Amyloid Neuropathies

CAMBRIDGE, Mass., March 18, 2024 (GLOBE NEWSWIRE) -- Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading clinical-stage gene editing company focused on revolutionizing medicine with CRISPR-based therapies, today announced the first patient dosed in the global pivotal, Phase 3 MAGNITUDE trial of NTLA-2001. NTLA-2001 is an investigational in vivo CRISPR-based therapy designed as a single-dose treatment to inactivate the TTR gene and thereby prevent the production of TTR protein for the treatment of transthyretin (ATTR) amyloidosis. The MAGNITUDE trial is evaluating the efficacy and safety of NTLA-2001 in patients with ATTR amyloidosis with cardiomyopathy. “Dosing of the first patient in the MAGNITUDE trial of NTLA-2001 puts us one step closer to bringing a potential one-time gene editing treatment to people living with ATTR amyloidosis,” said Intellia President and Chief Executive Officer John Leonard, M.D. “With multiple sites now enrolling patients, including in the U.S., we are off to a great start to rapidly enroll this landmark study. MAGNITUDE was informed by the compelling interim Phase 1 results reported last year. These data showed that a single-dose treatment of NTLA-2001 resulted in deep and durable reductions of the TTR protein responsible for the clinical consequences of the disease. We look forward to evaluating the efficacy and safety of NTLA-2001 in patients with cardiomyopathy in the pivotal Phase 3 trial. Assuming a positive outcome, it will pave the way for future global marketing applications, ultimately supporting our goal to bring forth a groundbreaking therapy for the ATTR amyloidosis community.” “The diagnosis of ATTR amyloidosis, a life-threatening condition leading to heart failure and other complications, is rapidly increasing,” said Julian Gillmore, M.D., Ph.D., Professor of Medicine, National Amyloidosis Centre, UCL Division of Medicine, Royal Free Hospital, U.K., and the Phase 3 study’s national coordinating investigator. “We, along with our colleagues at Richmond Pharmacology, are thrilled to be the first to dose a patient in the pivotal trial of NTLA-2001, an in vivo CRISPR-based treatment that offers the potential to dramatically reset the standard of care for people living with this devastating disease. There is remarkable interest from the ATTR amyloidosis patient community for a potential single-dose treatment, and we look forward to contributing to the advancement of novel treatment approaches.” About the MAGNITUDE Study The pivotal Phase 3 MAGNITUDE clinical trial is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of NTLA-2001 in approximately 765 patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). The primary endpoint of the study is a composite endpoint of cardiovascular (CV)-related mortality and CV-related events. Adult patients with hereditary or wild type ATTR-CM will be randomized 2:1 to receive a single 55 mg infusion of NTLA-2001 or placebo. For more information on MAGNITUDE (NCT06128629), please visit clinicaltrials.gov. About NTLA-2001Based on Nobel prize-winning CRISPR/Cas9 technology, NTLA-2001 has the potential to become the first one-time treatment for transthyretin (ATTR) amyloidosis. NTLA-2001 is designed to inactivate the TTR gene that encodes for the transthyretin (TTR) protein. NTLA-2001 is the first investigational CRISPR therapy to be administered systemically to edit genes inside the human body. Interim Phase 1 clinical data showed the administration of NTLA-2001 led to consistent, deep and long-lasting transthyretin (TTR) reduction. Intellia leads development and commercialization of NTLA-2001 as part of a multi-target discovery, development and commercialization collaboration with Regeneron. About Transthyretin (ATTR) Amyloidosis Transthyretin amyloidosis, or ATTR amyloidosis, is a progressive and fatal disease. Hereditary ATTR (ATTRv) amyloidosis occurs when a person is born with mutations in the TTR gene, which causes the liver to produce structurally abnormal transthyretin (TTR) protein with a propensity to misfold. These damaged proteins build up as amyloid in the body, causing serious complications in multiple tissues, including the heart, nerves and digestive system. ATTRv amyloidosis predominantly manifests as polyneuropathy (ATTRv-PN), which can lead to nerve damage, or cardiomyopathy (ATTRv-CM), which can lead to heart failure. Some individuals without the genetic mutation produce non-mutated, or wild-type, TTR proteins that become unstable over time, misfolding and aggregating in disease-causing amyloid deposits. This condition, called wild-type ATTR (ATTRwt) amyloidosis, primarily affects the heart. There are an estimated 50,000 people worldwide living with ATTRv amyloidosis and between 200,000 and 500,000 people with ATTRwt amyloidosis. There is no known cure for ATTR amyloidosis and currently available medications are limited to slowing accumulation of misfolded TTR protein. About Intellia Therapeutics Intellia Therapeutics, Inc. (NASDAQ:NTLA) is a leading clinical-stage gene editing company focused on revolutionizing medicine with CRISPR-based therapies. The company’s in vivo programs use CRISPR to enable precise editing of disease-causing genes directly inside the human body. Intellia’s ex vivo programs use CRISPR to engineer human cells outside the body for the treatment of cancer and autoimmune diseases. Intellia’s deep scientific, technical and clinical development experience, along with its people, is helping set the standard for a new class of medicine. To harness the full potential of gene