Intellia (NTLA) hits Phase 3 HAE success and starts BLA for lonvo-z
Rhea-AI Filing Summary
Intellia Therapeutics reported positive Phase 3 HAELO trial results for its in vivo CRISPR gene-editing candidate lonvoguran ziclumeran (lonvo-z) in hereditary angioedema. In the 80‑patient, placebo‑controlled study, lonvo-z achieved an 87% reduction in HAE attack rate versus placebo between weeks 5 and 28 and 62% of treated patients were completely attack‑free and off prophylactic therapy in that period. All 52 patients in the lonvo-z arm saw attack‑rate reductions, and early crossover data showed attack rates approaching zero in both arms. Safety appeared favorable, with no serious adverse events or grade ≥3 treatment‑emergent events reported in the lonvo-z group and mainly mild or moderate infusion‑related reactions. Intellia has initiated a rolling biologics license application with the FDA and is preparing to complete the submission in the second half of 2026 and for a potential U.S. launch in the first half of 2027, if approved.
Positive
- Transformative Phase 3 efficacy and clean safety profile for lonvo-z: In the 80-patient HAELO trial, lonvo-z achieved an 87% reduction in hereditary angioedema attack rates versus placebo, with 62% of patients attack‑free and off prophylaxis and no serious or grade ≥3 treatment-emergent adverse events reported in the treatment arm.
- Regulatory and commercialization path clearly underway: Intellia has initiated a rolling BLA submission for lonvo-z, aims to complete filing in the second half of 2026, and is preparing for a potential first-half 2027 U.S. launch, signaling a near-term commercial opportunity if approved.
Negative
- None.
Insights
Phase 3 success in HAE and BLA start mark a major value inflection for Intellia.
The HAELO trial showed that lonvo-z, a one-time in vivo CRISPR therapy, met its primary and all key secondary endpoints in hereditary angioedema. From weeks 5–28, treated patients saw an 87% reduction in investigator-confirmed attack rate versus placebo, with an odds ratio of 12.8 for being attack‑free.
Importantly, 62% of lonvo-z patients were completely attack‑free and off long-term prophylaxis during this period, and every treated patient experienced some reduction in attacks. Median follow-up at data cutoff was 7.5 months, and early crossover data suggest sustained, very low attack rates across arms.
Safety in this 80‑patient trial looked favorable: there were no serious adverse events or grade ≥3 treatment-emergent events in the lonvo-z arm, and infusion reactions were mild or moderate and transient. Intellia has initiated a rolling biologics license application, targeting completion in the second half of 2026 and a potential U.S. launch in the first half of 2027, if the FDA approves lonvo-z.
8-K Event Classification
Key Figures
Key Terms
in vivo CRISPR gene editing technical
biologics license application regulatory
long-term prophylaxis medical
treatment-emergent adverse events medical
odds ratio financial
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| Item 7.01 | Regulation FD Disclosure. |
On April 27, 2026, Intellia Therapeutics, Inc. (the “Company”) issued a press release titled “Intellia Therapeutics Reports Positive Phase 3 Results in Hereditary Angioedema, Marking a Global First for In Vivo Gene Editing” and presented topline data from the HAELO Phase 3 trial of lonvoguran ziclumeran (“lonvo-z”) for the treatment of hereditary angioedema (“HAE”) in a presentation titled “Phase 3 HAELO Clinical Trial: Topline Data for Lonvo-z.” A copy of the press release and presentation are furnished as Exhibits 99.1 and 99.2, respectively, to this Current Report on Form 8-K and are incorporated herein by reference.
The information under this Item 7.01, including Exhibits 99.1 and 99.2 hereto, are being furnished herewith and shall not be deemed “filed” for the purposes of Section 18 of the Exchange Act, or otherwise subject to the liabilities of that section, nor shall such information be deemed incorporated by reference into any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filing.
| Item 8.01. | Other Events. |
Updates about Lonvo-z for the Treatment of HAE
On April 27, 2026, Intellia announced positive topline results from the global Phase 3 HAELO clinical trial of lonvo-z in HAE. Lonvo-z is an in vivo CRISPR gene editing candidate that is designed as a one-time treatment, administered in an outpatient setting, to inactivate the kallikrein B1 (“KLKB1”) gene to permanently lower kallikrein and bradykinin levels.
HAELO is a randomized, double-blind, placebo-controlled Phase 3 trial designed to evaluate the efficacy and safety of a one-time 50 milligram dose of lonvo-z in adults and adolescents aged 16 years and older with Type I or Type II HAE. Key endpoints of the trial focused on the number of HAE attacks experienced by patients, quality of life, safety and tolerability.
A total of 80 patients were enrolled, with 52 receiving lonvo-z and 28 receiving placebo. Of the total population, 49% of patients were enrolled in the United States and 71% were on long-term prophylaxis (“LTP”) therapy at study entry. Patients on LTP therapy were required to discontinue those therapies in the weeks prior to dosing. After week 28, patients had the option to participate in a blinded crossover to receive lonvo-z, if they previously received placebo, or placebo, if they previously received lonvo-z. As of the data cutoff (February 10, 2026), the median follow-up for enrolled patients is 7.5 months. As of the data cutoff, all patients who received lonvo-z at baseline or in crossover after week 28 remained LTP free.
Key findings from HAELO include:
Efficacy of Lonvo-z
| • | The trial met its primary endpoint. For the six-month efficacy evaluation period (weeks 5 to 28), a one-time infusion of lonvo-z reduced attacks by 87% versus placebo, with a mean monthly attack rate of 0.26 in the lonvo-z arm compared with 2.10 in the placebo arm (p<0.0001). |
| • | The trial met all of its key secondary endpoints with statistical significance (p<0.0001). These included a 62% rate of patients who were entirely attack free and therapy free in the lonvo-z arm for the six-month efficacy evaluation period, compared with 11% of patients in the placebo arm. |
| • | All patients in the lonvo-z arm experienced a reduction in attack rate from baseline. For the 38% of patients in the lonvo-z arm who were not attack free during the primary observation period, a mean attack rate reduction of 72% was observed. |
Safety of Lonvo-z
| • | Favorable safety and tolerability data were observed for lonvo-z. The most common treatment emergent adverse events (“TEAEs”) during the primary observation period (infusion through week 28) were infusion-related reactions (“IRRs”), headache and fatigue. |
| • | All TEAEs reported as of the data cutoff were mild or moderate (Grade 1 or Grade 2) and there were no serious adverse events observed in the lonvo-z arm. |
| • | All reported IRRs were mild or moderate and were transient. |
| • | There was no meaningful difference between the lonvo-z and placebo arms in clinical chemistries. A single Grade 2 ALT elevation was observed in the lonvo-z arm that self-resolved in one week. |
| • | As of the data cutoff, the safety and tolerability data observed in patients participating in the crossover following week 28 was consistent with the safety and tolerability observed during the primary observation period. |
Also on April 27, 2026, Intellia announced that it initiated a rolling biologics license application (“BLA”) submission to the U.S. Food and Drug Administration to seek regulatory approval of lonvo-z for the treatment of HAE. Intellia is preparing to complete the BLA filing in the second half of 2026 and for a potential U.S. launch of lonvo-z in the first half of 2027, if approved.
Forward-Looking Statements
This Current Report on Form 8-K and certain of the materials furnished or filed herewith contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.
These forward-looking statements include, but are not limited to, express or implied statements regarding Intellia’s beliefs and expectations regarding: the success and advancement of its program for lonvoguran ziclumeran or “lonvo-z” (formerly known as NTLA-2002) for the treatment of hereditary angioedema (“HAE”), including its plan to complete the submission of a biologics license application (“BLA”) for lonvo-z in the second half of 2026, its expectations regarding review and approval of that BLA, and its expectations regarding a potential U.S. launch of lonvo-z in the first half of 2027; and the potential of one dose of lonvo-z to offer prolonged freedom from both attacks and the need for ongoing therapy.
Any forward-looking statements in this current report on Form 8-K 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: uncertainties related to the conduct of clinical studies and other development and commercialization requirements for its product candidates, including lonvo-z, including risks related to the ability to develop and successfully commercialize lonvo-z or any of Intellia’s product candidates; 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 contract manufacturers, collaborators, licensors and licensees; risks related to the ability of its licensors to protect and maintain their intellectual property position; risks related to the results of preclinical studies or clinical studies not being predictive of future results in connection with future studies; the risk that clinical study results will not be positive; and risks related to the potential delay of planned clinical trials or regulatory filings due to regulatory feedback or other developments. 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 and quarterly report on Form 10-Q, 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 current report on Form 8-K is as of the date of the report, and Intellia undertakes no duty to update this information unless required by law.
| Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits
| Exhibit No. |
Description | |
| 99.1 | Press Release dated April 27, 2026 titled “Intellia Therapeutics Reports Positive Phase 3 Results in Hereditary Angioedema, Marking a Global First for In Vivo Gene Editing” | |
| 99.2 | Presentation dated April 2026 titled “Phase 3 HAELO Clinical Trial: Topline Data for Lonvo-z” | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the Registrant has duly caused this report to be signed on its behalf by the undersigned thereunto duly authorized.
| Intellia Therapeutics, Inc. | ||||||
| Date: April 27, 2026 | By: | /s/ John M. Leonard | ||||
| Name: | John M. Leonard | |||||
| Title: | Chief Executive Officer and President | |||||
Exhibit 99.1
*** CONFIDENTIAL ***
Intellia Therapeutics Reports Positive Phase 3 Results in Hereditary
Angioedema, Marking a Global First for In Vivo Gene Editing
| • | Phase 3 HAELO trial of lonvoguran ziclumeran (lonvo-z) met primary and all key secondary endpoints; favorable safety and tolerability data observed |
| • | Single dose of lonvo-z freed most patients from both attacks and ongoing therapy for six-month efficacy evaluation period, demonstrating its potential to be the first and only one-time HAE treatment |
| • | Rolling biologics license application (BLA) submission initiated with the U.S. Food and Drug Administration (FDA); anticipate U.S. launch in the first half of 2027, if approved |
| • | Intellia to host webcast today at 8:00 a.m. ET |
CAMBRIDGE, Mass., April 27, 2026 – Intellia Therapeutics, Inc. (Nasdaq: NTLA), a leading biopharmaceutical company focused on revolutionizing medicine leveraging CRISPR gene editing and other core technologies, today announced positive topline results from the global Phase 3 HAELO clinical trial of lonvo-z (formerly known as NTLA-2002) in hereditary angioedema (HAE). HAE is a rare genetic condition in which patients experience recurrent and potentially life-threatening swelling (angioedema) attacks in various parts of their body, including the face, upper airway, abdomen and extremities due to an overproduction of bradykinin. Designed as a one-time treatment that is administered in an outpatient setting, lonvo-z is an in vivo CRISPR gene editing candidate that is intended to inactivate the kallikrein B1 (KLKB1) gene to permanently lower kallikrein and bradykinin levels.
