R&D programmes overview

Our development programmes focus on the potential of autologous ex-vivo gene therapy to restore normal gene function in primary immune deficiencies, metabolic diseases and haematological disorders

 
In-vitro PoC Animal PoC IND/non-clinical studies enabling CT Clinical PoC Pivotal trial
Primary immune deficiencies (PID)
ADA-SCID (OTL-101)
 
X-CGD (OTL-102)
 
Pipeline programs
 
Inherited metabolic diseases
MPS-IIIA (OTL-201)
 
MPS-IIIB (OTL-202)
 
Pipeline programs
 

ADA-SCID (adenosine deaminase severe combined immunodeficiency)

A rare, life-threatening primary immune deficiency

Severe combined immunodeficiencies (SCIDs) are rare and life-threatening inherited disorders of the immune system. Affected children are vulnerable to severe recurrent infections and have a high risk of death within the first year of life if not treated

ADA-SCID is characterized by a deficiency in the enzyme adenosine deaminase (ADA). It is caused by mutations in the ADA gene and accounts for 10–15% of all cases of SCID

ADA is normally expressed throughout the body, so in addition to a severely compromised immune system patients may also present with neurodevelopmental, behavioural, skeletal and hepatic abnormalities

Treatment options include allogenic haematopoietic stem cell transplant (HSCT), chronic enzyme replacement therapy or autologous ex-vivo  gene therapy. When a HLA-matched sibling or family donor is not available, allogeneic transplants are associated with a high risk of mortality.1 Enzyme replacement with pegylated-ADA can be highly effective in the short term, but chronic use involves lifelong weekly injections and long-term survival rate (78% at 20 years) is less promising2

Autologous ex-vivo lentiviral gene therapy

Orchard is developing ex-vivo lentiviral gene therapy to restore normal gene function in patients with ADA-SCID

For more information please contact:

info@orchard-tx.com


  1. Hassan et al. shows 1-year survival of 43-67% for transplants from haploidentical and HLA-matched donors. Hassan A et al. Blood 2012;120:3615–24
  2. Gaspar HB et al. Blood 2009;114:3524–32

X-CGD (chronic granulomatous disease)

Chronic granulomatous disease (or CGD) is rare and life-threatening inherited disorder of the immune system in which white blood cells especially neutrophils are unable to kill bacteria and other organisms

X-linked CGD is caused by a defect/mutation in gp-91, an important sub-unit of NADPH oxidase, which is inherited on the X-chromosome thereby affecting males. As a result neutrophils are unable to effectively kill and eradicate bacteria. This leads to repeated, chronic infections especially lung infections and abscesses in organs such as the liver1

Patients with CGD generally start to get infections in the first decade of life but with repeated infections there is a significant mortality associated with the disease and also a high level of infective burden for individuals in their later teens and early adulthood

Supportive care is available the form of prophylactic antibiotics but this does not always prevent severe infections. Haematopoietic stem cell transplantation is used in some centres and offers a curative option but this can be associated with significant toxicities especially when well matched donors are not available2

Autologous ex-vivo lentiviral gene therapy in X-CGD

Orchard has an exclusive option from Genethon (Evry, France) to license the data from ongoing clinical trials in the US and in the EU for an ex-vivo lentiviral gene therapy for X-linked chronic granulomatous disease (X-CGD) aiming at restoring normal gene function in patients

Summary of clinical data to date:

  • The data accrued to date in paediatric and adult patients demonstrates the potential of autologous ex-vivo lentiviral gene therapy to improve neutrophil function and therefore to clear or prevent infections
  • A first publication in a peer-reviewed journal is expected over by the Summer of 2018
  • The next steps are to complete the clinical and CMC development activities to position the program to regulatory filing
For more information please contact:

info@orchard-tx.com

  1. Winkelstein et al., 2000
  2. Gungor et al., 2014

MPS-IIIA (mucopolysaccharidosis type IIIA)

A fatal and progressive inherited metabolic disease with no effective treatment option

Mucopolysaccharidosis type III (MPS-III, Sanfilippo syndrome) consists of four clinically similar neurodegenerative, lysosomal storage diseases that affect ~1–2 in 100,000 births1

