Liver complications lead FDA to halt testing of Intellia gene-editing therapy for rare disease

The FDA has halted clinical testing of Intellia Therapeutics' gene-editing therapy after reports that a patient in a Phase 3 study was hospitalized due to liver complications.

Intellia said the liver problems met the protocol's criteria for halting the study, and the company paused the study on Monday. The therapy, called nexiguran ziclumeran or nex-z, is an experimental treatment for the rare disease transthyretin amyloidosis (ATTR). According to Intellia, the injured patient received nex-z on September 30. On October 24, the patient developed high levels of liver enzymes and compounds indicating damage to the organ. Intellia said the FDA verbally notified the company on Wednesday that two Phase 3 tests of the experimental therapy are now on clinical hold.

In ATTR, misfolding of the liver protein transthyretin (TTR) causes amyloid to accumulate in tissues, causing problems in the body. Nex-z uses CRISPR gene-editing technology to inactivate the gene encoding the TTR protein. Nex-z has entered two Phase 3 tests, one for ATTR cardiomyopathy and the other for ATTR polyneuropathy. Patients who developed liver complications were enrolled in the cardiomyopathy study.

New ATTR drugs are gaining traction on the market. While Pfizer's drugs Vyndaqel and Vyndamax are established as the standard treatments for ATTR cardiomyopathy, the FDA's approval last year of BridgeBio Pharma's Attruby and Alnylam Pharmaceuticals' Amvuttra gives patients more options. Amvuttra was first approved in 2022 to treat ATTR polyneuropathy.

Currently available ATTR drugs are chronic treatments. Intellia's nex-z offers the potential for a one-time treatment. The company is developing nex-z in partnership with Regeneron Pharmaceuticals. Intellia leads clinical development of nex-z, while Regeneron has option to co-commercialize the therapy in the U.S.

The FDA told Intellia that a formal clinical hold letter for the nex-z Phase 3 study will be issued within 30 days. In the meantime, the company said it intends to work with the agency to “resolve the clinical hold as quickly as possible.”

Here is a review of other recent regulatory developments:

FDA and EU regulatory approvals

—— GlaxoSmithKline (GSK) multiple myeloma drug Blenrep returns to the market. Three years ago, the pharmaceutical giant withdrew its antibody-drug conjugate after its confirmatory studies as a monotherapy failed. GSK's resubmission is based on Phase 3 testing of the drug in combination with standard therapies and as an early treatment option. Despite the success of these studies, the FDA approved Blenrep as a third-line or later treatment for multiple myeloma. The drug is approved in Europe, allowing its use as second-line treatment.

— The FDA approves Bayer's Lynkuet as a treatment for moderate to severe vasomotor symptoms of menopause. Orally administered small molecules inhibit NK1 and NK3 receptors, both of which regulate body temperature. Lynkuet will compete with Astellas Pharma's menopause drug Veozah, which blocks NK3 receptors.

—Boehringer Ingelheim’s drug Jascayd received FDA approval to treat adults with idiopathic pulmonary fibrosis, a chronic and ultimately fatal lung disease. The twice-daily tablet offers a different mechanism of action than Ofev, Boehringer Ingelheim's long-standing IPF drug and bestseller.

— Rhapsido is a BTK inhibitor discovered and developed by Novartis and approved by the FDA for the treatment of chronic idiopathic urticaria, an inflammatory skin disease that causes chronic hives. The regulatory decision covers the use of the twice-daily pill in patients who have failed to respond to first-line antihistamine therapy.

— The FDA approves Crinetics' Palsonify as a first-line treatment for acromegaly, a rare endocrine disorder. The once-daily pill offers an oral alternative to injectable blockbusters from Novartis and Ipsen.

— The FDA approved Keytruda Qlex, the injectable version of Merck's immunotherapy Keytruda. The regulatory decision covers nearly all cancer indications covered by the original intravenous infusion product. Keytruda Qlex is administered by subcutaneous injection in two minutes or less compared to the half hour required for Keytruda infusion.

—Kedrion Biopharma's Qivigy received FDA approval to treat adult patients with primary humoral immunodeficiencies, a group of disorders that impair immune system function. The drug is an intravenous immunoglobulin therapy made from antibodies from healthy donors. Intravenous infusion therapy has a boxed warning on the label that warns of the risk of thrombosis, renal dysfunction, and acute renal failure. Kedrion expects Qivigy to be available in early 2026.

—Stealth BioTherapeutics The long journey of the drug elamipriptide has finally resulted in accelerated approval from the FDA, making the drug the first treatment for the extremely rare mitochondrial disease Barth syndrome. Stealth will commercialize the drug as a once-daily subcutaneous injection under the brand name Forzinity.

—The European Commission granted marketing authorization to Biogen's Zurzuvae for the treatment of postpartum depression. The drug, developed by Sage Therapeutics, is taken daily for 14 days and will be approved by the FDA in 2023. Biogen holds rights to the molecule outside the United States (excluding Japan, Taiwan and South Korea).