Intellia separately announced today that it has initiated a rolling BLA submission to the FDA to seek regulatory approval. The company is preparing for a potential U.S. launch of lonvo-z in the first half of 2027.
“As the first Phase 3 data reported for an in vivo gene editing therapy, today’s HAELO results represent a profound milestone for Intellia, the broader CRISPR and precision medicine fields and, most importantly, the HAE community,” said John Leonard, M.D., Intellia President and Chief Executive Officer. “For those patients who have spent years battling unpredictable breakthrough swelling attacks, anxiety about their next attack or the many burdens associated with chronic prophylactic treatment, lonvo-z represents a potential paradigm shift in treatment. These data affirm lonvo-z’s potential, with one dose, to offer prolonged freedom from both attacks and the need for ongoing therapy.”
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“We extend our deep gratitude to the many patients, caregivers and clinicians who have helped advance gene editing science by participating in our clinical trials. It is because of their contribution that we are advancing toward our first potential approval, with the goal of making lonvo-z available to U.S. patients in the first half of 2027,” Dr. Leonard concluded.
HAELO Topline Results
HAELO is a randomized, double-blind, placebo-controlled Phase 3 trial designed to evaluate the efficacy and safety of a one-time 50 milligram dose of lonvo-z in adults and adolescents aged 16 years and older with Type I or Type II HAE. Key endpoints of the trial focused on the number of HAE attacks experienced by patients, quality of life, safety and tolerability.
A total of 80 patients were enrolled, with 52 receiving lonvo-z and 28 receiving placebo. Of the total population, 49% of patients were enrolled in the United States and 71% were on long-term prophylaxis (LTP) therapy at study entry. Patients on LTP were required to discontinue those therapies in the weeks prior to dosing.
Key findings from HAELO include:
| • | The trial met its primary endpoint. For the six-month efficacy evaluation period (weeks 5 to 28), a one-time infusion of lonvo-z reduced attacks by 87% versus placebo, with a mean monthly attack rate of 0.26 in the lonvo-z arm compared with 2.10 in the placebo arm (p<0.0001). |
| • | The trial met all of its key secondary endpoints with statistical significance (p<0.0001). These included a 62% rate of patients who were entirely attack free and therapy free in the lonvo-z arm for the six-month efficacy evaluation period, compared with 11% of patients in the placebo arm. |
| • | Favorable safety and tolerability data were observed for lonvo-z. The most common treatment emergent adverse events (TEAEs) during the primary observation period (infusion through week 28) were infusion-related reactions, headache and fatigue. All TEAEs reported as of the data cutoff (February 10, 2026) were mild or moderate and there were no serious adverse events observed in the lonvo-z arm. |
| • | As of the data cutoff, all patients who received lonvo-z at baseline or in crossover after week 28 remained LTP free. |
Additional clinical data from HAELO will be presented at the 2026 European Academy of Allergy and Clinical Immunology Congress (EAACI), taking place June 12-15 in Istanbul, Türkiye (abstract #100217).
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“Despite the availability of several HAE treatments, many patients continue to experience significant burdens related to the disease, including breakthrough attacks and challenges associated with chronic treatment,” said Aleena Banerji, M.D., Professor at Harvard Medical School, Director of Clinical Care, Center for Drug and Vaccine Allergy at Massachusetts General Hospital, and a HAELO principal investigator. “The results we are seeing from lonvo-z demonstrate its potential to eliminate the need for chronic medication and related challenges. If approved as a one-time treatment, I would expect lonvo-z to be an appealing option for many patients.”
Webcast Information
The company will host a conference call and webcast today at 8:00 a.m. ET to discuss the topline results. To join the webcast, please visit the Events page of the Investors & Media section on Intellia’s website at intelliatx.com. A replay of the webcast will be available for approximately 90 days.
About Lonvo-z
Based on Nobel Prize-winning CRISPR/Cas9 technology, lonvo-z has the potential to become the first one-time treatment for hereditary angioedema (HAE). Lonvo-z is an in vivo CRISPR gene editing candidate that is intended to permanently lower kallikrein by inactivating the kallikrein B1 (KLKB1) gene with a single dose. Lonvo-z has received five notable regulatory designations: Orphan Drug and RMAT Designation by the U.S. Food and Drug Administration (FDA), the Innovation Passport by the U.K. Medicines and Healthcare products Regulatory Agency (MHRA), Priority Medicines (PRIME) Designation by the European Medicines Agency, as well as Orphan Drug Designation (ODD) by the European Commission.
About Hereditary Angioedema
Hereditary angioedema (HAE) is a rare, genetic disease characterized by severe, recurring and unpredictable inflammatory attacks in various organs and tissues of the body, which can be painful, debilitating and life-threatening. It is estimated that one in 50,000 people are affected by HAE. There are preventative and on-demand treatment options to help manage the condition, including long- and short-term prophylaxis used to prevent swelling attacks. Current treatment options often include lifelong therapies, which may require chronic intravenous (IV) or subcutaneous (SC) administration as often as twice per week or daily oral administration to ensure constant pathway suppression for disease control. Despite chronic administration, breakthrough attacks still occur. Kallikrein inhibition is a clinically validated strategy for the preventive treatment of HAE attacks.
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About Intellia Therapeutics
Intellia Therapeutics, Inc. (Nasdaq: NTLA) is a leading clinical-stage biopharmaceutical company focused on revolutionizing medicine leveraging CRISPR gene editing and other core technologies. The company’s mission is to transform the lives of people with severe diseases by developing and commercializing potentially curative treatments. With deep scientific, technical and clinical development experience, Intellia aims to reset the standard for medicine by durably treating the root causes of disease. 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 concerning: the success and advancement of its program for lonvoguran ziclumeran or “lonvo-z” (also known as NTLA-2002) for the treatment of hereditary angioedema (“HAE”), including its plan to complete the submission of a biologics license application (“BLA”) for lonvo-z in the second half of 2026, its expectations regarding review and approval of that BLA, and its expectations regarding a potential U.S. launch of lonvo-z in the first half of 2027; and the potential of one dose of lonvo-z to offer prolonged freedom from both attacks and the need for ongoing therapy.
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: uncertainties related to the conduct of clinical studies and other development and commercialization requirements for its product candidates, including lonvo-z, including risks related to the ability to develop and successfully commercialize lonvo-z or any of Intellia’s product candidates; 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 contract manufacturers, collaborators, licensors and licensees; risks related to the ability of its licensors to protect and maintain their intellectual property position; risks related to the results of preclinical studies or clinical studies not being predictive of future results in connection with future studies; the risk that clinical study results will not be positive; and risks related to the potential delay of planned clinical trials or regulatory filings due to regulatory feedback or other developments. For a discussion of these and other risks and uncertainties, and other important factors, any of which could
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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, including its quarterly report on Form 10-Q. 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.
Investor Contact:
Jason Fredette
Vice President, Investor Relations and Corporate Communications
Intellia Therapeutics, Inc.
jason.fredette@intelliatx.com
Media Contact:
Mike Tattory
Vice President
LifeSci Communications
mtattory@lifescicommunications.com
# # #
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Exhibit 99.2
Phase 3 HAELO Clinical Trial: Topline Data for Lonvo-z April 27, 2026
Intellia Therapeutics’ Legal Disclaimer This presentation contains “forward-looking statements” of Intellia Therapeutics, Inc. (“Intellia”, “we” or “our”) 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 about Intellia’s beliefs and expectations regarding: our ability to successfully develop and commercialize lonvoguran ziclumeran (“lonvo-z”), formerly known as NTLA-2002, for the treatment of hereditary angioedema (“HAE”); our ability to achieve upcoming objectives, including completing the submission of a biologics license application for lonvo-z for the treatment of HAE in the second half of 2026, and successfully launching lonvo-z for the treatment of HAE in the U.S. in the first half of 2027; the potential commercial opportunities for lonvo-z and our other product candidates, including the value and market potential for lonvo-z and the potential of lonvo-z to eliminate attacks and ongoing therapy with one treatment; and our ability to complete our current lonvo-z priorities to prepare for a successful launch, including scaling a field sales and reimbursement teams, finalizing pricing, and finalizing a contracting strategy. Any forward-looking statements in this presentation 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 the ability to successfully develop and commercialize lonvo-z or any of our other product candidates; risks related to Intellia’s ability to protect and maintain its intellectual property position; risks related to Intellia’s relationship with third parties, including our contract manufacturers, licensors and licensees; risks related to the ability of our licensors to protect and maintain their intellectual property position; uncertainties related to the authorization, initiation and conduct of preclinical and clinical studies and other development requirements for our product candidates, including uncertainties related to regulatory approvals to conduct clinical trials; risks related to the results of preclinical studies or clinical studies not being predictive of future results in connection with future studies; the risk that clinical trial results will not be positive; risks related to the development and advancement of in vivo and ex vivo technologies for pipeline expansion and collaborations; risks related to Intellia’s future financial condition and our ability to fund our operations; risks related to Intellia’s collaborations with Regeneron or our other collaborations not continuing or not being successful; and risks related to Intellia’s ability to execute its strategic plans, including completing pivotal clinical trials and commercial launch of its 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 of Form 10-K and Quarterly Report on Form 10-Q 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 presentation is as of the date on its cover page, and Intellia undertakes no duty to update this information unless required by law.
Today’s Speakers Dr. John Leonard, President and Chief Executive Officer Intellia Therapeutics Dr. David Lebwohl, Executive Vice President and Chief Medical Officer Intellia Therapeutics Dr. Marc Riedl, Professor of Medicine, Clinical Director of the U.S. Hereditary Angioedema Association (HAEA) Angioedema Center University of California San Diego; HAELO principal investigator
Introduction Dr. John Leonard President & CEO, Intellia Therapeutics
CRISPR is Coming of Age 2020 1987 2012 Nobel Prize in Chemistry 2023 Discovery of natural CRISPR/Cas9 awarded to Intellia co-founder FDA approval of first ex vivo CRISPR systems in 2 publication in Science Jennifer Doudna CRISPR-based therapy E. coli bacteria1 2014 Intellia Therapeutics founded
Intellia’s Mission Statement To transform the lives of people with severe diseases by developing and commercializing potentially curative treatments.
