SEVILLE – Following the approval in December 2023 of the first CRISPR medicine, the cell and gene therapy field has been waiting for the next potential approval. In a plenary session at the European Society of Gene and Cell Therapy (ESGCT) devoted to in vivo therapies, Birgit Schultes, PhD, provided an update on three ongoing clinical programs conducted by Intellia Therapeutics.

An immunologist by training, Schultes was promoted to chief scientific officer in January 2025, succeeding Laura Sepp-Lorenzino, PhD, who announced she was stepping down. Since the company’s launch, Intellia has focused on in vivo delivery using lipid nanoparticles (LNPs). These offer multiple advantages to viral vectors, Schultes said, including excellent delivery to the liver, transient expression, redosing capability, scalability, biodegradability, and a large cargo capacity. Many non-clinical studies have ensured that there is no LNP delivery to germline cells, she added.

Over the past several years, Intellia has treated more than 350 patients, with some 200 patient-years’ experience and published five clinical trial papers in the New England Journal of Medicine.

In the lead

Intellia’s second program (NTLA-2002), treating hereditary angioedema (HAE), has overtaken the company’s first program, devoted to transthyretin amyloidoisis (ATTR).

HAE is a rare life-threatening disease usually diagnosed in the patient’s teens or 20s. Patients have unpredictable swelling attacks that can even lead to suffocation. There are about 6,000 HAE patients in U.S. Although some treatments are available, many patients suffer “breakthrough attacks” even while taking medication.

The goal of Intellia’s lonvo-z therapy is to inactivate the prekallikrein (KLKB1) in the liver. The goal is to achieve the same result as treatment with the C1-esterase inhibitor replacement therapy.

Schultes presented data on the two-part, multi-center study in adults with HAE types I and II. All doses of lonvo-z reduced kallikrein levels to less than 60% for durations up to and beyond two years. Other than some transient increases in liver enzyme levels, there were no serious adverse events.

Schultes showed swim plots that marked the frequency of attacks before and after therapy. “It takes a few months for the treatment to ‘settle in’,” Schultes said. Most of the ten Phase I patients were weaned off their prophylactic therapy.

Among the 27 patients in Phase II, the 50-mg dose offered the best results, with 70% of patients showing a complete response. A single dose of lonvo-z was well tolerated. The Phase II data “shows the potential of a single 50-mg dose to eliminate attacks and chronic prophylaxis,” Schultes said.

As announced last month, Intellia has now completed enrollment for its Phase III HAELO trial. Schultes said the primary data analysis should take place in mid-2026, giving the company hope that it can file a biologics license application (BLA) in Q3 next year. “We hope we still have a functional FDA,” Schultes quipped to an approving European crowd.

Unmet need

ATTR is a large growing market with significant unmet need. In partnership with Regeneron, Intellia is hoping its first clinical program launched will surpass the effectiveness of various commercial small-molecule therapies in preventing amyloid protein precipitation, including Alynylam’s vutrisiran.

In a two-part clinical study, Intellia has narrowed the range of nex-z (NTLA-2001) doses under investigation. After 24 months, most ATTR patients experienced improvements in the modified neuropathy impairment score (a metric used to assess neurological impairment)—something not seen in any other treatments, Schultes stressed.

“Patients are getting better,” she said. “Their TTR is not continuing to accumulate.” Schultes characterized the TTR reduction as “rapid, deep, consistent and durable.” Intellia hopes to wrap up this trial in 2027.

Schultes closed her talk with a brief update on the MAGNITUDE clinical trial—a large Phase III trial that is recruiting 1,200 patients with ATTR and cardiomyopathy (ATTR-CM). The goal of such a large trial is to show that Intellia’s therapy improves outcomes compared to other therapies in the clinic, Schultes said. The company hopes to complete the study in 2028 “or maybe sooner.”

In vivo insights

Schultes was joined in her plenary session by three other distinguished speakers offering updates on various in vivo gene therapy trials.

Jeffrey Chamberlain, PhD (University of Washington) provided an update on trials delivering micro-dystrophin for patients with Duchenne muscular dystrophy. The only approved gene therapy so far is Elevidys (Sarepta), which was approved by the FDA in May 2024.

Seven biotech companies are testing “different flavors of micro-dystrophin therapies,” Chamberlain said. Unfortunately, this approach “is not working nearly as well in the clinic as it has in animal models,” Chamberlain said. Reasons likely include lower levels of gene delivery; dose-limiting toxicity; cellular immune responses to dystrophin in a small fraction of patients; and potential functional limitations of the micro dystrophin.

Chamberlain’s group and others are developing more potent AAV vectors and dystrophin expression cassettes, as well as using a dual-AAV strategy involving split inteins, which overcomes the restrictions on AAV cargo space.

Indeed, Chamberlain’s group is attempting a triple-intein approach, as reported last year, to produce full-length dystrophin protein. Moreover, newer myotropic AAV vectors can deliver more dystrophin at lower and safer doses. Chamberlain said that a similar approach being tested in the clinic by Solid Biosciences (SGT-003) is showing “widespread micro-dystrophin expression.”

“It’s a promising new technology, but we’ll see whether it translates into clinical benefit,” he said.

Another approach is to focus gene targeting on muscle stem cells, so-called satellite cells. One of the limitations of AAV vectors is that they do not deliver to these stem cells.

Hear this

Ellen Reisinger, PhD (University of Tubingen, Germany) delivered a superb lecture on current progress in gene therapy for hearing loss, specifically a rare form of deafness caused by mutations in the otoferlin (OTOF) gene. Reisinger is the developer of one of several gene therapy approaches for this Mendelian disorder, which she licensed to Akouos, a company acquired by Lilly in 2022.

The ear is a good candidate for gene therapy given its architecture and the ability to obtain detailed measurements of auditory brain-stem response (ABR) as a marker of success. In the past two years, groups in China, Europe, and North America have reported results on children with OTOF deficiency—a disorder first described by French geneticist Christine Petit, PhD, in 1999. This disorder has emerged as the lowest hanging fruit in hearing loss, because unlike other genes, it can be administered after birth, and the gene is only expressed in the inner hair cells, where it is required for the fusion of synaptic vesicles.

“Gene therapy should be at least as good as cochlear implantation,” Reisinger said. Results from trials sponsored by Regeneron, Lilly, and teams in China show positive results, especially in terms of pitch perception, but no marked advantage regarding auditory perception compared to cochlear implants.

Speech comprehension outcomes will depend on protein expression levels, transduction rates, and the specifics of different languages (use of consonants, for example). Reisinger pointed to differences in AAV serotypes as the potential cause of reported trial result differences.

To be continued

Closing the session, Terry Flotte, MD, dean of the UMass Chan Medical School (and chief editor of GEN’s sister journal, Human Gene Therapy) reviewed recently published results in Nature Medicine on a Phase I-II clinical trial for GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases).

Flotte presented results using an AAV vector to treat nine children (ages 4-12 years) with escalating doses.  An infant’s skull is too pliable to use typical injections, so the clinicians rely on image-guided placement of catheters into the thalamus (using a robotic surgical assistant).

The results so far are a mixed bag. The injections are “remarkably well tolerated,” Flotte said, and seizure progression is slower. Two patients showed signs of myelin production. On the other hand, dystonia in the three juveniles continued to progress (and seemed to worsen in two of them). Some patients also showed signs of an immune response.

As Flotte and his colleagues noted in their Nature Medicine report, “With less than complete clinical efficacy and a limited ability to increase the dose further, the clinical utility of this approach is far from optimal.”

ESGCT 2025, Seville Spain: October 7-10, 2025.