A phase 3 trial of Intellia Therapeutics’ in vivo gene editing therapy lonvoguran ziclumeran (lonvo-z) has hit its primary endpoint, leading the biotech to start a rolling submission for FDA approval.
The study randomized 80 people with hereditary angioedema (HAE) to receive lonvo-z or placebo. HAE is a rare genetic condition characterized by recurrent and potentially life-threatening swelling. Noting that overproduction of bradykinin drives the disease, Intellia bet it could improve outcomes by using CRISPR to inactivate a gene needed to produce the peptide.
Intellia’s phase 3 Haelo data validate the hypothesis, while leaving the question of whether the bet will pay off commercially unanswered. One infusion of lonvo-z reduced swelling attacks by 87% compared to placebo during the six-month efficacy evaluation period, hitting the trial’s primary endpoint.
The investor bull case was for about a 90% placebo-normalized reduction in attack rates, William Blair analysts said in a note to investors Monday. However, hitting that target depended on a very low placebo response, which the analysts said “can be tricky to navigate for more mild attacks.” Intellia beat William Blair’s 80% base case, leading the analysts to call lonvo-z a “compelling one-time option.”
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The trial met all key secondary endpoints. Intellia said 62% of patients were attack- and therapy-free in the lonvo-z arm during the six-month efficacy evaluation period, compared with 11% of patients in the placebo cohort.
The data suggest lonvo-z is at least as effective as existing treatments for HAE. Ionis Pharmaceuticals won FDA approval for Dawnzera last year after linking the antisense oligonucleotide to an 81% reduction in attacks versus placebo. Other treatments include Takeda’s blockbuster standard of care, Takhzyro, and BioCryst Pharmaceuticals’ Orladeyo.
While the existing HAE arsenal contains a mix of injectable and oral drugs, all of the treatments require people to keep taking medicines to prevent attacks. Lonvo-z could permanently reduce HAE attacks after a single dose.
“Lonvo-z appears highly differentiated given its ability to free most patients from both attacks and ongoing treatment with just one dose,” Marc Riedl, M.D., clinical director of a HAE center at UC San Diego, said on Intellia’s call with analysts to discuss the phase 3 lonvo-z data. “The efficacy observed in Haelo appears highly competitive and attractive.”
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Intellia aims to complete its rolling submission in the second half of the year, putting it on track to launch the therapy in the first half of 2027. If the FDA approves lonvo-z, Intellia will face the challenge of reassuring patients that a treatment that permanently edits their DNA is safe and a better option than existing therapies.
The most common treatment-emergent adverse events (TEAEs) during the phase 3 primary observation period were infusion-related reactions, headache and fatigue. All TEAEs were mild or moderate and no serious adverse events were observed in the lonvo-z arm.
The safety of gene editing was thrust into the spotlight last year when a patient suffered liver injury and died after receiving Intellia’s nex-z. Lonvo-z was unaffected by the resulting clinical hold. Yet Guggenheim Securities analysts said in a note to investors at the time that the safety concerns mean lonvo-z may face commercial headwinds, especially as in their view the phase 3 trial was too small to allay the worries.
Intellia CEO John Leonard, M.D., said on the Monday analyst call that one grade 2 case of elevated liver enzymes was observed. The event happened a couple of weeks after dosing, was asymptomatic and resolved spontaneously within one week. Other patients had grade 1 cases.
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Some companies have struggled to get patients to switch from ongoing treatments to one-time genetic medicines. BioMarin recently pulled its hemophilia gene therapy Roctavian from the market after failing to capture a significant share of a market served by drugs such as Roche’s bispecific antibody Hemlibra.
Even those closest to HAE patients are unsure how widely lonvo-z will be adopted. Burden of treatment is a real thing for HAE patients, Riedl said. Yet while the doctor expects patients burdened by existing drugs to “look long and hard” at lonvo-z, he said he lacks “a good sense” of what percentage will elect to have the treatment.
Shares in Intellia rose 4% to $14.20 in premarket trading.