The relative prevalence of each form of MPS-III varies by geography
  • MPS-IIIA is the most common form in Northwestern Europe (~75% of patients in the UK)2
  • MPS-IIIB is the most common form in Southeast Europe1
  • Other forms (types C and D) are rare everywhere1

MPS-IIIA is an autosomal recessive disorder caused by mutations in the SGSH gene resulting in a deficiency of the enzyme heparan sulfamidase

MPS-IIIA affects children in early life, with a progressive decline in cognitive and behavioural functions and subsequent motor function decline. The disease ultimately results in severe dementia and early death, usually in late teens or early twenties

Currently, treatment options are limited to palliative care only. As yet, no treatment has been shown to correct or relieve the neurological manifestations of the disease1

Autologous ex-vivo lentiviral gene therapy in MPS-IIIA

Orchard is developing ex-vivo lentiviral gene therapy to restore normal gene function in patients with MPS-IIIA

Summary of preclinical data to date*

  • An increase in heparan sulfamidase expression in the periphery and the brain of pre-clinical models of MPS-IIIA, leading to clearance of lysosomal material in neurons
  • Evidence of normalization of hyperactive behaviour in pre-clinical models of MPS-IIIA
  • The next steps are to complete the ongoing pre-clinical programmes and open a first-in-man clinical study
For more information please contact:

info@orchard-tx.com

*As of March 2016
  1. Valstar MJ et al. J Inherit Metab Dis 2008;31:240–52
  2. University of Manchester / Central Manchester Foundation Trust

MPS-IIIB (mucopolysaccharidosis type IIIB)

A rare, life-threatening metabolic disease

Mucopolysaccharidosis type IIIB is one of the four forms of Sanfilippo syndrome and is the most common form in Southeast Europe1

MPS-IIIB is a rare and severe neurodegenerative inherited lysosomal storage disorder. MPS-IIIB is an autosomal recessive condition caused by mutations in the NAGLU gene located in the chromosome 17 and resulting in deficiency of the lysosomal enzyme N-acetyl-α-D-glucosaminidase (NAGLU). The enzymatic deficiency leads to accumulation of partially degraded glycosaminoglycans (GAGs) inside lysosomes and leads to lysosomal hypertrophy, cell death and ultimately organ dysfunction2

Similarly to MPS-IIIA, MPS-IIIB affects children in early life, as early as 2 years of age, with a progressive cognitive impairment and behavioural problems and subsequent motor function decline. The disease ultimately results in severe dementia and early death, usually in late teens or early twenties1

Currently, there is no effective treatment option for MPS-IIIB. Intravenous recombinant enzyme (ERT) has not been shown to effectively cross the blood-brain barrier (BBB), precluding its access to the central nervous system (CNS); thus, it does not prevent or treat the neurological manifestations of MPS-IIIB. Bone marrow transplantation has also shown to be ineffective in MPS-III probably because insufficient enzyme production to correct the central metabolic dysfunction3

Autologous ex-vivo lentiviral gene therapy in MPS-IIIB

Orchard is developing an autologous ex-vivo lentiviral gene therapy for Sanfilippo syndrome type B to restore normal gene function in patients

Summary of preclinical data to date:

  • Preclinical studies in an MPS-IIIB mouse model of the disease have produced encouraging results showing normalization of heparan sulphate levels in the brain and peripheral organs, as well as neurological disease correction.
  • The technology, developed in Professor Brian Bigger's laboratory was published in the journal Brain4 in December 2017
  • The next steps are to complete the pre-clinical studies required by regulatory authorities to enable the onset of clinical activities
For more information please contact:

info@orchard-tx.com

  1. Valstar MJ et al. J Inherit Metab Dis 2008;31:240–52
  2. Beesley et al J. Inherit. Metab. Dis. 28 (2005) 759–767
  3. Giugliani et al. Expert Opinion on Emerging Drugs, 21:1, 9-26
  4. Holley et al. Brain 2017

Follow-on ex-vivo lentiviral gene therapy programmes

  • Orchard has a pipeline of potentially transformative autologous ex-vivo gene therapies
  • Through its academic collaborations, Orchard has access to a significant number of programmes
  • We are actively seeking additional candidates in disease areas of high unmet need
  • Our mission is to accelerate promising pre-clinical and early clinical results into commercially approved and reimbursed medicines, globally