CRISPR is Coming of Age 2020 1987 2012 Nobel Prize in Chemistry 2023 Discovery of natural CRISPR/Cas9 awarded to Intellia co-founder FDA approval of first ex vivo CRISPR systems in 2 publication in Science Jennifer Doudna CRISPR-based therapy E. coli bacteria1 2024-2025 2020 Intellia doses first TODAY 2014 Intellia doses first patient patients with in vivo Intellia reports world’s Intellia Therapeutics with an in vivo CRISPR-based CRISPR-based first Ph3 in vivo CRISPR founded data; initiation of therapy (nex-z) therapies in Ph3 trials for HAE and ATTR rolling BLA
Intellia’s Pipeline Advancing Toward Significant Near-Term Milestones Research/ Early-Stage Late-Stage BLA Prog ram Indication Preclinical Clinical Clinical Submission Lonvo-z1 Hereditary Angioedema (HAE) Transthyretin Amyloidosis with LEAD Polyneuropathy (ATTRv-PN) Nex-z2 Transthyretin Amyloidosis with LEAD Cardiomyopathy (ATTR-CM) REGV131-LNP12653 Hemophilia B AVC-201 Acute Myeloid Leukemia (AML) 4 AVC-203 B-cell malignancies 5 Other Ongoing Various Research Programs
About HAE and Lonvo-z Dr. David Lebwohl Chief Medical Officer, Intellia Therapeutics
Hereditary Angioedema (HAE): Currently a Lifelong Condition with Significant Burden Rare, genetic and life-threatening disease • Caused by a hereditary deficiency or dysfunction of the C1 inhibitor protein that leads to an imbalance in the kallikrein-kinin system and an overproduction of bradykinin • Patients experience unpredictable, recurrent, painful and potentially life-threatening swelling attacks1,2 • Symptoms often begin in the first decade of life and typically worsen in puberty3,4 • Attacks can be triggered by stress, trauma, infection, fatigue and hormones2
Despite Available Treatments, Many Patients are Unable to Break the Chronic Cycle of Managing Their HAE Patient-Reported Burdens Lifelong Incomplete Significant Treatment for Control for Most Financial Impact All Life-Threatening Burden to Attacks Maintain Access 80% reported having 68% highly 45% highly ?1 HAE attack during concerned about concerned about the past year1 need for lifetime the financial burden of medication1 of HAE1 >50% experience 80% concerned their a laryngeal attack health insurance would in their lifetime2 change and impact medication access1
The Cumulative Costs for Chronic HAE Treatments are Sizable U.S. Treated Patients Average Age of HAE Cumulative U.S. Healthcare System Costs for with Type 1 & 2 HAE1 Diagnosis in U.S.2 Chronic and On-Demand HAE Therapies3 ~7,000 $19.1B On Demand LTP ~2,600 On Demand ~20 $11.5B ~4,400 LTP $3.8B $9 $3.0B 1 year 3 years 5 years
Lonvo-z is an Investigational One-Time HAE Treatment Intended to Permanently Inactivate the KLKB1 Gene In HAE, C1 inhibitor deficiency imbalances the Lonvo-z was designed to stop HAE attacks: kallikrein-kinin system (KKS), leading to excess Inactivating KLKB1 gene resets the KKS to stop protein production and debilitating swelling attacks excess protein production and HAE swellings Blood vessel with HAE Blood vessel after lonvo-z Factor XII Factor XIIa Factor XII Factor XIIa C1INH C1INH KLKB1 KLKB1 Prekallikrein Kallikrein Prekallikrein Kallikrein gene gene C1INH C1INH HMW kininogen Bradykinin HMW kininogen Bradykinin
Lonvo-z is Designed to be Administered in an Outpatient Setting in Two to Four Hours DAY PRIOR DAY OF One dose of orally One dose of each of Single outpatient infusion† Return home administered steroid the following: steroid, (at home)* histamine blocker, STP* gene the gene the editing and Targeting editing and rgetingTa This schedule reflects the HAELO Phase 3 clinical trial protocol. Schedule may vary if approved.
Pooled Analysis of Phase 1/2 Clinical Data: After Becoming Attack-Free and LTP-Free for ?6 Months, All Patients Maintained Their Response Patient ID* Baseline Monthly LTP initiation LTP withdrawal Attack-free and LTP-free: ?6 months <6 months Attack: Mild Moderate Severe Phase-Initial Dose-Pt # Attack Rate† 1-50-04 1.2 1-50-02 0‡ 1-50-03 0.7 1-50-01 6.5 2-50-04 1.0 2-50-03 0.9 2-50-01 1.9 2-50-05 4.8 2-50-08 2.1 2-50-09 8.7 2-50-10 7.8 2-50-11 1.0 2-PBO-23 1.1 2-PBO-25 3.7 2-PBO-24 4.3 1-25-03 2.9 2-PBO-22 2.8 2-PBO-27 1.5 24 patients have been 2-50-06 3.3 attack-free and LTP-free for 7-32 months 2-25-18 3.1 2-25-20 2.3 and remain so at last follow-up 2-25-19 6.4 1-25-02 7.2 2-25-17 1.4 2-50-02 2.8 2-PBO-26 5.2 2-25-13 3.1 7 patients have been 2-25-21 6.8 attack-free and LTP-free for <6 months 2-25-15 4.5 2-25-14 1.4 and remain so at last follow-up 2-25-16 2.9 2-50-07 5.4 59% reduction from BL in monthly attack rate
No Waning of Effect Observed: Kallikrein Reduction has Remained Deep and Durable Pooled Data from All 32 Patients Who Received 50 mg Dose of Lonvo-z in Phase 1/2 0% -10% -20% kallikrein SD) ± -30% (mean -40% plasma in -50% baseline -60% change from -70% -86% -87% Percent -80% -89% -89% -90% -100% BL 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Months after lonvo-z 50 mg infusion (N) 32 32 30 29 27 26 23 18 14 14 11 9 4
HAELO Phase 3 Clinical Data Dr. Marc Riedl Professor of Medicine, Clinical Director of the U.S. Hereditary Angioedema Association (HAEA) Angioedema Center at the University of California San Diego; HAELO principal investigator
A Placebo-Controlled, Double-Blind, Randomized Phase 3 Trial of Lonvo-z as a One-Time HAE Treatment End of Study Day 1 Week 28 Week 104 Lonvo-z 50 mg Placebo (n=52) All patients Efficacy invited to Screening 1 Screening 2 One-time infusion evaluation Optional, Follow-up enroll in the LTP washout Run-in period period blinded crossover (76 weeks) long-term (4-8 weeks) randomization 2:1 (Weeks 5-28) follow-up Placebo study Lonvo-z 50 mg (n=28) Key Secondary En dpoints Stratification Primary En dpoint • Time-normalized number of investigator-confirmed HAE attacks requiring Baseline number of investigator- Time-normalized number of on-demand treatment from Weeks 5 through 28 confirmed HAE attacks per month from investigator-confirmed HAE attacks Screening 2 to Randomization from Weeks 5 through 28 • Time-normalized number of moderate or severe investigator-confirmed HAE attacks from Weeks 5 through 28 • Investigator-confirmed HAE attack-free status from Weeks 5 through 28 • Change from baseline to Week 28 in AE-QoL Questionnaire total score Pre-specified primary analysis when ?60 patients reach Week 28
HAELO Phase 3 Clinical Data Dr. Marc Riedl Professor of Medicine, Clinical Director of the U.S. Hereditary Angioedema Association (HAEA) Angioedema Center at the University of California San Diego; HAELO principal investigator A Placebo-Controlled, Double-Blind, Randomized Phase 3 Trial of Lonvo-z as a One-Time HAE Treatment End of Study Day 1 Week 28 Week 104 Lonvo-z 50 mg Placebo (n=52) All patients Efficacy invited to Screening 1 Screening 2 One-time infusion evaluation Optional, Follow-up enroll in the LTP washout Run-in period period blinded crossover (76 weeks) long-term (4-8 weeks) randomization 2:1 (Weeks 5-28) follow-up Placebo study Lonvo-z 50 mg (n=28) Key Secondary En dpoints Stratification Primary En dpoint • Time-normalized number of investigator-confirmed HAE attacks requiring Baseline number of investigator- Time-normalized number of on-demand treatment from Weeks 5 through 28 confirmed HAE attacks per month from investigator-confirmed HAE attacks Screening 2 to Randomization from Weeks 5 through 28 • Time-normalized number of moderate or severe investigator-confirmed HAE attacks from Weeks 5 through 28 • Investigator-confirmed HAE attack-free status from Weeks 5 through 28 • Change from baseline to Week 28 in AE-QoL Questionnaire total score Pre-specified primary analysis when ?60 patients reach Week 28 HAELO Phase 3 Demographics and Baseline Characteristics Demographic Characteristics Lonvo-z (n=52) Placebo (n=28) Age, median years (range) 42 (23 – 71) 40 (19 – 76) Female, n (%) 35 (67%) 20 (71%) Enrolled in United States, n (%) 26 (50%) 13 (46%) Hereditary angioedema type, n (%) Type 1 49 (94%) 25 (89%) Type 2 3 (6%) 3 (11%) Long-term prophylaxis at study entry, n (%) 35 (67%) 22 (79%) Lanadelumab 25 (48%) 12 (43%) C1 esterase inhibitor 5 (10%) 3 (11%) Berotralstat 4 (8%) 1 (4%) Garadacimab 1 (2%) 3 (11%) Other 2 (4%) 3 (11%) On-Demand therapy only, n (%) 17 (33%) 6 (21%) Historic typical attack severity, n (%) Mild 7 (14%) 5 (18%) Moderate 30 (58%) 20 (71%) Severe 15 (29%) 3 (11%) Monthly attack rate during run-in, mean (SD)* 3.5 (1.8) 3.5 (1.9) Median follow-up for enrolled patients: 7.5 months
HAELO Trial Achieved its Primary and All Key Secondary Endpoints Mean Attack-Rate Reduction Weeks 5—28 Attack Free Weeks 5—28 (Primary Endpoint) 1,2 (Key Secondary Endpoint) 2 2.5 70% 2.10 62% 60% 2 50% 1.5 87% reduction patients of 40% Odds Ratio 12.8 attacks/month (95% CI: 78%-93%) E 1 p<0.0001 30% (95% CI: 3.5-47.6) HA p<0.0001 20% 0.5 11% 0.26 Percent Mean 10% 0 0% Placebo Lonvo-z Placebo Lonvo-z All other key secondary endpoints were achieved with high statistical significance (p<0.0001)
100% of Patients in Lonvo-z Arm Experienced Attack-Rate Reductions from Baseline During Weeks 5-28 Clinically relevant Attack-free and 62% 38% 72% mean attack-rate therapy-free reduction* All patients who received lonvo-z at baseline or in crossover were LTP-free
