values assigned to quantify the level of pigmentation. These data are not yet available for patients #2, #4 and #5.
Sustained engraftment demonstrated with stable VCN for patients beyond 12 months
Importantly, sustained engraftment has been observed in the first three patients, as evidenced by stable vector copy number (VCN) levels. At 17- to 27-months post gene therapy, their VCN is between 1.0 and 2.0 per diploid genome. The recently dosed fourth and fifth patient have a VCN of 0.7 and 1.3 per diploid genome at three-months and one-month post gene therapy, respectively.
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Safety and tolerability profile remains strong
Safety data from the five patients dosed to date indicate no AEs related to drug product. All AEs were related to myeloablative conditioning, stem cell mobilization, underlying disease or pre-existing conditions. The majority of AEs were mild or moderate and resolved without clinical sequelae.
Further details on the collaborator-sponsored Phase 1/2 trial (NCT03897361) are available on clinicaltrials.gov. For more information on the cystinosis trial data presented at ASGCT, please see data slides here.
AVROBIO-sponsored trial on track for 2023
Based on the data reported today, combined with feedback provided by the U.S. Food and Drug Administration (FDA) after a fall 2021 Type C meeting, and pending the outcome of further planned regulatory authority interactions this year, the company expects to initiate an AVROBIO-sponsored trial in 2023 in the U.S., followed by sites in the UK and Europe. AVROBIO’s current plan involves a two-part strategy, beginning in a pre-renal transplant population followed by a post-renal transplant population.
About cystinosis
Cystinosis is a rare, progressive disease marked by the accumulation of cystine in cellular organelles known as lysosomes. This buildup causes progressive organ damage and debilitating corneal damage, swallowing dysfunction, chronic kidney disease leading to end-stage renal disease and muscle wasting leading to a shortened lifespan. Currently, more than 90% of treated cystinosis patients require a renal transplant in the second or third decade of life. The current standard of care for cystinosis is cysteamine, a treatment regimen that can require dozens of pills per day, does not prevent overall disease progression and carries side effects, such as breath and body odor and gastrointestinal complications, which may be difficult to tolerate.
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. AVROBIO’s pipeline is powered by our industry-leading plato® gene therapy platform, our foundation designed to deliver gene therapy worldwide. It includes clinical programs in cystinosis and Gaucher disease type 1, as well as preclinical programs in Gaucher disease type 3, Hunter syndrome and Pompe disease. We are headquartered in Cambridge, Mass. 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
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forward-looking statements. These forward-looking statements include, without limitation, statements regarding our business strategy for and the potential therapeutic benefits of our product candidates, including AVR-RD-04 for the treatment of cystinosis, the design, commencement, enrollment and timing of ongoing or planned clinical trials, clinical trial results, product approvals and regulatory pathways, anticipated benefits of our gene therapy platform including potential impact on our commercialization activities, timing and likelihood of success, the expected benefits and results of our implementation of the plato platform in our clinical trials and gene therapy programs, and the expected safety profile of our investigational gene therapies. 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, including AVR-RD-04 for the treatment of cystinosis, 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, 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
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Media Contact:
Kit Rodophele
Ten Bridge Communications
617-999-9620
krodophele@tenbridgecommunications.com
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ASGCT 2022 Cystinosis data update MAY 17, 2022 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, including AVR-RD-04 for the treatment of cystinosis; 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 our clinical and preclinical product candidates, including timing, design and initiation of our potential clinical and registration trials and anticipated interactions with regulatory agencies; the timing of anticipated clinical and regulatory updates; 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 expected benefits and results of our manufacturing technology, including the implementation of our plato® platform in our clinical trials and gene therapy programs; and the expected safety profile of 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, including AVR-RD-04 for the treatment of cystinosis, will not be successfully developed or commercialized; the risk that regulatory agencies may disagree with our anticipated development approach for any one or more of our product candidates; 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 or potential use of monoclonal antibody conditioning agents, 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 ongoing COVID-19 pandemic 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, 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© 2022 AVROBIO, Inc. All rights reserved.
