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AVROBIO Presents Positive Initial Data for its Investigational Cystinosis Program and plato™ Platform, as well as Positive Data Out to 32 Months for its Ongoing Investigational Fabry Program
AVROBIO Presents Positive Initial Data for its Investigational Cystinosis Program and plato™ Platform, as well as Positive Data Out to 32 Months for its Ongoing Investigational Fabry Program
Early data trends from first patient dosed in the AVR-RD-04 investigational gene therapy program for cystinosis show improvements across multiple measures
Data from the Phase 1 and Phase 2 trials of AVR-RD-01 support potential long-term engraftment and durable, endogenous production of functional enzyme in patients with Fabry disease
First Phase 2 Fabry patient treated using plato gene therapy platform shows plasma enzyme activity at one month 4.0 times higher than mean activity of other Phase 2 patients treated using academic platform at same timepoint
Analyst and investor event will be webcast today,
“We have now dosed 10 patients across three trials for two lysosomal disorders and we’re delighted with the data we’re seeing. We have followed six patients in our Fabry trial for more than a year and one for nearly three years, and they are consistently producing the functional enzyme that was missing as a consequence of their genetic disease, suggesting a potentially durable effect from a single dose,” said
Three-month data from first patient in investigational AVR-RD-04 trial in cystinosis
As of the safety data cut-off date of
Three months following administration of AVR-RD-04, the first patient had a VCN of 2.0. VCN measures the average number of copies of the lentiviral-vector inserted transgene integrated into the genome of a cell and can be used to help assess the durability of a gene therapy. Initial data on another biomarker show that the patient’s average granulocyte cystine level -- one of the trial’s primary endpoints -- decreased from 7.8 nmol half cystine/mg protein two weeks after cysteamine discontinuation, to 1.5 at three months post-gene therapy.
The ongoing open-label, single-arm Phase 1/2 clinical trial evaluating the safety and efficacy of AVR-RD-04 is sponsored by AVROBIO’s academic collaborators at the
Interim data continue to support potential first line use of AVR-RD-01 in Fabry disease
Four patients have been dosed in the Phase 2 trial (FAB-201), and five patients in the Phase 1 investigator-led trial of AVR-RD-01 in Fabry disease.
VCN data continue to be stable at 32 months following AVR-RD-01 treatment for the first patient in the Phase 1 trial, suggesting successful engraftment, which is critical to the long-term success of investigational ex vivo lentiviral gene therapies. The VCN data trend was generally consistent across the seven other Phase 1 and Phase 2 trial participants out six to 24 months.
The first three AVR-RD-01 Phase 2 patients entered the study with minimal endogenous enzyme activity. At nine, 12 and 18 months after dosing, data from these three patients indicate sustained increased leukocyte and plasma enzyme activity, suggesting that they are now producing an endogenous supply of functional alpha-galactosidase (AGA) enzyme. This enzyme is essential for breaking down globotriaosylceramide (Gb3) in cells; without it, a toxic metabolite, lyso-Gb3, may accumulate, potentially causing cardiac and kidney damage and other symptoms.
For two Phase 2 patients, data indicate that their decreased plasma lyso-Gb3 levels, a key biomarker for monitoring Fabry disease, have been sustained below their baseline at six and 18 months after dosing. The third Phase 2 patient, a cardiac variant who does not have classic Fabry disease, did not show a decrease in plasma lyso-Gb3 levels, as expected. Cardiac and kidney function measures in the Phase 2 trial remained within normal range for patients who had available 12-month data.
As previously reported, a kidney biopsy taken at 12 months post-treatment for the first patient in the Phase 2 trial showed an 87-percent reduction in Gb3 inclusions per peritubular capillary. The company believes this data point, the primary efficacy endpoint for the Phase 2 trial, supports the potential of AVR-RD-01 to reduce Gb3 levels in tissue, including in the kidney.
In the Phase 1 trial of AVR-RD-01, four of the five patients had their plasma lyso-Gb3 levels reduced between 26 and 47 percent compared to their pre-treatment baseline levels. Data from the other patient in the trial, who remains off enzyme replacement therapy (ERT), through month six showed an initial decline and at month 12 showed a 23-percent increase in lyso-Gb3 levels, as compared to pre-treatment levels. This patient’s lyso-Gb3 levels remain within the range for the Fabry disease patients on ERT observed in this study.
Overall, three of the five Phase 1 patients have discontinued ERT and all three remain off ERT for six, 14 and 15 months.