HAELO Phase 3 Clinical Data Dr. Marc Riedl Professor of Medicine, Clinical Director of the U.S. Hereditary Angioedema Association (HAEA) Angioedema Center at the University of California San Diego; HAELO principal investigator A Placebo-Controlled, Double-Blind, Randomized Phase 3 Trial of Lonvo-z as a One-Time HAE Treatment End of Study Day 1 Week 28 Week 104 Lonvo-z 50 mg Placebo (n=52) All patients Efficacy invited to Screening 1 Screening 2 One-time infusion evaluation Optional, Follow-up enroll in the LTP washout Run-in period period blinded crossover (76 weeks) long-term (4-8 weeks) randomization 2:1 (Weeks 5-28) follow-up Placebo study Lonvo-z 50 mg (n=28) Key Secondary En dpoints Stratification Primary En dpoint • Time-normalized number of investigator-confirmed HAE attacks requiring Baseline number of investigator- Time-normalized number of on-demand treatment from Weeks 5 through 28 confirmed HAE attacks per month from investigator-confirmed HAE attacks Screening 2 to Randomization from Weeks 5 through 28 • Time-normalized number of moderate or severe investigator-confirmed HAE attacks from Weeks 5 through 28 • Investigator-confirmed HAE attack-free status from Weeks 5 through 28 • Change from baseline to Week 28 in AE-QoL Questionnaire total score Pre-specified primary analysis when ?60 patients reach Week 28 HAELO Phase 3 Demographics and Baseline Characteristics Demographic Characteristics Lonvo-z (n=52) Placebo (n=28) Age, median years (range) 42 (23 – 71) 40 (19 – 76) Female, n (%) 35 (67%) 20 (71%) Enrolled in United States, n (%) 26 (50%) 13 (46%) Hereditary angioedema type, n (%) Type 1 49 (94%) 25 (89%) Type 2 3 (6%) 3 (11%) Long-term prophylaxis at study entry, n (%) 35 (67%) 22 (79%) Lanadelumab 25 (48%) 12 (43%) C1 esterase inhibitor 5 (10%) 3 (11%) Berotralstat 4 (8%) 1 (4%) Garadacimab 1 (2%) 3 (11%) Other 2 (4%) 3 (11%) On-Demand therapy only, n (%) 17 (33%) 6 (21%) Historic typical attack severity, n (%) Mild 7 (14%) 5 (18%) Moderate 30 (58%) 20 (71%) Severe 15 (29%) 3 (11%) Monthly attack rate during run-in, mean (SD)* 3.5 (1.8) 3.5 (1.9) Median follow-up for enrolled patients: 7.5 months HAELO Trial Achieved its Primary and All Key Secondary Endpoints Mean Attack-Rate Reduction Weeks 5—28 Attack Free Weeks 5—28 (Primary Endpoint) 1,2 (Key Secondary Endpoint) 2 2.5 70% 2.10 62% 60% 2 50% 1.5 87% reduction patients of 40% Odds Ratio 12.8 attacks/month (95% CI: 78%-93%) E 1 p<0.0001 30% (95% CI: 3.5-47.6) HA p<0.0001 20% 0.5 11% 0.26 Percent Mean 10% 0 0% Placebo Lonvo-z Placebo Lonvo-z All other key secondary endpoints were achieved with high statistical significance (p<0.0001) 100% of Patients in Lonvo-z Arm Experienced Attack-Rate Reductions from Baseline During Weeks 5-28 Clinically relevant Attack-free and 62% 38% 72% mean attack-rate therapy-free reduction* All patients who received lonvo-z at baseline or in crossover were LTP-free Attack-Rate Reduction Observed Quickly Following Lonvo-z Dosing; Further Reduction Observed in Early Crossover Data Following Week 28 Mean Monthly Investigator-Confirmed HAE Attack Rate Over Time Lonvo-z Placebo Placebo?Lonvo-z (post crossover) per 5 Start of Crossover Period (SE) 4 Attacks E Mean 3 HA of 2 Month, Number 1 0 BL 4 8 12 16 20 24 28 32 36 40 44 48 LTP wash-out Weeks Since Initial Infusion Lonvo-z (n) 52 52 52 52 52 52 50 44 43 20 8 6 3 Placebo (n) 28 28 28 27 27 27 25 21 0 0 0 0 0 Placebo?Lonvo-z (n) 0 0 0 0 0 0 0 0 20 12 3 0 0
HAELO Phase 3 Clinical Data Dr. Marc Riedl Professor of Medicine, Clinical Director of the U.S. Hereditary Angioedema Association (HAEA) Angioedema Center at the University of California San Diego; HAELO principal investigator A Placebo-Controlled, Double-Blind, Randomized Phase 3 Trial of Lonvo-z as a One-Time HAE Treatment End of Study Day 1 Week 28 Week 104 Lonvo-z 50 mg Placebo (n=52) All patients Efficacy invited to Screening 1 Screening 2 One-time infusion evaluation Optional, Follow-up enroll in the LTP washout Run-in period period blinded crossover (76 weeks) long-term (4-8 weeks) randomization 2:1 (Weeks 5-28) follow-up Placebo study Lonvo-z 50 mg (n=28) Key Secondary En dpoints Stratification Primary En dpoint • Time-normalized number of investigator-confirmed HAE attacks requiring Baseline number of investigator- Time-normalized number of on-demand treatment from Weeks 5 through 28 confirmed HAE attacks per month from investigator-confirmed HAE attacks Screening 2 to Randomization from Weeks 5 through 28 • Time-normalized number of moderate or severe investigator-confirmed HAE attacks from Weeks 5 through 28 • Investigator-confirmed HAE attack-free status from Weeks 5 through 28 • Change from baseline to Week 28 in AE-QoL Questionnaire total score Pre-specified primary analysis when ?60 patients reach Week 28 HAELO Phase 3 Demographics and Baseline Characteristics Demographic Characteristics Lonvo-z (n=52) Placebo (n=28) Age, median years (range) 42 (23 – 71) 40 (19 – 76) Female, n (%) 35 (67%) 20 (71%) Enrolled in United States, n (%) 26 (50%) 13 (46%) Hereditary angioedema type, n (%) Type 1 49 (94%) 25 (89%) Type 2 3 (6%) 3 (11%) Long-term prophylaxis at study entry, n (%) 35 (67%) 22 (79%) Lanadelumab 25 (48%) 12 (43%) C1 esterase inhibitor 5 (10%) 3 (11%) Berotralstat 4 (8%) 1 (4%) Garadacimab 1 (2%) 3 (11%) Other 2 (4%) 3 (11%) On-Demand therapy only, n (%) 17 (33%) 6 (21%) Historic typical attack severity, n (%) Mild 7 (14%) 5 (18%) Moderate 30 (58%) 20 (71%) Severe 15 (29%) 3 (11%) Monthly attack rate during run-in, mean (SD)* 3.5 (1.8) 3.5 (1.9) Median follow-up for enrolled patients: 7.5 months HAELO Trial Achieved its Primary and All Key Secondary Endpoints Mean Attack-Rate Reduction Weeks 5—28 Attack Free Weeks 5—28 (Primary Endpoint) 1,2 (Key Secondary Endpoint) 2 2.5 70% 2.10 62% 60% 2 50% 1.5 87% reduction patients of 40% Odds Ratio 12.8 attacks/month (95% CI: 78%-93%) E 1 p<0.0001 30% (95% CI: 3.5-47.6) HA p<0.0001 20% 0.5 11% 0.26 Percent Mean 10% 0 0% Placebo Lonvo-z Placebo Lonvo-z All other key secondary endpoints were achieved with high statistical significance (p<0.0001) 100% of Patients in Lonvo-z Arm Experienced Attack-Rate Reductions from Baseline During Weeks 5-28 Clinically relevant Attack-free and 62% 38% 72% mean attack-rate therapy-free reduction* All patients who received lonvo-z at baseline or in crossover were LTP-free Attack-Rate Reduction Observed Quickly Following Lonvo-z Dosing; Further Reduction Observed in Early Crossover Data Following Week 28 Mean Monthly Investigator-Confirmed HAE Attack Rate Over Time Lonvo-z Placebo Placebo?Lonvo-z (post crossover) per 5 Start of Crossover Period (SE) 4 Attacks E Mean 3 HA of 2 Month, Number 1 0 BL 4 8 12 16 20 24 28 32 36 40 44 48 LTP wash-out Weeks Since Initial Infusion Lonvo-z (n) 52 52 52 52 52 52 50 44 43 20 8 6 3 Placebo (n) 28 28 28 27 27 27 25 21 0 0 0 0 0 Placebo?Lonvo-z (n) 0 0 0 0 0 0 0 0 20 12 3 0 0 Favorable Safety and Tolerability Data Primary Observation Period • No SAEs or Grade ?3 TEAEs Lonvo-z (N=52) Placebo (N=28) (Weeks 1 – 28) reported in lonvo-z arm TEAEs in ?10% of patients, n (%) • All IRRs were mild or moderate and Infusion-related reaction 32 (62%) 5 (18%) were transient Headache 10 (19%) 3 (11%) • No meaningful difference between arms in clinical chemistries; single Fatigue 7 (14%) 3 (11%) Grade 2 ALT elevation observed in Nasopharyngitis 7 (14%) 9 (32%) lonvo-z arm that self-resolved in one Back pain 6 (12%) 3 (11%) week Upper respiratory tract infection 6 (12%) 2 (7%) • Consistent safety and tolerability data observed in crossover following week Serious TEAEs 0 1 (4%)* 28 as of data cutoff Grade ?3 TEAEs 0 0
HAELO Phase 3 Clinical Data Dr. Marc Riedl Professor of Medicine, Clinical Director of the U.S. Hereditary Angioedema Association (HAEA) Angioedema Center at the University of California San Diego; HAELO principal investigator A Placebo-Controlled, Double-Blind, Randomized Phase 3 Trial of Lonvo-z as a One-Time HAE Treatment End of Study Day 1 Week 28 Week 104 Lonvo-z 50 mg Placebo (n=52) All patients Efficacy invited to Screening 1 Screening 2 One-time infusion evaluation Optional, Follow-up enroll in the LTP washout Run-in period period blinded crossover (76 weeks) long-term (4-8 weeks) randomization 2:1 (Weeks 5-28) follow-up Placebo study Lonvo-z 50 mg (n=28) Key Secondary En dpoints Stratification Primary En dpoint • Time-normalized number of investigator-confirmed HAE attacks requiring Baseline number of investigator- Time-normalized number of on-demand treatment from Weeks 5 through 28 confirmed HAE attacks per month from investigator-confirmed HAE attacks Screening 2 to Randomization from Weeks 5 through 28 • Time-normalized number of moderate or severe investigator-confirmed HAE attacks from Weeks 5 through 28 • Investigator-confirmed HAE attack-free status from Weeks 5 through 28 • Change from baseline to Week 28 in AE-QoL Questionnaire total score Pre-specified primary analysis when ?60 patients reach Week 28 HAELO Phase 3 Demographics and Baseline Characteristics Demographic Characteristics Lonvo-z (n=52) Placebo (n=28) Age, median years (range) 42 (23 – 71) 40 (19 – 76) Female, n (%) 35 (67%) 20 (71%) Enrolled in United States, n (%) 26 (50%) 13 (46%) Hereditary angioedema type, n (%) Type 1 49 (94%) 25 (89%) Type 2 3 (6%) 3 (11%) Long-term prophylaxis at study entry, n (%) 35 (67%) 22 (79%) Lanadelumab 25 (48%) 12 (43%) C1 esterase inhibitor 5 (10%) 3 (11%) Berotralstat 4 (8%) 1 (4%) Garadacimab 1 (2%) 3 (11%) Other 2 (4%) 3 (11%) On-Demand therapy only, n (%) 17 (33%) 6 (21%) Historic typical attack severity, n (%) Mild 7 (14%) 5 (18%) Moderate 30 (58%) 20 (71%) Severe 15 (29%) 3 (11%) Monthly attack rate during run-in, mean (SD)* 3.5 (1.8) 3.5 (1.9) Median follow-up for enrolled patients: 7.5 months HAELO Trial Achieved its Primary and All Key Secondary Endpoints Mean Attack-Rate Reduction Weeks 5—28 Attack Free Weeks 5—28 (Primary Endpoint) 1,2 (Key Secondary Endpoint) 2 2.5 70% 2.10 62% 60% 2 50% 1.5 87% reduction patients of 40% Odds Ratio 12.8 attacks/month (95% CI: 78%-93%) E 1 p<0.0001 30% (95% CI: 3.5-47.6) HA p<0.0001 20% 0.5 11% 0.26 Percent Mean 10% 0 0% Placebo Lonvo-z Placebo Lonvo-z All other key secondary endpoints were achieved with high statistical significance (p<0.0001) 100% of Patients in Lonvo-z Arm Experienced Attack-Rate Reductions from Baseline During Weeks 5-28 Clinically relevant Attack-free and 62% 38% 72% mean attack-rate therapy-free reduction* All patients who received lonvo-z at baseline or in crossover were LTP-free Attack-Rate Reduction Observed Quickly Following Lonvo-z Dosing; Further Reduction Observed in Early Crossover Data Following Week 28 Mean Monthly Investigator-Confirmed HAE Attack Rate Over Time Lonvo-z Placebo Placebo?Lonvo-z (post crossover) per 5 Start of Crossover Period (SE) 4 Attacks E Mean 3 HA of 2 Month, Number 1 0 BL 4 8 12 16 20 24 28 32 36 40 44 48 LTP wash-out Weeks Since Initial Infusion Lonvo-z (n) 52 52 52 52 52 52 50 44 43 20 8 6 3 Placebo (n) 28 28 28 27 27 27 25 21 0 0 0 0 0 Placebo?Lonvo-z (n) 0 0 0 0 0 0 0 0 20 12 3 0 0 Favorable Safety and Tolerability Data Primary Observation Period • No SAEs or Grade ?3 TEAEs Lonvo-z (N=52) Placebo (N=28) (Weeks 1 – 28) reported in lonvo-z arm TEAEs in ?10% of patients, n (%) • All IRRs were mild or moderate and Infusion-related reaction 32 (62%) 5 (18%) were transient Headache 10 (19%) 3 (11%) • No meaningful difference between arms in clinical chemistries; single Fatigue 7 (14%) 3 (11%) Grade 2 ALT elevation observed in Nasopharyngitis 7 (14%) 9 (32%) lonvo-z arm that self-resolved in one Back pain 6 (12%) 3 (11%) week Upper respiratory tract infection 6 (12%) 2 (7%) • Consistent safety and tolerability data observed in crossover following week Serious TEAEs 0 1 (4%)* 28 as of data cutoff Grade ?3 TEAEs 0 0 HAELO Data Summary • Novel one-time investigational treatment • Primary and all key secondary endpoints achieved. During the six-month efficacy observation period: – 87% attack-reduction rate for lonvo-z vs. placebo – 62% of patients entirely free from attacks (and therapy) • All patients in lonvo-z arm saw a reduction in attack rate from baseline • Early crossover data trending favorably with attack rates approaching zero in both trial arms • Favorable safety and tolerability data
HAELO Phase 3 Clinical Data Dr. Marc Riedl Professor of Medicine, Clinical Director of the U.S. Hereditary Angioedema Association (HAEA) Angioedema Center at the University of California San Diego; HAELO principal investigator A Placebo-Controlled, Double-Blind, Randomized Phase 3 Trial of Lonvo-z as a One-Time HAE Treatment End of Study Day 1 Week 28 Week 104 Lonvo-z 50 mg Placebo (n=52) All patients Efficacy invited to Screening 1 Screening 2 One-time infusion evaluation Optional, Follow-up enroll in the LTP washout Run-in period period blinded crossover (76 weeks) long-term (4-8 weeks) randomization 2:1 (Weeks 5-28) follow-up Placebo study Lonvo-z 50 mg (n=28) Key Secondary En dpoints Stratification Primary En dpoint • Time-normalized number of investigator-confirmed HAE attacks requiring Baseline number of investigator- Time-normalized number of on-demand treatment from Weeks 5 through 28 confirmed HAE attacks per month from investigator-confirmed HAE attacks Screening 2 to Randomization from Weeks 5 through 28 • Time-normalized number of moderate or severe investigator-confirmed HAE attacks from Weeks 5 through 28 • Investigator-confirmed HAE attack-free status from Weeks 5 through 28 • Change from baseline to Week 28 in AE-QoL Questionnaire total score Pre-specified primary analysis when ?60 patients reach Week 28 HAELO Phase 3 Demographics and Baseline Characteristics Demographic Characteristics Lonvo-z (n=52) Placebo (n=28) Age, median years (range) 42 (23 – 71) 40 (19 – 76) Female, n (%) 35 (67%) 20 (71%) Enrolled in United States, n (%) 26 (50%) 13 (46%) Hereditary angioedema type, n (%) Type 1 49 (94%) 25 (89%) Type 2 3 (6%) 3 (11%) Long-term prophylaxis at study entry, n (%) 35 (67%) 22 (79%) Lanadelumab 25 (48%) 12 (43%) C1 esterase inhibitor 5 (10%) 3 (11%) Berotralstat 4 (8%) 1 (4%) Garadacimab 1 (2%) 3 (11%) Other 2 (4%) 3 (11%) On-Demand therapy only, n (%) 17 (33%) 6 (21%) Historic typical attack severity, n (%) Mild 7 (14%) 5 (18%) Moderate 30 (58%) 20 (71%) Severe 15 (29%) 3 (11%) Monthly attack rate during run-in, mean (SD)* 3.5 (1.8) 3.5 (1.9) Median follow-up for enrolled patients: 7.5 months HAELO Trial Achieved its Primary and All Key Secondary Endpoints Mean Attack-Rate Reduction Weeks 5—28 Attack Free Weeks 5—28 (Primary Endpoint) 1,2 (Key Secondary Endpoint) 2 2.5 70% 2.10 62% 60% 2 50% 1.5 87% reduction patients of 40% Odds Ratio 12.8 attacks/month (95% CI: 78%-93%) E 1 p<0.0001 30% (95% CI: 3.5-47.6) HA p<0.0001 20% 0.5 11% 0.26 Percent Mean 10% 0 0% Placebo Lonvo-z Placebo Lonvo-z All other key secondary endpoints were achieved with high statistical significance (p<0.0001) 100% of Patients in Lonvo-z Arm Experienced Attack-Rate Reductions from Baseline During Weeks 5-28 Clinically relevant Attack-free and 62% 38% 72% mean attack-rate therapy-free reduction* All patients who received lonvo-z at baseline or in crossover were LTP-free Attack-Rate Reduction Observed Quickly Following Lonvo-z Dosing; Further Reduction Observed in Early Crossover Data Following Week 28 Mean Monthly Investigator-Confirmed HAE Attack Rate Over Time Lonvo-z Placebo Placebo?Lonvo-z (post crossover) per 5 Start of Crossover Period (SE) 4 Attacks E Mean 3 HA of 2 Month, Number 1 0 BL 4 8 12 16 20 24 28 32 36 40 44 48 LTP wash-out Weeks Since Initial Infusion Lonvo-z (n) 52 52 52 52 52 52 50 44 43 20 8 6 3 Placebo (n) 28 28 28 27 27 27 25 21 0 0 0 0 0 Placebo?Lonvo-z (n) 0 0 0 0 0 0 0 0 20 12 3 0 0 Favorable Safety and Tolerability Data Primary Observation Period • No SAEs or Grade ?3 TEAEs Lonvo-z (N=52) Placebo (N=28) (Weeks 1 – 28) reported in lonvo-z arm TEAEs in ?10% of patients, n (%) • All IRRs were mild or moderate and Infusion-related reaction 32 (62%) 5 (18%) were transient Headache 10 (19%) 3 (11%) • No meaningful difference between arms in clinical chemistries; single Fatigue 7 (14%) 3 (11%) Grade 2 ALT elevation observed in Nasopharyngitis 7 (14%) 9 (32%) lonvo-z arm that self-resolved in one Back pain 6 (12%) 3 (11%) week Upper respiratory tract infection 6 (12%) 2 (7%) • Consistent safety and tolerability data observed in crossover following week Serious TEAEs 0 1 (4%)* 28 as of data cutoff Grade ?3 TEAEs 0 0 HAELO Data Summary • Novel one-time investigational treatment • Primary and all key secondary endpoints achieved. During the six-month efficacy observation period: – 87% attack-reduction rate for lonvo-z vs. placebo – 62% of patients entirely free from attacks (and therapy) • All patients in lonvo-z arm saw a reduction in attack rate from baseline • Early crossover data trending favorably with attack rates approaching zero in both trial arms • Favorable safety and tolerability data Advancing Toward Lonvo-z’s Planned Launch Dr. John Leonard President & CEO, Intellia Therapeutics
HAELO Phase 3 Clinical Data Dr. Marc Riedl Professor of Medicine, Clinical Director of the U.S. Hereditary Angioedema Association (HAEA) Angioedema Center at the University of California San Diego; HAELO principal investigator A Placebo-Controlled, Double-Blind, Randomized Phase 3 Trial of Lonvo-z as a One-Time HAE Treatment End of Study Day 1 Week 28 Week 104 Lonvo-z 50 mg Placebo (n=52) All patients Efficacy invited to Screening 1 Screening 2 One-time infusion evaluation Optional, Follow-up enroll in the LTP washout Run-in period period blinded crossover (76 weeks) long-term (4-8 weeks) randomization 2:1 (Weeks 5-28) follow-up Placebo study Lonvo-z 50 mg (n=28) Key Secondary En dpoints Stratification Primary En dpoint • Time-normalized number of investigator-confirmed HAE attacks requiring Baseline number of investigator- Time-normalized number of on-demand treatment from Weeks 5 through 28 confirmed HAE attacks per month from investigator-confirmed HAE attacks Screening 2 to Randomization from Weeks 5 through 28 • Time-normalized number of moderate or severe investigator-confirmed HAE attacks from Weeks 5 through 28 • Investigator-confirmed HAE attack-free status from Weeks 5 through 28 • Change from baseline to Week 28 in AE-QoL Questionnaire total score Pre-specified primary analysis when ?60 patients reach Week 28 HAELO Phase 3 Demographics and Baseline Characteristics Demographic Characteristics Lonvo-z (n=52) Placebo (n=28) Age, median years (range) 42 (23 – 71) 40 (19 – 76) Female, n (%) 35 (67%) 20 (71%) Enrolled in United States, n (%) 26 (50%) 13 (46%) Hereditary angioedema type, n (%) Type 1 49 (94%) 25 (89%) Type 2 3 (6%) 3 (11%) Long-term prophylaxis at study entry, n (%) 35 (67%) 22 (79%) Lanadelumab 25 (48%) 12 (43%) C1 esterase inhibitor 5 (10%) 3 (11%) Berotralstat 4 (8%) 1 (4%) Garadacimab 1 (2%) 3 (11%) Other 2 (4%) 3 (11%) On-Demand therapy only, n (%) 17 (33%) 6 (21%) Historic typical attack severity, n (%) Mild 7 (14%) 5 (18%) Moderate 30 (58%) 20 (71%) Severe 15 (29%) 3 (11%) Monthly attack rate during run-in, mean (SD)* 3.5 (1.8) 3.5 (1.9) Median follow-up for enrolled patients: 7.5 months HAELO Trial Achieved its Primary and All Key Secondary Endpoints Mean Attack-Rate Reduction Weeks 5—28 Attack Free Weeks 5—28 (Primary Endpoint) 1,2 (Key Secondary Endpoint) 2 2.5 70% 2.10 62% 60% 2 50% 1.5 87% reduction patients of 40% Odds Ratio 12.8 attacks/month (95% CI: 78%-93%) E 1 p<0.0001 30% (95% CI: 3.5-47.6) HA p<0.0001 20% 0.5 11% 0.26 Percent Mean 10% 0 0% Placebo Lonvo-z Placebo Lonvo-z All other key secondary endpoints were achieved with high statistical significance (p<0.0001) 100% of Patients in Lonvo-z Arm Experienced Attack-Rate Reductions from Baseline During Weeks 5-28 Clinically relevant Attack-free and 62% 38% 72% mean attack-rate therapy-free reduction* All patients who received lonvo-z at baseline or in crossover were LTP-free Attack-Rate Reduction Observed Quickly Following Lonvo-z Dosing; Further Reduction Observed in Early Crossover Data Following Week 28 Mean Monthly Investigator-Confirmed HAE Attack Rate Over Time Lonvo-z Placebo Placebo?Lonvo-z (post crossover) per 5 Start of Crossover Period (SE) 4 Attacks E Mean 3 HA of 2 Month, Number 1 0 BL 4 8 12 16 20 24 28 32 36 40 44 48 LTP wash-out Weeks Since Initial Infusion Lonvo-z (n) 52 52 52 52 52 52 50 44 43 20 8 6 3 Placebo (n) 28 28 28 27 27 27 25 21 0 0 0 0 0 Placebo?Lonvo-z (n) 0 0 0 0 0 0 0 0 20 12 3 0 0 Favorable Safety and Tolerability Data Primary Observation Period • No SAEs or Grade ?3 TEAEs Lonvo-z (N=52) Placebo (N=28) (Weeks 1 – 28) reported in lonvo-z arm TEAEs in ?10% of patients, n (%) • All IRRs were mild or moderate and Infusion-related reaction 32 (62%) 5 (18%) were transient Headache 10 (19%) 3 (11%) • No meaningful difference between arms in clinical chemistries; single Fatigue 7 (14%) 3 (11%) Grade 2 ALT elevation observed in Nasopharyngitis 7 (14%) 9 (32%) lonvo-z arm that self-resolved in one Back pain 6 (12%) 3 (11%) week Upper respiratory tract infection 6 (12%) 2 (7%) • Consistent safety and tolerability data observed in crossover following week Serious TEAEs 0 1 (4%)* 28 as of data cutoff Grade ?3 TEAEs 0 0 HAELO Data Summary • Novel one-time investigational treatment • Primary and all key secondary endpoints achieved. During the six-month efficacy observation period: – 87% attack-reduction rate for lonvo-z vs. placebo – 62% of patients entirely free from attacks (and therapy) • All patients in lonvo-z arm saw a reduction in attack rate from baseline • Early crossover data trending favorably with attack rates approaching zero in both trial arms • Favorable safety and tolerability data Advancing Toward Lonvo-z’s Planned Launch Dr. John Leonard President & CEO, Intellia Therapeutics Additional HAELO Perspectives Significant Diverse Mix Extensive Patient Enthusiasm of Patients (and Still Expanding) Phase 3 Database 80 patients enrolled Multi-national trial with (original target: ?60) ~50% of enrolled patients Longest Phase 3 trial in U.S.; broad age range undertaken in HAE to date, All patients dosed within once completed nine months Population includes patients: With complete HAE control; Largest cohort of patients ~70% of patients washed partial control at entry receiving proposed label dose out of LTP to enroll (50 mg of lonvo-z) Who were on LTP and/or on-demand therapies at entry
HAELO Phase 3 Clinical Data Dr. Marc Riedl Professor of Medicine, Clinical Director of the U.S. Hereditary Angioedema Association (HAEA) Angioedema Center at the University of California San Diego; HAELO principal investigator A Placebo-Controlled, Double-Blind, Randomized Phase 3 Trial of Lonvo-z as a One-Time HAE Treatment End of Study Day 1 Week 28 Week 104 Lonvo-z 50 mg Placebo (n=52) All patients Efficacy invited to Screening 1 Screening 2 One-time infusion evaluation Optional, Follow-up enroll in the LTP washout Run-in period period blinded crossover (76 weeks) long-term (4-8 weeks) randomization 2:1 (Weeks 5-28) follow-up Placebo study Lonvo-z 50 mg (n=28) Key Secondary En dpoints Stratification Primary En dpoint • Time-normalized number of investigator-confirmed HAE attacks requiring Baseline number of investigator- Time-normalized number of on-demand treatment from Weeks 5 through 28 confirmed HAE attacks per month from investigator-confirmed HAE attacks Screening 2 to Randomization from Weeks 5 through 28 • Time-normalized number of moderate or severe investigator-confirmed HAE attacks from Weeks 5 through 28 • Investigator-confirmed HAE attack-free status from Weeks 5 through 28 • Change from baseline to Week 28 in AE-QoL Questionnaire total score Pre-specified primary analysis when ?60 patients reach Week 28 HAELO Phase 3 Demographics and Baseline Characteristics Demographic Characteristics Lonvo-z (n=52) Placebo (n=28) Age, median years (range) 42 (23 – 71) 40 (19 – 76) Female, n (%) 35 (67%) 20 (71%) Enrolled in United States, n (%) 26 (50%) 13 (46%) Hereditary angioedema type, n (%) Type 1 49 (94%) 25 (89%) Type 2 3 (6%) 3 (11%) Long-term prophylaxis at study entry, n (%) 35 (67%) 22 (79%) Lanadelumab 25 (48%) 12 (43%) C1 esterase inhibitor 5 (10%) 3 (11%) Berotralstat 4 (8%) 1 (4%) Garadacimab 1 (2%) 3 (11%) Other 2 (4%) 3 (11%) On-Demand therapy only, n (%) 17 (33%) 6 (21%) Historic typical attack severity, n (%) Mild 7 (14%) 5 (18%) Moderate 30 (58%) 20 (71%) Severe 15 (29%) 3 (11%) Monthly attack rate during run-in, mean (SD)* 3.5 (1.8) 3.5 (1.9) Median follow-up for enrolled patients: 7.5 months HAELO Trial Achieved its Primary and All Key Secondary Endpoints Mean Attack-Rate Reduction Weeks 5—28 Attack Free Weeks 5—28 (Primary Endpoint) 1,2 (Key Secondary Endpoint) 2 2.5 70% 2.10 62% 60% 2 50% 1.5 87% reduction patients of 40% Odds Ratio 12.8 attacks/month (95% CI: 78%-93%) E 1 p<0.0001 30% (95% CI: 3.5-47.6) HA p<0.0001 20% 0.5 11% 0.26 Percent Mean 10% 0 0% Placebo Lonvo-z Placebo Lonvo-z All other key secondary endpoints were achieved with high statistical significance (p<0.0001) 100% of Patients in Lonvo-z Arm Experienced Attack-Rate Reductions from Baseline During Weeks 5-28 Clinically relevant Attack-free and 62% 38% 72% mean attack-rate therapy-free reduction* All patients who received lonvo-z at baseline or in crossover were LTP-free Attack-Rate Reduction Observed Quickly Following Lonvo-z Dosing; Further Reduction Observed in Early Crossover Data Following Week 28 Mean Monthly Investigator-Confirmed HAE Attack Rate Over Time Lonvo-z Placebo Placebo?Lonvo-z (post crossover) per 5 Start of Crossover Period (SE) 4 Attacks E Mean 3 HA of 2 Month, Number 1 0 BL 4 8 12 16 20 24 28 32 36 40 44 48 LTP wash-out Weeks Since Initial Infusion Lonvo-z (n) 52 52 52 52 52 52 50 44 43 20 8 6 3 Placebo (n) 28 28 28 27 27 27 25 21 0 0 0 0 0 Placebo?Lonvo-z (n) 0 0 0 0 0 0 0 0 20 12 3 0 0 Favorable Safety and Tolerability Data Primary Observation Period • No SAEs or Grade ?3 TEAEs Lonvo-z (N=52) Placebo (N=28) (Weeks 1 – 28) reported in lonvo-z arm TEAEs in ?10% of patients, n (%) • All IRRs were mild or moderate and Infusion-related reaction 32 (62%) 5 (18%) were transient Headache 10 (19%) 3 (11%) • No meaningful difference between arms in clinical chemistries; single Fatigue 7 (14%) 3 (11%) Grade 2 ALT elevation observed in Nasopharyngitis 7 (14%) 9 (32%) lonvo-z arm that self-resolved in one Back pain 6 (12%) 3 (11%) week Upper respiratory tract infection 6 (12%) 2 (7%) • Consistent safety and tolerability data observed in crossover following week Serious TEAEs 0 1 (4%)* 28 as of data cutoff Grade ?3 TEAEs 0 0 HAELO Data Summary • Novel one-time investigational treatment • Primary and all key secondary endpoints achieved. During the six-month efficacy observation period: – 87% attack-reduction rate for lonvo-z vs. placebo – 62% of patients entirely free from attacks (and therapy) • All patients in lonvo-z arm saw a reduction in attack rate from baseline • Early crossover data trending favorably with attack rates approaching zero in both trial arms • Favorable safety and tolerability data Advancing Toward Lonvo-z’s Planned Launch Dr. John Leonard President & CEO, Intellia Therapeutics Additional HAELO Perspectives Significant Diverse Mix Extensive Patient Enthusiasm of Patients (and Still Expanding) Phase 3 Database 80 patients enrolled Multi-national trial with (original target: ?60) ~50% of enrolled patients Longest Phase 3 trial in U.S.; broad age range undertaken in HAE to date, All patients dosed within once completed nine months Population includes patients: With complete HAE control; Largest cohort of patients ~70% of patients washed partial control at entry receiving proposed label dose out of LTP to enroll (50 mg of lonvo-z) Who were on LTP and/or on-demand therapies at entry Lonvo-z: Unique Potential to Eliminate Attacks and Ongoing with One Treatment PHASE 3 CR OSS -T RIA L COM PARISO N* % of Patients Attack % Attack Reduction % of Patients Product & Therapy Free* vs. Placebo* Attack Free* Lifetime Dosing Burden lonvo-z 1x 62% 87% 62% (investigational) infusion 1 Daily berotralstat 0% 44% n/a therapies oral tablets 2 104 C1 est. inh. 0% 87% n/a (LTP) injections / year 3 7–13 donidalorsen 0% 55-81% 35-53% prophylaxis injections / year term 4 13—garadacimab 0% 89% 62% long injections / year 5 13–26 lanadelumab 0% 74-87% 31-44% Chronic injections / year For illustrative purposes only.