Expanding Phase 1/2 data set shows systemic gene therapy impact AVR-RD-04 is first and only investigational gene therapy for cystinosis Improvements in neurocognitive assessments Stable muscle/grip strength Reduction in cystine crystals in skin and gastrointestinal mucosa Improved or stable eye measures Reduction in leukocyte cystine to target levels Quantified increase in hair strand pigmentation * Data as of May 6, 2022 Proof-of-concept demonstrated in adult population Plan to meet with regulators in 2H 2022 to discuss company-sponsored trial Safety and tolerability profile remains strong* All five patients dosed remain off oral cysteamine
Cystinosis is an attractive commercial market * SOC: standard of care; WAC pricing from Redbook using standard dosing assumptions. Horizon’s Procysbi oral therapy (delayed release cysteamine bitartrate), midpoint between avg. adult and pediatric 5-year cystinosis SOC treatment cost ~$4.3 million* in U.S. ~1,600 patients in U.S., Europe and Japan alone Most severe form, infantile nephropathic cystinosis, affects ~95% of cystinosis population Billion-dollar revenue opportunity SOC does not stop disease progression Vision Corneal cystine accumulation, photophobia Endocrine disorders Softening & deformation of bones, hypothyroidism, diabetes, infertility CNS and muscular complications Myopathy, hypotonia, neurodevelopmental issues Kidney function Frequently require multiple kidney transplants Shortcomings of cysteamine pills often lead to poor patient compliance: Cause sulfur odor on body and breath High daily pill burden can lead to GI discomfort and vomiting SOC is burdensome Disease symptoms persist despite SOC:
NORMAL LYSOSOME CYSTINOSIS LYSOSOME Cystinosis caused by defective gene that encodes cystinosin, an exporter protein Cysteine (monomer of cystine) Functional exporter protein (Cystinosin) Defective exporter protein (Cystinosin) Cystine crystals Cystine crystals build up in lysosomes causing tissue and organ damage Source: Cherqui et al, Nat Rev Nephrol. 2017 Cystine (dimer)
PATIENT MONTHS OFF CYSTEAMINE PILLS AND EYE DROPS POST AVR-RD-04 INFUSION CURRENT STATUS cysteamine pills PATIENT 1 OFF PATIENT 2 OFF PATIENT 3 OFF PATIENT 4 OFF PATIENT 5 OFF cysteamine eye drops PATIENT 1 OFF PATIENT 2 ON (patient restarted July 2021) PATIENT 3 OFF PATIENT 4 Was not on cysteamine eye drops prior to infusion OFF PATIENT 5 OFF CYSTINOSIS PHASE 1/2 Note: Patients 2, 3 and 5 stopped cysteamine eye drops 1-month post-transplant (per protocol); Patient 1 stopped cysteamine eye drops prior to baseline; Patient 4 was not on cysteamine drops prior to infusion. Data as of May 6, 2022 CYSTINOSIS PHASE 1/2: PATIENTS 1-5 All patients continue to be oral cysteamine-independent Patient #1 out 2 ½ years NEW DATA
BEERY TEST OF VISUAL MOTOR INTEGRATION (VMI) Improvement in motor coordination and visual perception observed post gene therapy CYSTINOSIS PHASE 1/2: PATIENTS 1, 3 MOTOR COORDINATION SUBSCORE VISUAL PERCEPTION SUBSCORE NEW DATA Patient 1 Patient 3 Data for Patient 2 are not available; The Beery – Buktenica Developmental Test of Visual Motor Integration (Beery VMI) is a standardized test evaluating the ability of the brain to interpret and translate visual information into an exact motor response
Average Grip Strength (kg) is defined as the average of the largest reading from each hand Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 CYSTINOSIS PHASE 1/2: PATIENTS 1-5 Average grip strength stable up to 27 months Disease progression typically leads to loss of muscle strength over time NEW DATA
