In the five years since Italy-based Chiesi Group established its rare disease division in Boston, the unit has landed regulatory approvals worldwide for 10 therapies — all small molecules and engineered proteins. More recently, the company has been exploring how to grow its portfolio in ways that could have a larger and longer-lasting impact for patients. The next piece of this strategy takes the company into genetic medicines.
Chiesi Global Rare Diseases had worked with oral small molecules and enzyme replacement therapies because those were the types of drugs the company knew well, said Giacomo Chiesi, executive vice president of the rare disease unit. But he added that growth requires new modalities where the unit has no experience. The company is now adding CRISPR-based gene-editing to its toolbox, announcing this week the commitment of $115 million to begin a partnership with Arbor Biotechnologies, headquartered in nearby Cambridge, Massachusetts. The deal brings a clinical-stage rare disease therapy and access to the platform technology that created it.
“We felt like we were kind of falling behind a little bit by not being able to offer cures for patients,” Chiesi told MedCity News. “So from our perspective, this is another important tool in the set of solutions that we want to bring in a definitive way to patients in the future.”
The Arbor asset at the heart of the deal is ABO-101, a gene-editing therapy for primary hyperoxaluria type 1 (PH1). This inherited rare disease starts in the liver but manifests as problems in the kidneys. PH1 patients lack an enzyme needed to break down oxalate, a compound produced by the liver. Consequently, oxalate accumulates in the kidneys, forming kidney stones that damage the organ, Arbor CEO Devyn Smith explained. PH1 can lead to end-stage renal disease, which requires an organ transplant — a temporary solution. Because the root of the disease is in the liver, a new kidney doesn’t address excess oxalate in the body so the transplanted organ eventually becomes damaged as well.
The FDA-approved PH1 therapies currently available employ small-interfering RNA to stop production of an enzyme key to oxalate production. These genetic medicines do reduce oxalate levels, but they’re chronic therapies — Alnylam Pharmaceuticals’ Oxlumo is injected every three months while Novo Nordisk’s Rivfloza is administered once monthly. Arbor’s ABO-101 is a potential one-time treatment. It also goes beyond current approaches to gene-editing.
CRISPR first reached patients as ex vivo therapies in which the editing work is done in a lab and genetically engineered cells are infused back into the patient. Arbor’s ABO-101 does its editing work inside the patient. Its genetic cargo is encapsulated within a lipid nanoparticle, a type of particle that targets the liver. This Arbor therapy addresses the same enzyme target as the Alnylam and Novo Nordisk PH1 drugs, but uses CRISPR to knock out the gene that codes for it. Smith acknowledged the availability of chronic PH1 therapies, but says ABO-101 gives PH1 patients the opportunity to achieve freedom from the disease.
“If you think about one-and-done approaches as a parent, if my child had a chronic disease, I would much prefer to make the disease go away so they can live their life and do what they need to do and not have to have this burden of disease hanging over them for the rest of their lives,” he said.
Beyond the potential long-term durability of Arbor’s therapy, Chiesi said his company was looking to bring patients a better treatment experience. The first generation of gene-editing medicines requires a conditioning regimen to prepare a patient’s body to receive the treatment. This regimen uses toxic drugs, which can be difficult for patients, particularly children. Because Arbor’s therapy does its editing work inside the patient, preconditioning is not needed.
The field of biotechs developing in vivo gene-editing therapies includes Editas Medicines, Intellia Therapeutics, Mammoth Biosciences, Precision Biosciences, and Scribe Therapeutics. All of these companies already have partners. Arbor also has partners, though those agreements are for ex vivo therapies. Chiesi said his company spoke with several gene-editing biotechs with programs in various stages of development and selected Arbor after an 18-month due diligence process.
Arbor was not initially planning on partnering ABO-101, its most advanced program, Smith said. Earlier this year, Arbor closed a $73.9 million Series C financing to support clinical development of the PH1 program. But he added that as a startup with a platform technology, Arbor constantly fields inquiries about its technology and pipeline. Smith said partnering with Chiesi Global Rare Diseases puts ABO-101 in the hands of a company that’s committed to rare disease and brings knowledge and experience in this space. With ABO-101‘s development now being led by a partner, Arbor can focus on other indications that bring in vivo gene-editing beyond the liver. Arbor’s pipeline includes three preclinical programs, each addressing different targets for amyotrophic lateral sclerosis (ALS).
Chiesi Global Rare Diseases is starting the Arbor alliance with up to $115 million in upfront and near-term payments to its partner. The gene-editing company could receive up to $2 billion in milestone payments as well as royalties from sales of approved products that stem from the research.
ABO-101 began a Phase 1/2 clinical trial over the summer; the targeted enrollment is 23 patients. Arbor remains the sponsor of that trial, but Chiesi Global Rare Diseases will collaborate on this study and will lead future clinical tests of the therapy, Chiesi said. The agreement also grants the rare disease company the option to use Arbor’s gene-editing platform to develop novel liver-targeted therapies for rare diseases. Chiesi said those targets are predefined but remain undisclosed. The two privately held companies are also not disclosing timelines for a readout of the ABO-101 study, but Chiesi said the clinical trial and the broader partnership are proceeding with a sense of urgency.
“Patients can’t wait for new solutions — that drives both organizations,” he said. “So we’re going to be expeditious and efficient in the future clinical development.”
Illustration: libre de droit, via Getty Images