editing, Intellia continues to expand the capabilities of its CRISPR-based platform with novel editing and delivery technologies. Learn more at intelliatx.com and follow us @intelliatx. Forward-Looking Statements This press release contains “forward-looking statements” of Intellia Therapeutics, Inc. (“Intellia” or the “Company”) within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, but are not limited to, express or implied statements regarding Intellia’s beliefs and expectations regarding: the safety, efficacy, success and advancement of its clinical program for NTLA-2001 for transthyretin (“ATTR”) amyloidosis pursuant to its clinical trial applications and investigational new drug submission, including its ability to rapidly enroll and complete the Phase 3 Magnitude study; the success of its Phase 3 Magnitude study; its submission of global marketing applications; and its ability to bring forth NTLA-2001 as a groundbreaking therapy to the ATTR amyloidosis community and dramatically reset the standard of care. Any forward-looking statements in this press release are based on management’s current expectations and beliefs of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: risks related to Intellia’s ability to protect and maintain its intellectual property position; risks related to Intellia’s relationship with third parties, including its licensors and licensees; risks related to the ability of its licensors to protect and maintain their intellectual property position; uncertainties related to the authorization, initiation, enrollment and conduct of studies and other development requirements for its product candidates, including NTLA-2001; the risk that any one or more of Intellia’s product candidates, including NTLA-2001, will not be successfully developed and commercialized; and the risk that the results of preclinical studies or clinical studies, such as the Phase 1 clinical study of NTLA-2001, will not be predictive of future results in connection with future studies for the same product candidate or Intellia’s other product candidates. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause Intellia’s actual results to differ from those contained in the forward-looking statements, see the section entitled “Risk Factors” in Intellia’s most recent annual report on Form 10-K as well as discussions of potential risks, uncertainties, and other important factors in Intellia’s other filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Intellia undertakes no duty to update this information unless required by law. Intellia Contacts: Investors:Ian KarpSenior Vice President, Investor Relations and Corporate Communicationsian.karp@intelliatx.com Lina LiSenior Director, Investor Relations and Corporate Communications lina.li@intelliatx.com Media:Matt CrensonTen Bridge Communicationsmedia@intelliatx.commcrenson@tenbridgecommunications.com

Researchers have translated a cutting-edge tactic for treating genetic disorders into a fresh approach for potentially stymying cancer. Cell division is the generative spark of nearly every lifeform on Earth. But if healthy growth goes unchecked, cell division can turn lethal, overwhelming the organism. Such is the case with so-called oncogenes. When altered by a mutation, these growth-moderating genes go haywire, producing a geyser of cancer cells as a result. Oncogenes are also insidiously adept at generating tumors that over time become genetically "independent" from their origin, so it has been exceedingly difficult for scientists to shut down their replication at the source. Now Rockefeller University researchers have discovered a new way to target the oncogene behind a rare and often deadly liver disease using small interfering RNAs (siRNAs), an innate mechanism for silencing gene expression. As described in Molecular Therapy, the researchers slipped siRNAs inside fibrolamellar hepatocellular carcinoma (FLC) cells through a surface receptor, where they blocked the oncogene from producing illness-inducing proteins that lead to tumor formation. It's the first time that siRNAs have been used to hobble the progression of FLC, says first author Christoph Neumayer, a Ph.D. student in Rockefeller's Laboratory of Cellular Biophysics, headed by Sanford M. Simon. But the findings have wider applications as well. "That's the really exciting part," says Neumayer. "This is proof of concept that siRNAs can be used for FLC, as well as adult liver cancers, which are much more common, and other tumor types elsewhere in the body." The fusion oncogene FLC is caused by the fusion of two genes located on chromosome 19: DNAJB1, which produces heat-shock proteins that encourage cell homeostasis, and PRKACA, which produces an enzyme called kinase A that's key to cellular metabolic function. The resulting fusion, known as DNAJB1::PRKACA, brings together the proteins and a catalytic subunit of the kinase. This dysfunctional union promotes FLC formation, but how, exactly, is still unknown. Researchers in Simon's lab discovered that this fusion caused FLC in 2014, several years after Simon's own teenage daughter, Elana, was diagnosed with liver disease. After having the resulting tumor removed -- the only treatment option available to people with FLC -- Elana went on to collaborate with her father to unearth its cause, publishing the results in Science. Since then, Simon and his group have continued to reveal the mechanisms behind the disease as well as develop therapeutics. The siRNA research is part of a three-part strategy which also includes repurposing drugs for treating FLC and using