HAELO Phase 3 Clinical Data Dr. Marc Riedl Professor of Medicine, Clinical Director of the U.S. Hereditary Angioedema Association (HAEA) Angioedema Center at the University of California San Diego; HAELO principal investigator A Placebo-Controlled, Double-Blind, Randomized Phase 3 Trial of Lonvo-z as a One-Time HAE Treatment End of Study Day 1 Week 28 Week 104 Lonvo-z 50 mg Placebo (n=52) All patients Efficacy invited to Screening 1 Screening 2 One-time infusion evaluation Optional, Follow-up enroll in the LTP washout Run-in period period blinded crossover (76 weeks) long-term (4-8 weeks) randomization 2:1 (Weeks 5-28) follow-up Placebo study Lonvo-z 50 mg (n=28) Key Secondary En dpoints Stratification Primary En dpoint • Time-normalized number of investigator-confirmed HAE attacks requiring Baseline number of investigator- Time-normalized number of on-demand treatment from Weeks 5 through 28 confirmed HAE attacks per month from investigator-confirmed HAE attacks Screening 2 to Randomization from Weeks 5 through 28 • Time-normalized number of moderate or severe investigator-confirmed HAE attacks from Weeks 5 through 28 • Investigator-confirmed HAE attack-free status from Weeks 5 through 28 • Change from baseline to Week 28 in AE-QoL Questionnaire total score Pre-specified primary analysis when ?60 patients reach Week 28 HAELO Phase 3 Demographics and Baseline Characteristics Demographic Characteristics Lonvo-z (n=52) Placebo (n=28) Age, median years (range) 42 (23 – 71) 40 (19 – 76) Female, n (%) 35 (67%) 20 (71%) Enrolled in United States, n (%) 26 (50%) 13 (46%) Hereditary angioedema type, n (%) Type 1 49 (94%) 25 (89%) Type 2 3 (6%) 3 (11%) Long-term prophylaxis at study entry, n (%) 35 (67%) 22 (79%) Lanadelumab 25 (48%) 12 (43%) C1 esterase inhibitor 5 (10%) 3 (11%) Berotralstat 4 (8%) 1 (4%) Garadacimab 1 (2%) 3 (11%) Other 2 (4%) 3 (11%) On-Demand therapy only, n (%) 17 (33%) 6 (21%) Historic typical attack severity, n (%) Mild 7 (14%) 5 (18%) Moderate 30 (58%) 20 (71%) Severe 15 (29%) 3 (11%) Monthly attack rate during run-in, mean (SD)* 3.5 (1.8) 3.5 (1.9) Median follow-up for enrolled patients: 7.5 months HAELO Trial Achieved its Primary and All Key Secondary Endpoints Mean Attack-Rate Reduction Weeks 5—28 Attack Free Weeks 5—28 (Primary Endpoint) 1,2 (Key Secondary Endpoint) 2 2.5 70% 2.10 62% 60% 2 50% 1.5 87% reduction patients of 40% Odds Ratio 12.8 attacks/month (95% CI: 78%-93%) E 1 p<0.0001 30% (95% CI: 3.5-47.6) HA p<0.0001 20% 0.5 11% 0.26 Percent Mean 10% 0 0% Placebo Lonvo-z Placebo Lonvo-z All other key secondary endpoints were achieved with high statistical significance (p<0.0001) 100% of Patients in Lonvo-z Arm Experienced Attack-Rate Reductions from Baseline During Weeks 5-28 Clinically relevant Attack-free and 62% 38% 72% mean attack-rate therapy-free reduction* All patients who received lonvo-z at baseline or in crossover were LTP-free Attack-Rate Reduction Observed Quickly Following Lonvo-z Dosing; Further Reduction Observed in Early Crossover Data Following Week 28 Mean Monthly Investigator-Confirmed HAE Attack Rate Over Time Lonvo-z Placebo Placebo?Lonvo-z (post crossover) per 5 Start of Crossover Period (SE) 4 Attacks E Mean 3 HA of 2 Month, Number 1 0 BL 4 8 12 16 20 24 28 32 36 40 44 48 LTP wash-out Weeks Since Initial Infusion Lonvo-z (n) 52 52 52 52 52 52 50 44 43 20 8 6 3 Placebo (n) 28 28 28 27 27 27 25 21 0 0 0 0 0 Placebo?Lonvo-z (n) 0 0 0 0 0 0 0 0 20 12 3 0 0 Favorable Safety and Tolerability Data Primary Observation Period • No SAEs or Grade ?3 TEAEs Lonvo-z (N=52) Placebo (N=28) (Weeks 1 – 28) reported in lonvo-z arm TEAEs in ?10% of patients, n (%) • All IRRs were mild or moderate and Infusion-related reaction 32 (62%) 5 (18%) were transient Headache 10 (19%) 3 (11%) • No meaningful difference between arms in clinical chemistries; single Fatigue 7 (14%) 3 (11%) Grade 2 ALT elevation observed in Nasopharyngitis 7 (14%) 9 (32%) lonvo-z arm that self-resolved in one Back pain 6 (12%) 3 (11%) week Upper respiratory tract infection 6 (12%) 2 (7%) • Consistent safety and tolerability data observed in crossover following week Serious TEAEs 0 1 (4%)* 28 as of data cutoff Grade ?3 TEAEs 0 0 HAELO Data Summary • Novel one-time investigational treatment • Primary and all key secondary endpoints achieved. During the six-month efficacy observation period: – 87% attack-reduction rate for lonvo-z vs. placebo – 62% of patients entirely free from attacks (and therapy) • All patients in lonvo-z arm saw a reduction in attack rate from baseline • Early crossover data trending favorably with attack rates approaching zero in both trial arms • Favorable safety and tolerability data Advancing Toward Lonvo-z’s Planned Launch Dr. John Leonard President & CEO, Intellia Therapeutics Additional HAELO Perspectives Significant Diverse Mix Extensive Patient Enthusiasm of Patients (and Still Expanding) Phase 3 Database 80 patients enrolled Multi-national trial with (original target: ?60) ~50% of enrolled patients Longest Phase 3 trial in U.S.; broad age range undertaken in HAE to date, All patients dosed within once completed nine months Population includes patients: With complete HAE control; Largest cohort of patients ~70% of patients washed partial control at entry receiving proposed label dose out of LTP to enroll (50 mg of lonvo-z) Who were on LTP and/or on-demand therapies at entry Lonvo-z: Unique Potential to Eliminate Attacks and Ongoing with One Treatment PHASE 3 CR OSS -T RIA L COM PARISO N* % of Patients Attack % Attack Reduction % of Patients Product & Therapy Free* vs. Placebo* Attack Free* Lifetime Dosing Burden lonvo-z 1x 62% 87% 62% (investigational) infusion 1 Daily berotralstat 0% 44% n/a therapies oral tablets 2 104 C1 est. inh. 0% 87% n/a (LTP) injections / year 3 7–13 donidalorsen 0% 55-81% 35-53% prophylaxis injections / year term 4 13—garadacimab 0% 89% 62% long injections / year 5 13–26 lanadelumab 0% 74-87% 31-44% Chronic injections / year For illustrative purposes only. Preparing for a Successful Launch in 1H 2027* Established core commercialization team Deployed field medical team Priorities ahead… Finalized overall launch strategy Complete BLA submission Commenced payer engagement Scale field sales and reimbursement teams Continued patient advocacy group/medical society engagements Finalize pricing Finalized distribution model for launch Finalize contracting strategy Identified potential treatment centers Initiated rolling BLA submission with FDA 2025 Accomplishment 2026 Accomplishment
HAELO Phase 3 Clinical Data Dr. Marc Riedl Professor of Medicine, Clinical Director of the U.S. Hereditary Angioedema Association (HAEA) Angioedema Center at the University of California San Diego; HAELO principal investigator A Placebo-Controlled, Double-Blind, Randomized Phase 3 Trial of Lonvo-z as a One-Time HAE Treatment End of Study Day 1 Week 28 Week 104 Lonvo-z 50 mg Placebo (n=52) All patients Efficacy invited to Screening 1 Screening 2 One-time infusion evaluation Optional, Follow-up enroll in the LTP washout Run-in period period blinded crossover (76 weeks) long-term (4-8 weeks) randomization 2:1 (Weeks 5-28) follow-up Placebo study Lonvo-z 50 mg (n=28) Key Secondary En dpoints Stratification Primary En dpoint • Time-normalized number of investigator-confirmed HAE attacks requiring Baseline number of investigator- Time-normalized number of on-demand treatment from Weeks 5 through 28 confirmed HAE attacks per month from investigator-confirmed HAE attacks Screening 2 to Randomization from Weeks 5 through 28 • Time-normalized number of moderate or severe investigator-confirmed HAE attacks from Weeks 5 through 28 • Investigator-confirmed HAE attack-free status from Weeks 5 through 28 • Change from baseline to Week 28 in AE-QoL Questionnaire total score Pre-specified primary analysis when ?60 patients reach Week 28 HAELO Phase 3 Demographics and Baseline Characteristics Demographic Characteristics Lonvo-z (n=52) Placebo (n=28) Age, median years (range) 42 (23 – 71) 40 (19 – 76) Female, n (%) 35 (67%) 20 (71%) Enrolled in United States, n (%) 26 (50%) 13 (46%) Hereditary angioedema type, n (%) Type 1 49 (94%) 25 (89%) Type 2 3 (6%) 3 (11%) Long-term prophylaxis at study entry, n (%) 35 (67%) 22 (79%) Lanadelumab 25 (48%) 12 (43%) C1 esterase inhibitor 5 (10%) 3 (11%) Berotralstat 4 (8%) 1 (4%) Garadacimab 1 (2%) 3 (11%) Other 2 (4%) 3 (11%) On-Demand therapy only, n (%) 17 (33%) 6 (21%) Historic typical attack severity, n (%) Mild 7 (14%) 5 (18%) Moderate 30 (58%) 20 (71%) Severe 15 (29%) 3 (11%) Monthly attack rate during run-in, mean (SD)* 3.5 (1.8) 3.5 (1.9) Median follow-up for enrolled patients: 7.5 months HAELO Trial Achieved its Primary and All Key Secondary Endpoints Mean Attack-Rate Reduction Weeks 5—28 Attack Free Weeks 5—28 (Primary Endpoint) 1,2 (Key Secondary Endpoint) 2 2.5 70% 2.10 62% 60% 2 50% 1.5 87% reduction patients of 40% Odds Ratio 12.8 attacks/month (95% CI: 78%-93%) E 1 p<0.0001 30% (95% CI: 3.5-47.6) HA p<0.0001 20% 0.5 11% 0.26 Percent Mean 10% 0 0% Placebo Lonvo-z Placebo Lonvo-z All other key