Pharming And Orchard Seek Stem Cell Solution To Hereditary Angioedema
Duo To Develop Hematopoietic Stem Cell Gene Therapy
Executive Summary
Orchard Therapeutics of the US and Dutch biotech Pharming have agreed to jointly research, develop, manufacture and commercialize the former’s newly disclosed investigational ex vivo autologous hematopoietic stem cell gene therapy as a treatment for hereditary angioedema.
Netherlands-basedPharming Group N.V. is tapping the gene therapy abilities of Orchard Therapeutics Limited of the US in hopes of developing a therapy that could ultimately cure hereditary angioedema (HAE), but their development plans are in the early stages.
Orchard is a gene therapy specialist whose approach harnesses the power of genetically modified blood stem cells and seeks to correct the underlying cause of disease in a single administration.
Pharming hopes that through the alliance with Orchard, announced 1 July, it can build on the commercial success of its sole product, Ruconest, in HAE, which is a rare genetic disorder caused by a deficiency of the C1 esterase inhibitor protein, normally present in blood and helps control inflammation and parts of the immune system.
Their strategic collaboration spans the research, development, manufacture and commercialization of OTL-105, a newly disclosed investigational ex vivo autologous hematopoietic stem cell (HSC) gene therapy for the treatment of HAE, a life-threatening rare disorder that causes recurring swelling attacks in the face, throat, extremities and abdomen.
“We have partnered with Orchard, 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,” Pharming’s CEO Sijmen de Vries told an analyst call outlining the partnership.
If the duo succeed, it could open up a significant commercial opportunity given that the HAE market is expected to be worth $2bn in sales in 2021, and is currently growing at 8% per annum, he said.
Pharming’s confidence reflects 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, de Vries said, adding: “This a significant first step in developing a potentially transformative one-time treatment for HAE.”
OTL-105 Explained
OTL-105 is an investigational HSC gene therapy designed to increase C1 esterase inhibitor (C1-INH) in HAE patient serum to prevent HAE 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.
“Essentially, we take the patient's own blood stem cells, we purify those cells,” explained Bobby Gaspar, Orchard’s CEO.
Describing the process to analysts, he said “the cells first are taken from the patient in hospital, then transported to a manufacturing site where we introduce a working copy of the gene into those cells. The gene modified cells are then frozen down, and we do quality control around them before the cells go back to the hospital site where the patient receives conditioning, and then the cells are infused into a vein, and then they kind of find their way to the bone marrow and start to produce the necessary factor. The whole process takes about four weeks,” he said.
The duo said the project is in very early stages, so their clinical development plans are not final and no regulatory discussions had occurred yet.
“Over the next couple of years, we will do the necessary proof of concept and IND enabling studies to be able to enter the clinic. We'll be working very closely with Pharming with respect to what needs to be done before we get into a first-in-man study,” Gaspar said,
In preclinical studies, OTL-105 has 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.
“The ultimate goal [for this gene therapy] is to reduce and hopefully completely eliminate attacks on these HAE patients,” Anurag Relan, Pharming’s chief medical officer, told the analysts call.
“Exactly how we do those comparisons, whether we do those among patients or within a patient, those things still need to be worked out,” he added.
Deal Terms
Under the terms of the 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. Both companies will explore the application of non-toxic conditioning regimen for use with OTL-105 administration.
For its efforts, Orchard will receive an upfront payment of $17.5m comprising $10m in cash and a $7.5m equity investment from Pharming at an undisclosed premium to Orchard's recent share price. Orchard is also eligible to receive up to $189.5m in development, regulatory and sales milestones as well as mid-single to low double-digit royalty payments on future worldwide sales.
Orchard’s CEO said the envisioned gene therapy would be manageable and improve quality of life for HAE patients.
Crowded HAE Landscape
But the duo’s development timeline for OTL-105 is not a short one and the therapeutic landscape for HAE is getting increasingly crowded in the meantime.
Players today include Takeda Pharmaceutical Co. Ltd..'s Takhzyro (lanadelumab), an injected kallikrein inhibitor, and plasma-derived C1-INH therapies such as CSL Behring’s Haegarda (C1 esterase inhibitor subcutaneous [human]). (Also see "KalVista Reports Positive Phase II Data For Oral HAE Attack Therapy KVD900" - Scrip, 9 Feb, 2021.) In March, Ionis Pharmaceuticals, Inc..'s investigational antisense medicine IONIS-PKK-LRx produced impressive topline results in a Phase II trial in HAE, easily hitting primary and secondary endpoints and producing a 90% reduction in the number of monthly HAE attacks. (Also see "Ionis’ HAE Opportunity Boosted By Positive Phase II Data" - Scrip, 30 Mar, 2021.)