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OT-58 is being developed as an innovative enzyme replacement therapy (ERT) for the treatment of Homocystinuria.

About Homocystinuria (HC)

HC is a rare, devastating, genetic disorder, with high unmet need and poor prognosis, caused due to the lack or absence of active Cystathionine Beta-Synthase (CBS) enzyme. Individuals with this disease are unable to fully metabolize methionine, an amino acid found in nearly all foods, and this leads to accumulation of toxic levels of related metabolites, which in turn causes medical complications and early death.

Source: Kraus’ lab, University of Colorado School of Medicine

Clinical features of HC are serious, some are life-threatening and some significantly affect quality of life. The most common symptoms include mental retardation, lens dislocation (leading to blindness if not treated), thromboembolism (a major cause of patients’ early death), skeletal manifestations, osteoporosis, and seizures.

Whereas about 40% of the patients are responsive to vitamin B6 supplementation, about 60% are non-responders. Treatment options include mainly methionine-restricted diet and supplementation of betaine (Cystadane), do not restore the deficient enzyme and therefore do not normalize all metabolic abnormalities. As such, patients still suffer from clinical symptoms and experience lower life expectancy. In addition, they are associated with several significant limitations, such as  increased risk for dangerous complications (Cystadane is associated with increased risk for accumulation of toxic levels of methionine, as well as risk for cerebral edema) and severe impact on quality of life which also result in poor compliance (the diet is horrid tasting, nearly impossible to comply with). Therefore, there is a crucial need for a new and effective therapeutic option.

About the Technology

CBS is the enzyme that is deficient in HC patients, and OT-58 is an innovative ERT developed for treating this debilitating disease. OT-58 corrects the underlying cause of the disease by restoring normal metabolism of methionine.  This therapeutic approach avoids accumulation of toxic levels of metabolites, which further avoids the appearance of new symptoms or the deterioration of existing symptoms, thereby representing a potentially ideal therapy for HC.

OT-58, a proprietary truncated recombinant human CBS, shows superior enzymatic activity in-vivo, 5-fold compared to the wild-type enzyme. In addition, it does not require allosteric activation by S-adenosyl-L-methionine (AdoMet), which paved the way, for the first time, for ERT for HC. Encouraging in-vivo proof of principle was achieved in knock-out mouse models of the disease, in which OT-58 was able to normalize the toxic levels of the disease-related toxins, with no apparent side-effects.

The proposed therapy is expected to have great value for individuals with HC, and first-in-human clinical trials are scheduled to start in 2014.

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OT-15 is an innovative and highly specialized cell-based and personalized ERT for Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE).


MNGIE is an ultra-rare, fatal, inherited metabolic disorder caused by mutations in the nuclear TYMP gene encoding for the enzyme thymidine phosphorylase (TP). The resulting enzyme deficiency leads to plasma and tissue accumulation of thymidine and deoxyuridine which generate imbalances within the mitochondrial nucleotide pools, causing impairment of mitochondrial DNA (mtDNA) replication and repair. Ultimately, this leads to mitochondrial failure due to progressive accumulation of mtDNA defects and mtDNA depletion.

MNGIE is characterized by abnormalities of the digestive and nervous systems. Abnormalities of the digestive system lead to abdominal pain, diarrhea, and intestinal blockage, which in turn lead to extreme weight loss and cachexia, while neurologic symptoms include mainly peripheral neuropathy, ptosis, ophthalmoplegia and hearing loss. MNGIE is relentlessly progressive, with patients dying at an average age of 37.6 years.

About Erythrocyte Encapsulated Thymidine Phosphorylase (EE-TP)

OT-15 is based on encapsulation of TP within autologous erythrocytes. This approach, Erythrocyte Encapsulated Thymidine Phosphorylase (EE-TP), addresses the underlying cause of MNGIE by replacement of the missing enzyme and as such preventing or reversing the severe and life-threatening complications in patients with MNGIE. The encapsulation technology has the advantage of prolonging the circulatory half-life of enzymes and minimizing immunogenic reactions.

Several patients with urgent medical needs have obtained access to the therapy through compassionate use treatment. A proof of concept study was conducted in a single patient diagnosed with MNGIE and a compassionate pilot clinical evaluation in two patients with confirmed diagnosis of MNGIE (1,2). Administration of EE-TP was reported to be effective in reducing/eliminating the elevated plasma and urine concentrations of thymidine and deoxyuridine. Three months after initiating therapy, one patient reported a reduction in the number of nausea and vomiting attacks and gained 4 kg, and the second patient, after only two cycles of therapy, reported an improvement in distal sensation in his hands and fingers, with continuing improvements at 3 months, such that he was able to return to guitar playing (1,2).

OT-15 has been granted orphan designation by both FDA and EMA. Upon approval, this will be the first approved treatment for a mitochondrial disease.

Erythrocyte encapsulated- enzyme replacement. The pathologically elevated plasma metabolite permeates the erythrocyte membrane into the cell where the encapsulated enzyme catalyzes its metabolism to the normal product. The product is free to diffuse out of the cell into the blood plasma where it will be further metabolized as normal.

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OT-81 is an innovative and highly specialized cell-based and personalized ERT for the treatment of severe combined immunodeficiency (SCID) due to Adenosine Deaminase deficiency (ADA-SCID).


SCID is a severe form of heritable immunodeficiency, which leads to the absence of virtually all immune protection from bacteria, viruses, and fungi, making patients extremely vulnerable to repeated and persistent infections that can be very serious or life-threatening. ADA-SCID is the second most common form of SCID.

ADA-SCID is a rare, fatal, inherited metabolic disease which is caused by defects in the activity of the purine nucleotide catabolism enzyme, adenosine deaminase (ADA). This defect leads to elevated cellular levels of deoxyadenosine triphosphate (dATP) and systemic accumulation of its precursor, 2-deoxyadenosine. These metabolites impair lymphocyte differentiation, proliferation and function, and inactivate S-adenosylhomocysteine hydrolase (SAHH), respectively, leading to severe immunodeficiency. If not treated in a way that restores immune function, children with SCID usually live only a year or two.

About Erythrocyte Encapsulated Adenosine Deaminase (EE-ADA)

OT-81 is based on encapsulation of Adenosine Deaminase (ADA) within autologous erythrocytes. The efficacy and safety of OT-81 has been reported in the treatment of an ADA-SCID refractory patient who previously failed Adagen treatment due to immunogenic response, and currently being treated with EE-ADA for over 15 years(3). Treatment with OT-81 was reported to be metabolically and clinically effective, maintaining adequate clinical immunity in terms of preventing hospital admissions for respiratory disease, and prevent the formation of neutralizing antibodies against the encapsulated ADA.

1. Moran NF, Bain MD, Muqit MMK and Bax BE. Carrier erythrocyte entrapped thymidine phosphorylase therapy for MNGIE. Neurology. 2008;71:686-688.
2. Godfrin Y and Bax, BE. Enzyme bioreactors as drugs. Drugs of the Future. 2012; 37: 263-272.
3. Bax BE, Bain MD, Fairbanks LD, Webster ADB, Ind PW, Hershfield MS and Chalmers RA. A nine year evaluation of carrier erythrocyte encapsulated adenosine deaminase therapy in a patient with adult-type adenosine deaminase deficiency. European Journal of Haematology. 2007; 79: 338-348

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Additional programs

Additional programs are in discovery and preclinical stages for potential therapies for rare disorders. All programs are for indication with high unmet medical needs and with potential for Orphan and Fast Track Designations. These programs will reach the clinical stage within 2 years.