An experimental CRISPR-based treatment from Intellia Therapeutics is already promising early clinical data show that it leads to a decrease in the levels of a liver protein that causes a rare and potentially fatal swelling disorder. The results reported Friday come alongside additional data reported separately for a different Intellia CRISPR therapy targeting 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 further validation for Intellia’s approach, which offers the potential for a one-time treatment of disease using CRISPR therapies that carry out their editing inside the 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 disease in which fluid builds up outside the blood vessels, leading to bouts of swelling throughout the body. This swelling results from the deficiency or dysfunction of proteins that maintain fluid flow through the capillaries.
Cambridge, Massachusetts-based Intellia aims to treat HAE by targeting proteins associated with the occurrence of swelling attacks. One of these proteins is called bradykinin. High levels of bradykinin result from uncontrolled activity of yet another protein, kallikrein. The class of drugs called kallikrein inhibitors have already validated blocking this protein as a way to treat HAE, but these drugs are chronic therapies. (Takeda Pharmaceutical and BioCryst Pharmaceuticals have marketed kallikrein inhibitors for HAE; KalVista Pharmaceuticals has reached Phase 3 testing by one.) By knocking out a gene in liver cells responsible for coding for kallikrein, Intellia’s NTLA-2002 could offer patients a one-time cure for the disease.
Early clinical results are for six patients evaluated with two different doses of IV therapy – three patients for each dose. The closing date for these results was July 27. Intellia reported a mean reduction in kallikrein of 65% for the low-dose group and 92% in the high-dose group. The company said these reductions were sustained for at least 16 weeks for the low dose and eight weeks for the high dose.
The study also tracked the frequency of HAE swelling attacks per month. In the low-dose group, Intellia said its therapy resulted in a 91 percent reduction in HAE attacks over a 16-week observation period. Additionally, all three patients have been seizure-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 American College of Allergy, Asthma and Immunology (ACAAI) annual scientific meeting in November.
Intellia plans to continue clinical development of its HAE therapy. Based on the encouraging early data so far, Intellia said it has selected an intermediate dose that will be evaluated in the ongoing dose-escalation portion of the Phase 1/2 study. The company said up to two doses will be selected for further testing in the larger, placebo-controlled part of the phase 2 clinical trial, which is expected to begin in the first half of 2023.
In a research note sent to investors on Friday, William Blair analyst Raju Prasad said that by achieving more than an 80% reduction in kallikrein activity, the HAE therapy exceeded the mark that investors had been looking for to show that the therapy could beat the Phase 2 results published by Ionis Pharmaceuticals’ experimental therapy. Intellia will still need to replicate its strong performance in a larger Phase 2 study, but Prasad said that based on early results showing a 92% reduction in kallikrein in the high-dose group, his company sees “high potential for these patients to show no attacks” in the November data update.
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 results from genetic mutations that result in abnormal versions of a protein called transthyretin (TTR). These misfolded proteins accumulate in the body, causing complications in various tissues and organs.
In June, Intellia reported data showing durability of therapy in patients whose hATTR causes polyneuropathy. On Friday, the company provided long-awaited data on patients with cardiomyopathy, a 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 on 12 adults whose hATTR resulted in cardiomyopathy. Two different doses were tested in patients spanning three different classes of heart failure. In these classes, NTLA-2001 resulted in up to a 94% reduction in blood TTR levels by day 28 of the study. Intellia said these reductions persisted throughout the observation period; patient follow-up ranged from two months to six months from the July 1 end date.
William Blair’s Prasad said the greater than 90% reductions in blood TTR levels achieved by all 12 patients removed much of the risk of testing the low dose in the phase 1/2 study. Further mitigating the risk was the report of no new safety events. In this larger sample size at this dose, Prasad said the one patient who had previously shown elevated liver enzymes — a sign of drug toxicity — was likely an outlier.
“Given that this [adverse event] was observed in only one patient out of 32 patients treated so far, we consider the safety concerns of potential investors to be exaggerated,” said Prasad.
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 neural and cardiac complications of hATTR.
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