As of the safety data cut-off date of
The Phase 1 trial is fully enrolled.
Successful clinical debut of platoTM gene therapy platform
These two patients both had rapid neutrophil and platelet count recovery, with a trajectory that was similar to the patients who enrolled earlier in the Fabry trials and who received a melphalan conditioning regimen. Side effects, which included nausea, mucositis, fever, rash and hair loss, developed eight to 10 days after dosing with busulfan and then resolved quickly.
The company also reported preliminary data from the first drug product produced using the plato gene therapy platform, which was used to dose the fourth patient in the Phase 2 Fabry trial (FAB-201). Early data indicate that enzyme activity and transduction efficiency for the drug product used to dose the fourth patient were 2.2 times higher than the mean of the drug product used to dose the first three patients in FAB-201. VCN for the drug product used to dose the fourth patient was 1.8 times higher than the mean of the drug product for the first three patients dosed in FAB-201. The drug product for the first three patients in FAB-201 was manufactured using a manual process first developed by AVROBIO’s academic collaborators. The automated manufacturing embedded in plato leverages optimized processes developed at
At one month following administration of the plato-produced investigational gene therapy for the fourth patient in the Phase 2 Fabry trial, initial data show the patient’s plasma enzyme activity level to be 4.0 times higher than the mean activity level of the first three patients in the Phase 2 Fabry trial at the same timepoint.
The investigational drug product used to dose the first patient in the AVR-RD-04 program for cystinosis, which included a four-plasmid vector but not plato’s automated manufacturing process, also showed increased performance in line with the increased performance recorded for the drug product in the Fabry trial. The investigational drug product and VCN assay are different for each trial.
“We believe these data are an early, but exciting, validation of our decision to invest in technological innovation rather than build expensive bricks-and-mortar manufacturing facilities,” said MacKay. “The plato platform gives us control over the production and scaling of our investigational gene therapies through an efficient, automated manufacturing system that is designed to be deployed in standard contracted sites around the world. The four-plasmid vector, conditioning regimen with precision dosing and other elements of plato are designed to optimize the safety, potency and durability of our investigational lentiviral gene therapies.”
About AVROBIO’s ex vivo approach to gene therapy
Our investigational ex vivo gene therapies start with the patient’s own stem cells. In the manufacturing facility, a lentiviral vector is used to insert a therapeutic gene designed to enable the patient to produce a functional supply of the protein they lack. These cells are then infused back into the patient, where they are expected to engraft in the bone marrow and produce generations of daughter cells, each containing the therapeutic gene. This approach is designed to drive durable production of the functional protein throughout the patient’s body, including hard-to-reach tissues such as the brain, muscle and bone. It is a distinguishing feature of this type of gene therapy that the corrected cells are expected to cross the blood-brain barrier and thereby potentially address symptoms originating in the central nervous system.
Lentiviral vectors are differentiated from other delivery mechanisms because of their large cargo capacity and their ability to integrate the therapeutic gene directly into the patient’s chromosomes. This integration is designed to maintain the transgene’s presence as the patient’s cells divide, which may improve the expected durability of the therapy and potentially enable dosing of pediatric patients, whose cells divide rapidly as they grow. Because the transgene is integrated ex vivo into patients’ stem cells, patients are not excluded from receiving the investigational therapy due to pre-existing antibodies to the viral vector.
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About
Our mission is to free people from a lifetime of genetic disease with a single dose of gene therapy. We aim to halt or reverse disease throughout the body by driving durable expression of functional protein, even in hard-to-reach tissues and organs including the brain, muscle and bone. Our clinical-stage programs include Fabry disease, Gaucher disease and cystinosis and we also are advancing a program in Pompe disease.
Forward-Looking Statements
This press release contains forward-looking statements, including statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words and phrases such as “aims,” “anticipates,” “believes,” “could,” “designed to,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will,” and variations of these words and phrases or similar expressions that are intended to identify forward-looking statements. These forward-looking statements include, without limitation, statements regarding our business strategy for and the potential therapeutic benefits of our prospective product candidates, the design, commencement, enrollment and timing of ongoing or planned clinical trials, clinical trial results, product approvals and regulatory pathways, and anticipated benefits of our gene therapy platform including potential impact on our commercialization activities, timing and likelihood of success. 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
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Investor Contact:
Christopher F. Brinzey
Westwicke, an ICR Company
339-970-2843
chris.brinzey@westwicke.com
Media Contact:
Tom Donovan
Ten Bridge Communications
857-559-3397
tom@tenbridgecommunications.com