molecules known as PROTACs to selectively degrade the DNAJB1::PRKACA protein that drives FLC. The drug repurposing is in advanced preparation for a clinical trial, and some of the PROTAC work is part of an international collaboration that was just awarded a $25 million Cancer Grand Challenges grant to develop treatments for high-risk, oncogene-driven cancers in children. Recently, Simon's lab discovered that they could completely stop FLC tumor growth in mice using shRNAs, short sequences of RNA that can be engineered to disrupt mRNA. The approach also caused many tumors to shrink or disappear. Having shown that quelling the fused oncogene killed tumor cells, they decided to experiment with derailing kinase A activity, which research indicated was driving tumor growth. Unlocking the cell door The problem was, fused kinase A and its "wild type" form are nearly identical, so "any drug you developed that blocks fused kinase A activity would affect all kinase A, including in normal cells," Neumayer says. "In other words, you would incur a host of problematic side effects." They had to find a way to disable toxic kinase while containing the impact so that kinase in other cells weren't affected. To do that, they specifically designed siRNAs to aim at the fusion. But because siRNAs cannot cross cell membranes, the researchers needed to figure out a way to get the siRNA inside. Luckily, a door into the cell had already been identified: a receptor called ASGR1 that's only expressed in liver cells. Its key had been too: a binding molecule known as GalNAc. Together, the duo function as a waste disposal team. GalNAc conjugate therapies, which attach siRNA molecules to the ligand to deliver therapies inside cells, are already on the market for conditions such as hereditary transthyretin-mediated amyloidosis and atherosclerotic cardiovascular disease. The team wondered if they could use the same approach to thwart the kinase driving FLC tumors. Stabilization and shrinkage To test their theory, the researchers attached a custom siRNA to the receptor's ligand and studied the method in a variety of tumor models in mice and in human cell cultures. The conjugate therapy was not only successfully delivered into the cells in all contexts, but it also caused a reduction of mRNA in the oncogene, preventing the production of the protein and resulting in the tumors stagnating or shrinking, unable to grow. They also did not detect any liver toxicity in the mice, indicating the animals tolerated the siRNAs well. "What we saw was tumor inhibition, when we had hoped to outright kill the tumor," Neumayer notes. "Our future direction will be to try to figure out how to improve that." They also tested the specificity of the siRNA by injecting it into tumor cells of another type of liver cancer. It had no toxic impact on them -- exactly as the researchers hoped. "We wanted to show that our siRNA is so targeted to the FLC fusion oncogene that it has no side effects on other cells -- even on other cancer cells," he notes. Neumayer says the findings suggest that siRNAs may be effective beyond FLC, capable of treating tumors throughout the body with a high degree of specificity: "I think siRNA medicines as a class will have a big impact over time as a new kind of genetic therapy."

Dive Brief:AstraZeneca is bolstering its rare disease division with the purchase of Amolyt Pharma, an endocrine disease specialist backed by Novo Holdings.Under the deal announced Thursday, AstraZeneca will pay Amolyt shareholders $800 million in cash up front, with the potential for another $250 million for reaching a specific regulatory milestone. The companies expect the transaction to close in the third quarter.For AstraZeneca, the jewel of the acquisition is eneboparatide, a drug in Phase 3 testing to treat patients with hypoparathyroidism. The disease, which mostly affects women, is caused by a deficiency in parathyroid production that lowers calcium in the blood and can lead to debilitating symptoms including kidney disease. It affects about 115,000 people in the U.S.Dive Insight:The $39 billion acquisition of Alexion three years ago instantly transformedAstraZeneca into a major player in rare diseases. Since then, the U.K. drugmaker has been selectively picking up additional assets.In September 2021, the company exercised an option to buy the rest of rare disease drugmaker Caelum Biosciences for $150 million. A few months later, AstraZeneca struck two deals in transthyretin amyloidosis, paying $30 million to Switzerlands Neurimmunefor rights to an experimental therapy and inking a development pact with Ionis Pharmaceuticals for a drug that won approval in late 2023.AstraZeneca is also using its foothold in rare diseases to make forays into genetic medicine, acquiring gene-editing specialist LogicBio Therapeutics and scooping up Pfizers early gene therapy work for as much as $1 billion. And last year, the company announced plans to work with Quell Therapeutics to develop cell-based treatments for autoimmune diseases.Amolyt has moved from a startup with preclinical assets to a Phase 3 company in less than five years. Its largest investor is Novo Holdings, the controlling shareholder of both Novo Nordisk and Novozymes. Owned by the Novo Nordisk Foundation, Novo Holdings co-led the Series A financing for Amolyt in 2019 and added to its investment with Series B and Series C funding rounds.In addition to eneboparatide, Amolyt has an experimental drug called AZP-3813 designed as a potential treatment for acromegaly, which occurs when the body makes too much growth hormone. '