Reduction in number of skin cystine crystals below patients’ own SOC baseline at 12+ months CYSTINOSIS PHASE 1/2: PATIENT 1-5 SKIN BIOPSY: AVERAGE INTRACYTOPLASMIC CRYSTALS PER CELL NEW DATA POINT Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 35% reduction 8% reduction 64% reduction 81% reduction For Patient 4 and 5, only their Baseline data is currently available
Reduction in number of cystine crystals in gastrointestinal mucosa below patients’ own SOC baseline at 12+ months CYSTINOSIS PHASE 1/2: PATIENT 1-5 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 76% reduction 73% reduction 53% reduction 28% reduction 86% reduction 85% reduction 83% reduction For Patient 4 and 5, only their Baseline data is currently available RECTAL BIOPSY: AVERAGE INTRACYTOPLASMIC CRYSTALS PER CELL NEW DATA POINT
Crystal buildup in eye clearly visible before gene therapy Treatment goal is to prevent or halt further accumulation of corneal crystals; complete clearance not expected CYSTINOSIS PHASE 1/2: PATIENT 1 Patient 1 at baseline
Decline in corneal crystals and improved photophobia grade CYSTINOSIS PHASE 1/2: PATIENT 1 IVCM: In Vivo Confocal Microscopy; exploratory method; These results are for a single patient only and may vary in the study population; OD: Oculus Dexter (right eye); HRT3: Heidelberg Retina Tomograph 3; Scoring instructions: for each layer, assign a score of 0-4, where 0=no crystal; 1 <25%; 2=25-50%; 3=50-75%; 4>75%; Liang et al., IOVS 2015; * Score range: 1-5 where 1 is no photophobia and 5 is severe; Images obtained for Patient 1 at baseline using Nidek Confoscan and used Heidelberg HRT3 w/ Rostock Corneal Module for all other images BASELINE 18 MONTHS IMAGES/24 MONTHS PHOTOPHOBIA GRADE IVCM Images Photophobia Grade* (patient reported) IVCM Images Photophobia Grade* (patient reported) PATIENT 1 3 1 CORNEAL CRYSTALS 174 µm, OD 331 µm, OD Front of Cornea Back of Cornea 176 µm, OD 331 µm, OD Front of Cornea Back of Cornea Eye layers Right eye Left eye Baseline 12 months Baseline 12 months Anterior Stroma 4 3 4 1.9 Middle Stroma 4 3 4 1.7 Posterior Stroma 4 2.1 4 2 Preliminary scoring performed by Dr. Hong Liang CNRS, Paris, France NEW DATA POINT
Stable corneal crystals and photophobia grade CYSTINOSIS PHASE 1/2: PATIENTS 2 & 3 IVCM: In Vivo Confocal Microscopy; exploratory method; These results are for a single patient only and may vary in the study population; OD: Oculus Dexter (right eye); HRT3: Heidelberg Retina Tomograph 3; Scoring instructions: for each layer, assign a score of 0-4, where 0=no crystal; 1 <25%; 2=25-50%; 3=50-75%; 4>75%; Liang et al., IOVS 2015; * Score range: 1-5 where 1 is no photophobia and 5 is severe; BASELINE 12 MONTHS IVCM Images Photophobia Grade (patient reported) IVCM Images Photophobia Grade (patient reported) PATIENT 2 2 or 3 2 PATIENT 3 2 2 Front of Cornea Back of Cornea Front of Cornea Back of Cornea 43 µm, OD 66 µm, OD 43 µm, OD 66 µm, OD 178 µm, OD 331 µm, OD 178 µm, OD 331 µm, OD NEW DATA
Early cystinosis treatment is essential to prevent kidney complications Frequency1 Characteristics of phenotype1 Disease phenotype Nephropathic cystinosis ~95% of patients Clinical symptoms related to renal Fanconi syndrome during first year of life Fanconi syndrome: Defect of kidney tubules resulting in malabsorption of electrolytes / substances in kidneys2 Frequently require multiple renal transplants with lifetime of immunosuppression Most severe form of cystinosis Infantile Juvenile (“late-onset”) <5% of patients Usually diagnosed later in childhood or during adolescence (after age 10) Typically experience renal Fanconi syndrome and proteinuria Frequently require multiple renal transplants with lifetime of immunosuppression Source: Simon-Kucher & Partners 2020. 1. Emma et al. (2014). Nephropathic Cystinosis: an international consensus document. Nephrology Dialysis Transplantation, 29(4), iv87-iv94; 2. Keefe et al. (2020). Fanconi Syndrome. StatPearls.
