Tafamidis Meglumine

In one of the most closely-watched arenas in biotech, Intellia says its gene editing treatment for a heart muscle disease can stabilize or improve outcomes where other treatments have only been shown to slow the disease’s progression. But results are from a small, early-stage study with no comparison group and must be replicated in a larger Phase 3 trial. On Saturday, the Cambridge, MA-based company presented the first clinical outcomes from 36 patients in a Phase 1 study of its gene editing treatment nex-z for ATTR amyloidosis with cardiomyopathy, a disease in which misfolded proteins build up in the heart. On the six-minute walk test, a common tool used in heart and lung disease trials, patients who received nex-z saw a median 5-meter improvement one year after treatment. In addition, Intellia reported that 92% of the patients saw either improvement or no change in their New York Heart Association class. Intellia CEO John Leonard highlighted that the patients enrolled in the Phase 1 study saw disease stasis — or, in some cases, improvement — despite how a greater proportion of patients had more advanced disease compared to key studies of other therapies that have been shown to slow down the progression of ATTR cardiomyopathy. That includes Alnylam’s pivotal trial readout earlier this year of an RNA silencing drug for ATTR cardiomyopathy, which was dubbed by some to be the biggest biotech readout of 2024. “This is encouraging, but it does not yet rise to a level where we would say, ‘OK, there is a very clear signal that we are actually improving how patients are doing.’ That’s because of the open-label nature, the small sample size,” said Ahmad Masri, director of the Hypertrophic Cardiomyopathy Center at Oregon Health & Science University. “Nonetheless, it is very exciting,” he added. Masri was not involved with the Phase 1 study, but is an investigator on a Phase 3 study that’s currently ongoing. The Phase 1 outcomes were presented at the American Heart Association scientific meeting on Saturday and concurrently published in the New England Journal of Medicine . Intellia is now running a much larger 765-patient Phase 3 study called MAGNITUDE comparing nex-z to placebo in ATTR cardiomyopathy. “This is, in a way, the first time ever we have a treatment that can suppress TTR to this degree. Whether this extra suppression of TTR is adding value or not — that’s where the question is, and that’s what the MAGNITUDE trial hopefully can answer,” Masri said. At one year, the mean TTR reduction in the Phase 1 study was 90%. Intellia’s treatment nex-z is designed to use gene editing to inactivate the gene that encodes for a protein called transthyretin, which is behind the buildups that accumulate in the heart. Currently, Pfizer’s tafamidis, which is marketed as Vyndamax or Vyndaqel, is the only drug approved to treat ATTR cardiomyopathy and last year generated $3.3 billion in sales. But two new drugs are expected to reach the market soon — BridgeBio’s acoramidis and Alnylam’s vutrisiran. AstraZeneca and partner Ionis are also running a Phase 3 study of an experimental treatment for the heart muscle disease. Intellia also shared additional data on nex-z in the form of the disease that causes nerve damage, called ATTR polyneuropathy. In 33 patients who received a dose of 0.3 mg/kg or higher, the mean TTR reduction was 91%. Intellia likewise pointed to early trends in clinical measures that suggested the disease stabilized or improved in a small group of patients. Intellia is developing nex-z as part of a larger collaboration with Regeneron.

Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) presents with symptoms primarily related to heart failure and impaired cardiac function. Credit: Rawpixel.com via Shutterstock. Intellia Therapeutics has announced early-stage clinical data suggesting that its investigational gene editing treatment may stabilise or improve outcomes for patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM), a rare and progressive heart condition. The Phase I study (NCT04601051), involving 36 patients, showed that one year after a single dose of NTLA-2001 (nexiguran ziclumeran), patients experienced a median five-meter improvement in the six-minute walk test – a common measure of lung and heart function. Additionally, 92% of patients either improved or maintained their New York Heart Association (NYHA) class, a key metric for assessing heart failure severity. The US-based company presented the data at the 2024 American Heart Association scientific meeting on Saturday 16 November in Chicago. Intellia’s CEO John Leonard said in a statement that these early results provide evidence that NTLA-2001 has the potential to modify the progression of ATTR amyloidosis. “The stability or improvement observed after a single dose of NTLA-2001 in multiple markers of cardiac disease progression is remarkable, especially considering the high proportion of patients with cardiomyopathy who had advanced heart failure,” Leonard said. “We observed similarly positive and consistent trends, indicative of a disease-modifying effect, in patients with hereditary ATTR amyloidosis with polyneuropathy.” ATTR amyloidosis occurs when misfolded transthyretin (TTR) proteins accumulate in the heart, impairing its function. NTLA-2001 employs clustered regularly interspaced short palindromic repeat (CRISPR) technology to inactivate the TTR gene, reducing the production of the problematic protein. The Phase I study showed a mean TTR reduction of 90% after one year. Intellia is now evaluating NTLA-2001 in the pivotal 765-patient Phase III MAGNITUDE trial (NCT06128629), which is comparing the investigational CRISPR therapy to a placebo in ATTR-CM. The first patient was dosed in the randomised, double-blind trial in March 2024. NTLA-2001 is being developed in collaboration with Regeneron. Intellia and the US biotech initially teamed up in 2016, but the companies entered an expanded research collaboration in October 2023. This move helped extend Intellia’s cash runway through to 2026. In 2019, Pfizer secured US Food and Drug Administration (FDA) approval for Vyndamax (tafamidis) and Vyndaqel (tafamidis meglumine) – the only currently approved therapies for ATTR-CM. The drugs pulled in $3.3bn in sales in 2023, as per Pfizer’s financials. However, sales are expected to drop to $1.9bn by 2030 due to patent expiry in 2026, as per GlobalData, the parent company of Pharmaceutical Technology. GlobalData market analysts predict that NTLA-2001 could generate up to $1.2bn in revenue for Intellia by 2030. The announcement comes as competition in the ATTR CM treatment space intensifies. Two new drugs – BridgeBio’s acoramidis and Alnylam’s vutrisiran – are gearing up for approval after successful Phase III readouts . Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva . Editorial content is independently produced and follows the highest standards of journalistic integrity. Topic sponsors are not involved in the creation of editorial content. Free Whitepaper Optimise your cell therapy process: a guide to cell thawing Typically carried out at the point of care, errors in cell therapy thawing could compromise treatment efficacy, leading to significant patient impact as well as high costs and a compromised reputation for the product’s developer. This guide addresses how cell thawing has historically developed into the new techniques used today, along with the physical and biological implications of key metrics and components such as warming rate and ice structure. Also included are reviews of key studies from scientific literature and a consideration of the interactions between cooling and warming rates, as applicable to cell and gene therapies. Thank you. You will receive an email shortly. Please check your inbox to download the Whitepaper. By Cytiva Thematic By downloading this Whitepaper, you acknowledge that GlobalData may share your information with Cytiva Thematic and that your personal data will be used as described in their Privacy Policy