Lonvoguran

Shares in Intellia rose 4% to $14.20 in premarket trading. \n 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.” 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.” 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 from septic shock following rupture in the intestine 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. 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. 

An experimental treatment that uses CRISPR to edit genes directly inside the body has just succeeded in a Phase 3 trial — a first for the technology — putting it on track for a potential FDA approval in the first half of next year. The therapy, made by Intellia Therapeutics, uses the molecular scissors of CRISPR to break a gene that contributes to disfiguring and dangerous swelling attacks in people with hereditary angioedema. The one-time infusion reduced those attacks by 87% compared to placebo, the company announced Monday morning. “This is truly a first,” Intellia CEO John Leonard told Endpoints News . It’s one of the biggest milestones yet for CRISPR, a nearly 14-year-old technology that has promised to bring cures to thousands of diseases. But as in vivo gene editing gets closer to becoming a bona fide drug, skepticism about how big a role the technology will have in medicine and this disease has grown. “This example is indicative of what’s entirely possible for CRISPR-based therapy,” Leonard said. Known as lonvo-z, the therapy is given as a one-time infusion over four hours. It comprises many little packages of gene editors designed to inactivate a gene that encodes a precursor to a protein called kallikrein. When activity of that protein gets out of control, it leads to the swelling attacks characteristic of HAE and which can be deadly when they constrict the airways. Intellia’s Phase 3 trial included 80 patients, 52 of whom received lonvo-z and the rest who received placebo. Most patients were taking chronic preventive treatments prior to enrolling, but had to stop in the weeks leading up to the CRISPR infusion. The data are promising — the 87% decrease is similar to what’s seen with other effective long-term preventive therapies for HAE. At six months, 62% of patients who received lonvo-z had been entirely attack-free and therapy-free, compared to 11% in the placebo arm. Earlier in the drug’s development, Leonard told Endpoints that the treatment “may be a functional cure.” But he was more cautious in interpreting the new data. “Cure is a very loaded word,” Leonard said. “We’ll leave it to the experts to decide how they determine that for any one of their patients.” Massachusetts General Hospital’s Aleena Banerji, who was an investigator on the Phase 3 trial, gave a more straightforward answer. To her, the treatment’s not a cure. “It’s not zero attacks,” she said. In the HAE study, Intellia reported only mild-to-moderate safety events, the most common of which were infusion-related reactions, headache and fatigue. Last year, a patient who received a different gene editing treatment from Intellia for a different disease faced serious liver injury and subsequently died. Two studies of that therapy were paused for several months by the FDA, though those holds have since been lifted. Intellia’s therapies are all based on the same gene editing enzyme, Cas9, and use the same lipid nanoparticle formulation to deliver the treatment to the liver. But Leonard noted that the HAE patient population is generally younger and healthier, and that the therapies target different genes. Intellia, headquartered in Cambridge, MA, intends to submit an application for approval to the FDA in the second half of this year, and if all goes as planned, it expects to launch the therapy in the US in the first half of next year. People with hereditary angioedema already have a growing number of treatments, including several medicines intended to prevent attacks. If Intellia’s treatment is approved, it will have to compete with daily pills, antibodies administered every two to four weeks, and an RNA-based drug injected every four or eight weeks. Other treatments are in the works too, and investors have increasingly questioned whether doctors, patients and payers will believe that a one-time solution is worth the costs and inherent risks associated with permanently altering DNA. But to Banerji, the gene editing therapy has potential to substantially lower the burden of treatment on patients, who may need regular therapies to prevent attacks as well as on-demand ones to treat them. “The idea of a one-time treatment that really could significantly decrease the risk of attacks and not necessarily require ongoing long-term prophylaxis, which has a burden of treatment itself,” Banerji said, “I think that’s most exciting.” An approval is no sure thing, though. Regulators have often scrutinized therapies based on entirely new technologies, and the FDA has been slower than regulators in other countries to let companies start trials of gene editing therapies. Monday’s results suggest Intellia’s technology works, and works well. Now the company faces a potentially even bigger challenge: making gene editing a business. Endpoints is fielding the next Biopharma Sentiment Index (BPSI) — a concise, three-minute survey that distills thousands of industry views into a clear quarterly benchmark. This year is pivotal for biopharma, and we need your perspective on where things are going. Take the survey here.