Orchard Therapeutics Unveils Details on New HSC Gene Therapy Research Programs as Part of R&D Investor Event Tomorrow at 9:00 a.m. ET
First look at preclinical data in frontotemporal dementia with progranulin mutations (GRN-FTD) and new amyotrophic lateral sclerosis (ALS) program
NOD2 mutation revealed as Crohn’s disease (CD) genetic target, associated with 7-10% of all CD cases in the
Deep dive on transduction enhancers and stable cell line technology innovations that support manufacturing for larger indications
“We are excited to draw back the curtain at tomorrow’s event on our work in larger indications that form an important part of Orchard’s evolution as a company, including a new program in ALS, in addition to our work in genetic subsets of FTD and Crohn’s disease,” said
OTL-204 for GRN-FTD and new ALS research program
The GRN-FTD and ALS programs are based on the same HSC gene therapy approach that has been clinically validated with Libmeldy (OTL-200), Orchard’s program for metachromatic leukodystrophy, and is under clinical evaluation in the OTL-203 and OTL-201 programs for mucopolysaccharidosis type I and mucopolysaccharidosis type IIIA, respectively. Development work in GRN-FTD and ALS will be undertaken as part of a collaboration with Boston Children’s Hospital (BCH), the
- OTL-204 for GRN-FTD: Orchard’s preclinical program in GRN-FTD seeks to introduce a working copy of the GRN gene into HSCs, which can differentiate into microglia and secrete progranulin in the central nervous system, potentially correcting the underlying cause of the disease.
- Preclinical work completed to date demonstrates that gene-modified HSCs can lead to GRN expression and secretion in the culture medium and uptake by GRN-negative cells.
- Epidemiological studies suggest the FTD prevalent population in the
U.S.and Europeis more than 50,000 patients with approximately 5% caused by mutations in the GRN gene, resulting in up to 2,500 GRN-FTD prevalent patients in the U.S.and Europe, with approximately 800 new patients diagnosed each year.1
- ALS research program: Orchard’s new gene therapy research program in ALS will aim to restore healthy, non-activated microglia with genetically modified HSCs to favorably modulate neuroinflammation, improve symptoms and prolong survival.
- Preclinical work previously undertaken by
Prof. Biffiat BCH is based on exploiting shRNA mediated suppression of NADPH oxidase 2 (NOX2) activity to modulate neuroinflammation and neurodegeneration.
- Rather than focusing on restoring gene function in patients with specific genetic susceptibility, this approach targets neuroinflammatory responses to support neuronal survival and could be applicable to a broader population of ALS patients.
- Preclinical work previously undertaken by
OTL-104 for NOD2-CD
Orchard’s preclinical program in CD targets mutations in the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene, which plays a role in immune cell response to bacterial peptides in the gastrointestinal (GI) tract. The company’s proposed approach leverages this link, using gene modified HSC-derived cells (monocytes) to replace GI resident macrophages, thus potentially correcting the inflammation and colitis associated with NOD2-CD.
- OTL-104 preclinical work completed to date demonstrates successful restoration of NOD2 expression and functional correction in response to bacterial peptide stimulation, in NOD2 defective murine and human cells.
- Epidemiological studies suggest the NOD2 genetic subset is associated with 7-10% of all cases of CD, with up to 200,000 patients in the
U.S.and Europewith two NOD2 mutated alleles.2
Manufacturing Innovations to Support Work in Larger Indications
Transduction enhancers (TEs) and stable cell line technology (SCLT)
Orchard has completed a thorough TE screening process and identified and validated several novel TE compounds, which in combination, facilitate lentiviral vector entry into HSCs and have shown a greater than 50% reduction in vector requirements. The enhancers’ mode of action is expected to be effective in each of Orchard’s HSC gene therapy programs. An evaluation of enhancer-treated HSC engraftment potential in mice is currently underway.
The company has worked extensively with SCLT, including the technology licensed from GSK for certain programs, to both develop processes to efficiently create SCLs for new vectors and scale up the production of SCLs to clinical grade. Results have delivered consistent levels of high-titer lentiviral production comparable to those seen using conventional methods. Selection of single high-titer clones for new vectors using this method has been achieved within three months. Work at Orchard is ongoing to develop upstream and downstream processes to further improve productivity and scalability.
“We have a clear roadmap for Orchard’s future that prioritizes strategic growth and draws on the many synergies across our scientific, manufacturing and emerging commercial platforms,” said
A live webcast of the presentation “New Horizons in Gene Therapy” will be available under “Events” in the Investors & Media section of the company’s website at www.orchard-tx.com. A replay of the webcast will be archived on the Orchard website following the presentation.
About Orchard’s Research Collaborations
In connection with its previously disclosed collaboration with Prof.
Availability of Other Information About Orchard
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This press release contains certain forward-looking statements about Orchard’s strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may be identified by words such as “anticipates,” “believes,” “expects,” “plans,” “intends,” “projects,” and “future” or similar expressions that are intended to identify forward-looking statements. Forward-looking statements include express or implied statements relating to, among other things, Orchard’s business strategy and goals, including with respect to its manufacturing strategy, expected future milestones, and its plans and expectations for the development of its product candidates, including the product candidates referred to in this release, and the therapeutic and commercial potential of its product candidates. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchard’s control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, these risks and uncertainties include, without limitation: the risk that any one or more of Orchard’s product candidates, including the product candidates referred to in this release, will not be approved, successfully developed or commercialized; the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials of Orchard’s product candidates will not be repeated or continue in ongoing or future studies or trials involving its product candidates; the risk that the market opportunity for its product candidates may be lower than estimated; and the severity of the impact of the COVID-19 pandemic on Orchard’s business, including on preclinical and clinical development, its supply chain and commercial programs. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.
Other risks and uncertainties faced by Orchard include those identified under the heading “Risk Factors” in Orchard’s quarterly report on Form 10-Q for the quarter ended
Director, Investor Relations
Vice President, Corporate Affairs
1 Knopman DS, Roberts RO. J Mol Neurosci. 2011, Onyike CU, Diehl-Schmid J. Int Rev Psychiatry. 2013 and Riedl L, et al Neuropsychiatr Dis Treat. 2014
Source: Orchard Therapeutics (Europe) Limited