—The European Commission approved Deciphera Pharmaceuticals’ vimseltinib (trade name Romvimza), making it the EU’s first and only treatment for giant cell tumor of the tenosynovium. The FDA approved Romvimza in February this year. Deciphera operates as a subsidiary of Ono Pharmaceutical, which acquired the biotech company in 2024 for $2.4 billion.

— Enbumyst, Corstasis Therapeutics' diuretic bumetanide nasal spray, is FDA-approved to treat edema associated with congestive heart failure, liver disease and kidney disease. The approval was based on clinical trial results showing that its diuretic response was comparable to intravenous bumetanide.

— Johnson & Johnson's Inlexzo receives FDA approval to treat non-muscle-invasive bladder cancer. The drug/device combination product enables prolonged local delivery of gemcitabine, a chemotherapy drug.

Expanding the scope of FDA approval

—Syndax Pharmaceuticals' Revuforj is now approved to treat adults and children with relapsed or refractory acute myeloid leukemia who carry NPM1 mutations. Revuforj is an oral small molecule menin inhibitor. The drug was first approved last year to treat advanced leukemia driven by KMT2A mutations.

—Roche’s drug Gazyva is now approved to treat adults with active lupus nephritis who are receiving standard treatments. Gazyva is an antibody that binds to the CD20 protein on B cells, causing the depletion of immune cells that drive these autoimmune diseases. The drug was first used to treat certain blood cancers.

— AstraZeneca and Amgen's drug Tezspire expanded its approved uses to include treatment of chronic sinusitis in patients 12 years and older with nasal polyps. This is the first biologic approved for this indication. Tezspire was first approved in 2021 to treat asthma.

—Regeneron Pharmaceuticals drug Libtayo expands FDA-approved indications to include use as adjuvant treatment for cutaneous squamous cell carcinoma. Regeneron said the new FDA decision makes Libtayo the first immunotherapy approved as an adjuvant for this common skin cancer. Adjuvants are used after initial treatment to prevent cancer from coming back.

—Jazz Pharmaceuticals' drug Zepzelca has expanded FDA approval to include first-line treatment of extensive-stage small cell lung cancer when used with Roche's immunotherapy Tecentriq. Zepzelca is an intravenous drug first approved in 2020 to treat metastatic small cell lung cancer.

— Johnson & Johnson's biologic drug Tremfya's label now includes treatment for pediatric patients with plaque psoriasis and active psoriatic arthritis. Tremfya is an antibody designed to block IL-23, a signaling protein associated with inflammation. The new approval makes the drug the first IL-23 inhibitor approved for use in pediatric patients for these indications.

— Vyjuvek, Krystal Biotech’s gene therapy for the rare genetic skin disease dystrophic epidermolysis bullosa, is now available to treat newborn children. Updates to topical gel labeling also provide patients with full flexibility in product application. When Vyjuvek was first approved by the FDA in 2023, the regulatory decision covered patients 6 months of age and older, and the product could only be used by clinicians.

— Incyte's atopic dermatitis drug Opzelura has expanded FDA approval to include treatment of children ages 2 to 11. The FDA approved Opzelura in 2021, covering its use in patients 12 years and older.

Complete response letters and other regulatory setbacks

— The FDA rejected Xspray Pharma's application seeking approval of Dasynoc to treat chronic myelogenous leukemia and acute lymphoblastic leukemia. The FDA flagged issues with the drug's contract manufacturer, according to the company. Although there were no problems with the Dasynoc production line, the FDA suspended approval of the product produced at the plant until corrective actions are taken.

—The full response letter for Sentynl Therapeutics’ CUTX-101 drug also cited production issues. The drug was developed to treat Menkes disease, a rare disease caused by mutations in the gene encoding ATP7A, a copper transporter. The FDA's letter did not raise any concerns about the effectiveness or safety of Sentynl therapy.

— The FDA rejected Scholar Rock's application seeking approval of apitegromab to treat spinal muscular atrophy. The only approval issues cited were manufacturing issues at contract manufacturer Catalent's Indiana filling and processing plant, which is now owned by Novo Nordisk, according to the biotech company. The site has dismissed other regulatory submissions. The FDA cited problems at the Indiana plant this summer in a letter rejecting Regeneron Pharmaceuticals' drug.

— Partners Otsuka Pharmaceuticals and Lundbeck have encountered setbacks in expanding Rexulti into the treatment of post-traumatic stress disorder when it was used with the antidepressant sertraline. The FDA's full response letter said the application lacked sufficient evidence of effectiveness, according to the companies. In July, an FDA advisory committee voted that efficacy had not been established. The companies said they will review the letter with the FDA to determine next steps.

—Saol Therapeutics received a complete response letter for SL1009, a drug used to treat pyruvate dehydrogenase complex deficiency, an extremely rare mitochondrial disease affecting children. The company did not describe the observations cited by regulators, saying only that they did not involve manufacturing. Saol said it is looking for a path forward that does not require another clinical trial.

— Ocaliva, a drug from Intercept Pharmaceuticals that received accelerated FDA approval in 2016 as a second-line treatment for the rare liver disease primary biliary cholangitis, has been voluntarily withdrawn from the market. Intercept said the move came at the request of the FDA, which had raised safety concerns about the product.

Photo: Streeter Lecka, Getty Images