eGFR data reinforce need for early intervention Entered trial with progressive kidney disease (eGFR of 48), decline accelerates in line with natural history CYSTINOSIS PHASE 1/2: PATIENT 1 NEW DATA POINT eGFR: Estimated Glomerular Filtration Rate; eGFR calculated using CKD-EPI formula Normal Kidney Function Mild CKD Moderate CKD Severe CKD
12 Month CYSTINOSIS PHASE 1/2: PATIENT 2-3 15 Transplanted kidney not impacted by treatment, as expected Serum creatinine remains stable post infusion NEW DATA POINT NEW DATA Patient 2 – Serum Creatinine (mg/dL) Normal Range: 0.7 – 1.2 Patient 3 – Serum Creatinine (mg/dL) Normal Range: 0.7 – 1.2
Note: Data from Patient 1 up to 12 months have been previously disclosed. Therapeutic range is <1.0 Half Cystine (nmol/mg protein). Measure of 1 is level of healthy heterozygote.; For Patient 1, Leukocyte Cystine Quantification was initiated at approximately week 20 ; *Patient 1: Hemolyzed sample which may potentially lead to lower results; **Patient 1: Sample processed outside of the range of the stability; †Patient 2: Sample was not collected and shipped according to study protocol CYSTINOSIS PHASE 1/2: PATIENTS 1-5 NEW DATA Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 † * * * Leukocyte cystine levels in blood suppressed out to 28 months
CYSTINOSIS PHASE 1/2: PATIENT 1 Cystinosin is located in melanosomes and regulates melanin synthesis Note: GT: gene therapy; Source: Chiaverini et al., FESEB, 2012 Pre-Infusion PATIENT 1 Post-Infusion 24 months 12 Months post GT 24 Months post GT Patient 1 Hair color – RGB intensity NEW DATA Hair strand Darker pigmentation may be a sign of multi- functional cystinosin activity post gene therapy Further enforces systemic reach of gene therapy 25% reduction
CYSTINOSIS PHASE 1/2: PATIENT 3 Cystinosin is located in melanosomes and regulates melanin synthesis Source:* Do not have permission to show patient image; Chiaverini et al., FESEB, 2012 12 Months PT Baseline Patient 3 Hair color – RGB intensity NEW DATA Darker pigmentation may be a sign of multi-functional cystinosin activity post gene therapy Further enforces systemic reach of gene therapy Hair strand PATIENT 3* 37% reduction
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 * From second apheresis; VCN: Vector Copy Number; PBCs: Peripheral Blood Cells; dg: Diploid Genome Drug Product VCN/dg Patient 1 2.1 Patient 2 1.3* Patient 3 1.6 Patient 4 0.6 Patient 5 2.5 CYSTINOSIS PHASE 1/2: PATIENTS 1-5 Sustained engraftment to date demonstrated by VCN plateau for patients beyond 12 months NEW DATA: 9 &12 Months NEW DATA POINT
Phase 1/2 Cystinosis trial (5 patients) No unexpected safety events or trends related to AVR-RD-04 identified No SAEs or AEs related to AVR-RD-04 drug product No SAEs reported Preliminary AEs reported N=40 for subject 1; N=22 for subject 2; N=8 for subject 3; N=25 for subject 4; N=13 for subject 5 Majority of AEs are mild or moderate 1 severe -- Appendicitis unrelated to study treatment or procedures AEs generally consistent with myeloablative conditioning or underlying disease: Pre-treatment and prior to conditioning (not all events listed) Diarrhea, hypokalemia, dizziness Dehydration, vomiting Post-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 AE: Adverse Event; SAE: Serious Adverse Event; safety data cut-off date is May 6, 2022 CYSTINOSIS PHASE 1/2 CYSTINOSIS PHASE 1/2: PATIENTS 1-5
