An experimental CRISPR-based medicine from Intellia Therapeutics reduced biological markers of disease and relieved symptoms in patients with a rare condition called hereditary angioedema.
Results from an early-stage clinical trial, presented at a medical meeting Friday, showed Intellia’s gene editing treatment, known as NTLA-2002, lowered levels of a protein implicated in the disease by an average of 65% and 92% among six patients given a low or a high dose, respectively.
For the three patients on the lower dose, who were followed for four months afterwards, treatment cut by 91% the number of inflammatory attacks they experienced. These attacks, which are painful and life-threatening, are a hallmark of the disease, often abbreviated as HAE.
Intellia’s results add to an early, but growing, body of evidence indicating CRISPR gene editing within the body may be a safe and effective way to treat disease.
The biotechnology company’s data last year in a disease called transthyretin amyloidosis, or TTR, were viewed as a landmark moment for the Nobel Prize-winning technology. They proved that genetic instructions for CRISPR editing tools could be shuttled into a patient’s cells, where they cut DNA encoding a harmful protein and reduced its production.
Intellia achieved that goal by building on the progress of others like Alnylam Pharmaceuticals, which validated a genetic target for TTR and spent years figuring out how to develop a drug that could stifle it. Intellia went after the same target but used CRISPR gene editing, aiming to provide a one-time fix for a disease that currently requires chronic therapy.
Intellia is now following a similar blueprint with HAE.
Drugs from Takeda, CSL and others are approved to treat or prevent the disease’s swelling attacks. But they have limitations, as they don’t completely ward off the attacks and must be taken for life. Still, they’ve proven that lowering production of plasma kallikrein — a protein involved in blood clotting and other processes — can lead to fewer swelling episodes.
The data Intellia presented Friday are the first indication NTLA-2002 can do that, too, by making a cut to a gene that encodes for kallikrein. The results are limited by the small number of patients involved and short follow-up, however.
“We have already observed within only weeks of dosing just how profoundly genome editing can impact the disease itself,” said Intellia CEO John Leonard on a conference call Friday.
The study was designed to test whether treatment is safe and to help find the best dose to advance into further testing. Still, the results give an early glimpse of NTLA-2002’s effectiveness, allowing preliminary comparisons to existing treatments.
The three patients who received the low dose had experienced an average of 1 to 7 attacks per month in a screening period prior to the study’s start. Two of the three haven’t had an attack since being treated. The third, who began the study with a much higher monthly attack rate, has been attack free since week 10 post-treatment.
Two patients were able to stop taking preventive drugs, while the other wasn’t receiving prophylactic treatment after getting NTLA-2002.
Data on the attack rates for the three patients on the high dose aren’t yet available and will be presented in November, Intellia said.
Importantly, treatment did not lead to a significant increase in liver enzymes in any patients, which was a concern previously highlighted by analysts. Intellia did report low-grade and short-lived liver enzyme spikes in some patients, though.
Liver enzyme elevations can be a warning sign of more serious side effects and, last month, Intellia altered the design of its TTR trial due to increased liver enzyme counts.
Nonetheless, the results met expectations. Luca Issi, an analyst at RBC Capital Markets, wrote in a note to clients that Intellia’s results surpassed protein and attack rate reductions seen in testing of drugs from Takeda and Ionis Pharmaceuticals. In those studies, patients’ kallikrein levels were lowered by about 60% to 70% and attack rates by 73% to 90%, according to Issi.
Intellia is now testing a mid-range dose and plans to enroll more patients in a Phase 2, placebo-controlled portion of the study that should begin next year. Chief medical officer David Lebwohl noted that breakthrough attacks have historically been observed in patients with 60% reductions in kallikrein, and Intellia is aiming higher.
“Our objective would be to eliminate all attacks,” said CEO Leonard. “That's certainly what we're shooting for.”
Despite the data, shares in Intellia sank in early trading Friday. During its conference call, Intellia noted that the liver enzyme elevation previously reported in the TTR trial was judged to be a more serious "Grade 4," or potentially life-threatening, adverse event. The patient was asymptomatic, Intellia confirmed to BioPharma Dive in an email after publication.
Separately on Friday, Intellia reported additional results for its TTR medicine in patients with a form of the disease that affects the heart rather the nerves, which was the focus of the company’s first readout. Data showed two tested doses of Intellia’s drug lowered levels of a protein associated with disease progression by over 90%.