Orphan Therapeutics Accelerator In-Licenses Its First Gene Therapy, Eyes Pipeline Expansion

Recently, the Orphan Therapeutics Accelerator (OTXL) announced an agreement with UCL Ventures, the commercialization company of University College London (UCL), and Children’s Medical Research Institute (CMRI) to in-license an investigational therapy program for ornithine transcarbamylase deficiency (OTCD), a rare, X-linked metabolic disorder. The drug candidate in question, now dubbed OTXL-101, was formally known as AAVLK03hOTC. It was developed through a collaboration between Paul Gissen, MBCHB, PhD, and the OTCD project team at University College London, and Ian Alexander, MBBS, PhD, and his team at CMRI. 

This marks the first therapy in-licensed by OTXL, a nonprofit biotech set up specifically to utilize tax and other incentives to “liberate and reininitiate development of shelved therapies for rare and ultra rare conditions” that have been shelved in recent years for various reasons, according to Craig Martin, OTXL’s CEO and co-founder. 

The nonprofit biotech is one part of a four-pronged approach targeting shelved cell and gene therapies. The other parts include the Orphan ClinDevNet, a network of affiliated contract development and manufacturing organizations, contract research organizations, and other partners who have agreed to work under reduced-cost, success-based agreements. 

Approved products can be commercialized through Orphan Therapies, OTXL’s commercial subsidiary, which was established a year ago, or outlicensed to biotech or biopharma partners. Recently, Orphan Therapies established commercial availability for an ex vivo cell therapy for patients with Wiskott-Aldrich syndrome. 

Finally, support for OTXL and other programs in need of financing or partners can be accelerated and facilitated through CGTxchange, an artificial intelligence-enabled marketplace, diligence, and deal-making platform established through a joint venture between OTXL and the American Society of Gene & Cell Therapy (ASGCT). It serves as a marketplace for shelved therapies with potential that could be picked up by both traditional and non-traditional kinds of investors or funders.

In fact, OTXL-101 was initially identified with the help of the platform that now underlies CGTxchange, according to Martin. He told GEN that prior to in-licensing OTXL-101, the OTXL team looked at more than 80 different therapeutic programs. “We first started looking at it almost two years ago,” he said. At the time, OTXL-101 was outlicensed to Bloomsbury Genetic Therapies, which had initiated a Phase I/II study dubbed the Halting Ornithine transcarbamylase deficiency with Recombinant AAV in Children or HORACE trial. 

The first patient, a 10-year-old male with late-onset OTCD, was treated at Great Ormond Street Hospital in December 2023. The plan was to run a 12-patient trial, however when the Bloomsbury Genetic Therapies shut down in 2025, the program was returned to UCL and CMRI. Preliminary results from the first patient were presented at the 2025 ASGCT annual meeting.

OTXL had moved on to other candidates at the time, Martin said, but when the initial plans for the treatment fell through, and the therapy was returned to UCL and CMRI, they reconsidered. “We started negotiating with them and found everybody was really feeling like this was a therapy that needed to get to patients. And we were able to structure the deal in such a way that it really fit our model and provided a more viable path forward for the therapy,” he said. 

A rare disease therapy gets a new life

Ornithine transcarbamylase deficiency or OTCD is caused by mutations in the OTC gene that reduce or eliminate ornithine transcarbamylase activity. This enzyme is essential to the liver’s urea cycle, which converts toxic ammonia from protein metabolism into urea for elimination. When ammonia builds up in the blood, it can cause hyperammonemic decompensations, brain injury, and coma. 

The condition is currently managed medically by protein restriction, nitrogen-scavenging medicines, and amino acid supplements. But patients remain at risk for elevated blood ammonia and serious complications. Another option is liver transplantation which can restore metabolic control but carries surgical risks and requires lifelong immunosuppression. Estimates from Orphanet indicate that its birth frequency ranges from approximately one in 56,500 to one in 113,000 live births. 

If it passes further testing and is approved, OTXL-101 could be an important treatment tool. To treat OTCD, OTXL-101 uses a liver-targeted adeno-associated virus vector to deliver a functional OTC gene and restore urea cycle activity. The gene therapy is intended to treat children and adolescents with OTCD and has received U.S. and EU orphan drug designations as well as a U.S. rare pediatric disease designation. 

This initial clinical evidence of the efficacy of OTXL-101, which now spans more than two and a half years, “gives us a sense of its potential to benefit patients,” Martin said. In his conversation with GEN, he explained: The data showed that following treatment with the gene therapy, the patient had successfully been taken off Ravicti, a prescription nitrogen-binding medicine for long-term management of high ammonia levels, as well as off of a restricted diet. And they have continued to do well. 

The type of evidence that OTXL will consider for future in-licensed candidates and therapies that are included in the CGTxchange will vary, Martin said. For one thing, not all rare disease therapies will have years of post-treatment data on patients as that will depend on factors such as when the trials were stopped or suspended and their specific endpoints. In general, “the criteria that are most important to us are ‘is this an area of high unmet medical need? Is it a therapeutic approach that we have a good understanding of and based on evidence from clinical trials, wherever they are in that process?’” he said. Other pertinent questions focus on who the partners involved are and whether they can work with OTXL. 

In terms of OTXL-101, “we are going through the process of doing stability and potency testing on the material that had been manufactured for the trial,” Martin said. Also, “we’ve done some other things related to extending patents in a number of countries so that we know we’ve got the ability to provide access in a variety of places.” Finally, the therapy will be listed on the CGTxchange. “We have some of the funds required to continue to move it forward, but we’d like to be able to have a set of funding that would allow us to extend ideally past the next inflection point,” Martin explained. 

Meanwhile, OTXL is exploring other candidates for potential in-licensing deals. “We’re actually in some conversations now and not just around the clinical stage, but also other commercial-stage or commercial products that we might be able to help move forward,” Martin said. It is important to note here that OTXL is modality agnostic and is willing to consider other kinds of treatment approaches beyond cell and gene therapies. Martin pointed to the team’s recent work on the ex vivo cell therapy for patients with Wiskott-Aldrich syndrome. “If there are other therapies like that out there where the traditional commercial model just doesn’t work for big biotechs or biopharma companies, those would be good candidates for us to … put into our existing infrastructure and move forward.”

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