Rare Daily Staff

Orchard Therapeutics and Pharming Group entered a strategic collaboration to research, develop, manufacture and commercialize OTL-105, an experimental gene therapy for the treatment of hereditary angioedema, a life-threatening rare disorder.

Hereditary angioedema (HAE) is a rare genetic disorder caused by a deficiency of the C1 esterase inhibitor protein, which is normally present in blood and helps control inflammation (swelling) and parts of the immune system. Deficient C1 inhibitor does not adequately perform its regulatory function and, as a result, a biochemical imbalance can occur and produce unwanted peptides that induce the capillaries to release fluids into surrounding tissue, thereby causing swelling or edema.

HAE is characterized by spontaneous and recurrent episodes of swelling (edema) of the skin in different parts of the body, as well as in the airways and internal organs. Almost all HAE patients also suffer from bouts of severe abdominal pain, nausea, vomiting, and diarrhea caused by swelling of the intestinal wall. Edema of the throat, nose, or tongue is particularly dangerous and potentially life-threatening as it can lead to obstruction of the airway passages. Although there is currently no known cure for HAE, it is possible to treat the symptoms associated with angioedema attacks. HAE affects about 1 in 10,000 to 1 in 50,000 people worldwide.

Orchard’s OTL-105 is an experimental hematopoietic stem cell (HSC) gene therapy designed to increase C1 esterase inhibitor (C1-INH) in HAE patient serum to prevent hereditary angioedema attacks. OTL-105 inserts one or more functional copies of the SERPING1 gene into patients own HSCs ex vivo which are then transplanted back into the patient for potential durable C1-INH production. In preclinical studies, to date, OTL-105 demonstrated high levels of SERPING1 gene expression via lentiviral-mediated transduction in multiple cell lines and primary human CD34+ HSCs. Furthermore, the program achieved production of functional C1-INH protein, as measured by a clinically validated assay.

Under the terms of their collaboration, Pharming has been granted worldwide rights to OTL-105 and will be responsible for clinical development, regulatory filings, and commercialization of the investigational gene therapy, including associated costs. Orchard will lead the completion of IND-enabling activities and oversee manufacturing of OTL-105 during preclinical and clinical development, which will be funded by Pharming. In addition, both companies will explore the application of a non-toxic conditioning regimen for use with OTL-105 administration.

Orchard will receive an upfront payment of $17.5 million comprising $10 million in cash and a $7.5 million equity investment from Pharming at a premium to Orchard’s recent share price. Orchard is also eligible to receive up to $189.5 million in development, regulatory and sales milestones as well as mid-single to low double-digit royalty payments on future worldwide sales.

“Given the combination of our expertise in HSC gene therapy with Pharming’s long-standing legacy and experience, we have the potential to reinvent the treatment paradigm for HAE by providing people living with this life-threatening disorder a sustained therapy with a single administration,” said Bobby Gaspar, CEO of Orchard Therapeutics.

Pharming Group already markets Ruconest, a recombinant human C1 esterase inhibitor that is the first and only plasma-free rhC1INH protein replacement therapy and is approved for the treatment of acute HAE attacks in the United States, European Union, and United Kingdom.

“Pharming has been committed to the HAE community for more than two decades,” said “We have partnered with Orchard Therapeutics, a leader in the development of autologous HSC gene therapy, to develop a potentially curative treatment for HAE. “Based on Pharming’s experience in HAE, we believe that HSC gene therapy has the potential for the highest probability of success,” said Sijmen de Vries, CEO of Pharming. “This confidence is based on the durability of effect and safety observed in approved treatments from Orchard’s HSC gene therapy portfolio and positive clinical data in several other programs. This a significant first step in developing a potentially transformative one-time treatment for HAE.”

According to the companies, the HAE market is expected to generate about $2 billion in sales in 2021, currently growing at 8 percent per year.

Photo: Bobby Gaspar, CEO of Orchard Therapeutics

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