An experimental CRISPR-based treatment from Intellia Therapeutics now has encouraging early clinical data showing it led to reductions in levels of a liver protein that drives a rare and potentially fatal swelling disorder. The results reported Friday come alongside additional data reported separately for a different Intellia CRISPR therapy addressing another protein disorder.
Both clinical trials are small studies designed to find the appropriate dose to test in larger groups of patients. But the results so far provide additional validation for Intellia’s approach, which offers the potential for one-time treatment of disease using CRISPR therapies that perform their editing work inside a patient’s body.
Intellia presented the interim results for NTLA-2002 on Friday at the 2022 Bradykinin Symposium in Berlin. The therapy is being developed as a treatment for hereditary angioedema (HAE), an inherited disorder in which fluids accumulate outside of blood vessels, leading to swelling attacks throughout the body. This swelling stems from the deficiency or dysfunction of proteins that maintain the flow of fluids through capillaries.
Cambridge, Massachusetts-based Intellia aims to treat HAE by addressing proteins associated with the manifestation of swelling attacks. One of those proteins is called bradykinin. High bradykinin levels stem from uncontrolled activity of yet another protein, kallikrein. The class of drugs called kallikrein inhibitors have already validated blocking this protein as a way of treating HAE, but these drugs are chronic therapies. (Takeda Pharmaceutical and BioCryst Pharmaceuticals have commercialized kallikrein inhibitors for HAE; KalVista Pharmaceuticals has reached Phase 3 testing with one.) By knocking out a gene in liver cells responsible for encoding kallikrein, Intellia’s NTLA-2002 could offer patients the opportunity for a one-time treatment of the disease.
The early clinical results are for six patients being evaluated with two different doses of the intravenously administered therapy—three patients for each dose. The cut-off date for these results was July 27. Intellia reported average kallikrein reductions of 65% for the low dose group and 92% in the high dose group. The company said those reductions were sustained through at least 16 weeks for the low dose and for eight weeks at the high dose.
The study is also tracking the rates of HAE swelling attacks per month. In the low dose group, Intellia said its therapy led to a 91% reduction in HAE attacks throughout a 16-week observation period. Furthermore, all three patients have been attack-free since week 10. Patients in the high-dose group have not yet completed the 16-week observation period, but Intellia said those results will be presented at the annual scientific meeting of the American College of Allergy, Asthma & Immunology (ACAAI) in November.
Intellia is making plans to continue clinical development of its HAE therapy. Based on the encouraging early data so far, Intellia said it has selected a middle dose that will be evaluated in the ongoing dose-escalation part of the Phase 1/2 study. The company said up to two doses will be selected for further testing in the larger, placebo-controlled Phase 2 portion of the clinical trial, which is expected to start in the first half of 2023.
In a research note sent to investors on Friday, William Blair analyst Raju Prasad said that by achieving greater than 80% reduction in kallikrein activity, the HAE therapy surpassed a mark that investors were looking for in order to show the therapy can beat Phase 2 results posted by an experimental Ionis Pharmaceuticals therapy. Intellia will still need to replicate its strong showing in a larger Phase 2 study, but Prasad said that based on the early results showing 92% kallikrein reduction in the high dose group, his firm sees a “high potential for these patients to show no attacks” in the data update in November.
Encouraging cardiomyopathy data for Intellia
Intellia’s first in vivo CRISP-editing gene therapy, NTLA-2001, is in Phase 1 testing in hereditary transthyretin amyloidosis (hATTR). This disease stems from genetic mutations that lead to abnormal versions of a protein called transthyretin (TTR). Those misfolded proteins build up in the body, causing complications in various tissues and organs.
In June, Intellia reported data showing the durability of the therapy in patients whose hATTR causes polyneuropathy. On Friday, the company provided highly anticipated data for patients experiencing cardiomyopathy, disease of the heart muscle that makes it difficult for the organ to pump blood. This problem can lead to heart failure.
Intellia reported interim data for 12 adults whose hATTR led to cardiomyopathy. Two different doses were tested in patients spanning three different classes of heart failure. Across those classes, NTLA-2001 led to up to 94% reductions of TTR levels in the blood by day 28 of the study. Intellia said those reductions were sustained throughout the observation period; patient follow-up ranged from two months to six months as of the July 1 cut-off date.
William Blair’s Prasad said that the greater than 90% reductions in TTR levels in the blood achieved by all 12 patients removes much of the risk for testing the low dose in the Phase 1/2 study. Further reducing the risk was the report of no new safety events. In this larger sample size at this dose, Prasad said that a single patient who previously showed elevated liver enzymes—a sign of drug toxicity—was likely an outlier.
“Given that this [adverse event] was seen only in a single patient of the 32 patients treated so far, we see potential investor concerns over safety as overblown,” Prasad said.
In an investor presentation, Intellia said it expects to complete enrollment in both the polyneuropathy and cardiomyopathy arms of the clinical trial by the end of this year. The company is also evaluating design options for potentially pivotal clinical trials testing the drug in both the nerve and heart complications of hATTR.
Photo: Sakramir, Getty Images
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