AVROBIO IND FDA approved July 2021 Building regulatory momentum Active IND with US/EU Orphan Designation and US Fast Track Designation Preclinically focused FDA Type C meeting Dec. 2021 Clinical/CMC FDA Type C meeting planned 2022 Plan to initiate AVROBIO-sponsored trial 2023 Two-stage clinical strategy planned: Pre-renal transplant population for initiation in 2023 Post-renal transplant population as second stage Several endpoints across renal/ocular/neuromuscular systems under evaluation US, UK and EU trial sites Trial enabling interaction Actionable feedback incorporated Long-term follow-up study
Expanding Phase 1/2 data set shows systemic gene therapy impact AVR-RD-04 is first and only investigational gene therapy for cystinosis Improvements in neurocognitive assessments Stable muscle/grip strength Reduction in cystine crystals in skin and gastrointestinal mucosa Improved or stable eye measures Reduction in leukocyte cystine to target levels Quantified increase in hair strand pigmentation * Data as of May 6, 2022 Proof-of-concept demonstrated in adult population Plan to meet with regulators in 2H 2022 to discuss company-sponsored trial Safety and tolerability profile remains strong* All five patients dosed remain off oral cysteamine
Appendix
PATIENT 1 PATIENT 2 PATIENT 3 PATIENT 4 PATIENT 5 Patient baseline characteristics Age of symptom onset/diagnosis 0 year / 8 months 0 year / 6 months 4 years 6 years 8 months Age dosed with CTNS-RD-04 20 years Infused October 2019 46 years Infused June 2020 22 years Infused November 2020 33 years Infused November 2021 31 years Infused March 2022 Gender Male Male Male Male Female Mutation 57-kb deletion c.696dupC, p.Val233Argfs*63 57-kb deletion c.473T>C, p.Leu158Pro c.18_21del, p.Thr7Phefs*7 c.295_298del, p.Val99Ilefs*18 57-kb deletion c.473T>C, p.Leu158Pro 57-kb deletion c.414G>A, p.Trp138* Kidney transplant status and cysteamine dosing prior to CTNS-RD-04 dosing No kidney transplant; stage 3 (moderate CKD) renal failure On oral Cysteamine On Cysteamine drops 2 renal transplants (1987 and 1999) On oral Cysteamine On Cysteamine drops 1 renal transplant (2010) On oral Cysteamine On Cysteamine drops 2 renal transplants (2008 and 2017) On oral Cysteamine Off Cysteamine drops No renal transplant; stage 3 (moderate CKD) renal failure On oral Cysteamine On Cysteamine drops Manufactured CTNS-RD-04 product and busulfan dose 7.88 x 10e6 CD34+ cells/kg VCN: 2.07 94% viability AUC Bu: 81.8 mg.h/L 5.07 x 10e6 CD34+ cells/kg VCN: 1.27 91% viability AUC Bu: 86.7 mg.h/L 9.59 x 10e6 CD34+ cells/kg VCN: 1.59 95% viability AUC Bu: 90 mg.h/L 3.63 x 10e6 CD34+ cells/kg VCN: 0.59 90% viability AUC Bu: 88.5 mg.h/L 9.12 x 10e6 CD34+ cells/kg VCN: 2.5 95% viability AUC Bu: 88.2 mg.h/L CYSTINOSIS PHASE 1/2