secondary endpoints were achieved with high statistical significance (p<0.0001) 100% of Patients in Lonvo-z Arm Experienced Attack-Rate Reductions from Baseline During Weeks 5-28 Clinically relevant Attack-free and 62% 38% 72% mean attack-rate therapy-free reduction* All patients who received lonvo-z at baseline or in crossover were LTP-free Attack-Rate Reduction Observed Quickly Following Lonvo-z Dosing; Further Reduction Observed in Early Crossover Data Following Week 28 Mean Monthly Investigator-Confirmed HAE Attack Rate Over Time Lonvo-z Placebo Placebo?Lonvo-z (post crossover) per 5 Start of Crossover Period (SE) 4 Attacks E Mean 3 HA of 2 Month, Number 1 0 BL 4 8 12 16 20 24 28 32 36 40 44 48 LTP wash-out Weeks Since Initial Infusion Lonvo-z (n) 52 52 52 52 52 52 50 44 43 20 8 6 3 Placebo (n) 28 28 28 27 27 27 25 21 0 0 0 0 0 Placebo?Lonvo-z (n) 0 0 0 0 0 0 0 0 20 12 3 0 0 Favorable Safety and Tolerability Data Primary Observation Period • No SAEs or Grade ?3 TEAEs Lonvo-z (N=52) Placebo (N=28) (Weeks 1 – 28) reported in lonvo-z arm TEAEs in ?10% of patients, n (%) • All IRRs were mild or moderate and Infusion-related reaction 32 (62%) 5 (18%) were transient Headache 10 (19%) 3 (11%) • No meaningful difference between arms in clinical chemistries; single Fatigue 7 (14%) 3 (11%) Grade 2 ALT elevation observed in Nasopharyngitis 7 (14%) 9 (32%) lonvo-z arm that self-resolved in one Back pain 6 (12%) 3 (11%) week Upper respiratory tract infection 6 (12%) 2 (7%) • Consistent safety and tolerability data observed in crossover following week Serious TEAEs 0 1 (4%)* 28 as of data cutoff Grade ?3 TEAEs 0 0 HAELO Data Summary • Novel one-time investigational treatment • Primary and all key secondary endpoints achieved. During the six-month efficacy observation period: – 87% attack-reduction rate for lonvo-z vs. placebo – 62% of patients entirely free from attacks (and therapy) • All patients in lonvo-z arm saw a reduction in attack rate from baseline • Early crossover data trending favorably with attack rates approaching zero in both trial arms • Favorable safety and tolerability data Advancing Toward Lonvo-z’s Planned Launch Dr. John Leonard President & CEO, Intellia Therapeutics Additional HAELO Perspectives Significant Diverse Mix Extensive Patient Enthusiasm of Patients (and Still Expanding) Phase 3 Database 80 patients enrolled Multi-national trial with (original target: ?60) ~50% of enrolled patients Longest Phase 3 trial in U.S.; broad age range undertaken in HAE to date, All patients dosed within once completed nine months Population includes patients: With complete HAE control; Largest cohort of patients ~70% of patients washed partial control at entry receiving proposed label dose out of LTP to enroll (50 mg of lonvo-z) Who were on LTP and/or on-demand therapies at entry Lonvo-z: Unique Potential to Eliminate Attacks and Ongoing with One Treatment PHASE 3 CR OSS -T RIA L COM PARISO N* % of Patients Attack % Attack Reduction % of Patients Product & Therapy Free* vs. Placebo* Attack Free* Lifetime Dosing Burden lonvo-z 1x 62% 87% 62% (investigational) infusion 1 Daily berotralstat 0% 44% n/a therapies oral tablets 2 104 C1 est. inh. 0% 87% n/a (LTP) injections / year 3 7–13 donidalorsen 0% 55-81% 35-53% prophylaxis injections / year term 4 13—garadacimab 0% 89% 62% long injections / year 5 13–26 lanadelumab 0% 74-87% 31-44% Chronic injections / year For illustrative purposes only. Preparing for a Successful Launch in 1H 2027* Established core commercialization team Deployed field medical team Priorities ahead… Finalized overall launch strategy Complete BLA submission Commenced payer engagement Scale field sales and reimbursement teams Continued patient advocacy group/medical society engagements Finalize pricing Finalized distribution model for launch Finalize contracting strategy Identified potential treatment centers Initiated rolling BLA submission with FDA 2025 Accomplishment 2026 Accomplishment Summary #1 HAELO trial achieved Global first Intellia advancing its primary and all key for in vivo rapidly toward secondary endpoints gene editing potential approval with favorable safety and first planned and tolerability data launch in 1H 2027*
HAELO Phase 3 Clinical Data Dr. Marc Riedl Professor of Medicine, Clinical Director of the U.S. Hereditary Angioedema Association (HAEA) Angioedema Center at the University of California San Diego; HAELO principal investigator A Placebo-Controlled, Double-Blind, Randomized Phase 3 Trial of Lonvo-z as a One-Time HAE Treatment End of Study Day 1 Week 28 Week 104 Lonvo-z 50 mg Placebo (n=52) All patients Efficacy invited to Screening 1 Screening 2 One-time infusion evaluation Optional, Follow-up enroll in the LTP washout Run-in period period blinded crossover (76 weeks) long-term (4-8 weeks) randomization 2:1 (Weeks 5-28) follow-up Placebo study Lonvo-z 50 mg (n=28) Key Secondary En dpoints Stratification Primary En dpoint • Time-normalized number of investigator-confirmed HAE attacks requiring Baseline number of investigator- Time-normalized number of on-demand treatment from Weeks 5 through 28 confirmed HAE attacks per month from investigator-confirmed HAE attacks Screening 2 to Randomization from Weeks 5 through 28 • Time-normalized number of moderate or severe investigator-confirmed HAE attacks from Weeks 5 through 28 • Investigator-confirmed HAE attack-free status from Weeks 5 through 28 • Change from baseline to Week 28 in AE-QoL Questionnaire total score Pre-specified primary analysis when ?60 patients reach Week 28 HAELO Phase 3 Demographics and Baseline Characteristics Demographic Characteristics Lonvo-z (n=52) Placebo (n=28) Age, median years (range) 42 (23 – 71) 40 (19 – 76) Female, n (%) 35 (67%) 20 (71%) Enrolled in United States, n (%) 26 (50%) 13 (46%) Hereditary angioedema type, n (%) Type 1 49 (94%) 25 (89%) Type 2 3 (6%) 3 (11%) Long-term prophylaxis at study entry, n (%) 35 (67%) 22 (79%) Lanadelumab 25 (48%) 12 (43%) C1 esterase inhibitor 5 (10%) 3 (11%) Berotralstat 4 (8%) 1 (4%) Garadacimab 1 (2%) 3 (11%) Other 2 (4%) 3 (11%) On-Demand therapy only, n (%) 17 (33%) 6 (21%) Historic typical attack severity, n (%) Mild 7 (14%) 5 (18%) Moderate 30 (58%) 20 (71%) Severe 15 (29%) 3 (11%) Monthly attack rate during run-in, mean (SD)* 3.5 (1.8) 3.5 (1.9) Median follow-up for enrolled patients: 7.5 months HAELO Trial Achieved its Primary and All Key Secondary Endpoints Mean Attack-Rate Reduction Weeks 5—28 Attack Free Weeks 5—28 (Primary Endpoint) 1,2 (Key Secondary Endpoint) 2 2.5 70% 2.10 62% 60% 2 50% 1.5 87% reduction patients of 40% Odds Ratio 12.8 attacks/month (95% CI: 78%-93%) E 1 p<0.0001 30% (95% CI: 3.5-47.6) HA p<0.0001 20% 0.5 11% 0.26 Percent Mean 10% 0 0% Placebo Lonvo-z Placebo Lonvo-z All other key secondary endpoints were achieved with high statistical significance (p<0.0001) 100% of Patients in Lonvo-z Arm Experienced Attack-Rate Reductions from Baseline During Weeks 5-28 Clinically relevant Attack-free and 62% 38% 72% mean attack-rate therapy-free reduction* All patients who received lonvo-z at baseline or in crossover were LTP-free Attack-Rate Reduction Observed Quickly Following Lonvo-z Dosing; Further Reduction Observed in Early Crossover Data Following Week 28 Mean Monthly Investigator-Confirmed HAE Attack Rate Over Time Lonvo-z Placebo Placebo?Lonvo-z (post crossover) per 5 Start of Crossover Period (SE) 4 Attacks E Mean 3 HA of 2 Month, Number 1 0 BL 4 8 12 16 20 24 28 32 36 40 44 48 LTP wash-out Weeks Since Initial Infusion Lonvo-z (n) 52 52 52 52 52 52 50 44 43 20 8 6 3 Placebo (n) 28 28 28 27 27 27 25 21 0 0 0 0 0 Placebo?Lonvo-z (n) 0 0 0 0 0 0 0 0 20 12 3 0 0 Favorable Safety and Tolerability Data Primary Observation Period • No SAEs or Grade ?3 TEAEs Lonvo-z (N=52) Placebo (N=28) (Weeks 1 – 28) reported in lonvo-z arm TEAEs in ?10% of patients, n (%) • All IRRs were mild or moderate and Infusion-related reaction 32 (62%) 5 (18%) were transient Headache 10 (19%) 3 (11%) • No meaningful difference between arms in clinical chemistries; single Fatigue 7 (14%) 3 (11%) Grade 2 ALT elevation observed in Nasopharyngitis 7 (14%) 9 (32%) lonvo-z arm that self-resolved in one Back pain 6 (12%) 3 (11%) week Upper respiratory tract infection 6 (12%) 2 (7%) • Consistent safety and tolerability data observed in crossover following week Serious TEAEs 0 1 (4%)* 28 as of data cutoff Grade ?3 TEAEs 0 0 HAELO Data Summary • Novel one-time investigational treatment • Primary and all key secondary endpoints achieved. During the six-month efficacy observation period: – 87% attack-reduction rate for lonvo-z vs. placebo – 62% of patients entirely free from attacks (and therapy) • All patients in lonvo-z arm saw a reduction in attack rate from baseline • Early crossover data trending favorably with attack rates approaching zero in both trial arms • Favorable safety and tolerability data Advancing Toward Lonvo-z’s Planned Launch Dr. John Leonard President & CEO, Intellia Therapeutics Additional HAELO Perspectives Significant Diverse Mix Extensive Patient Enthusiasm of Patients (and Still Expanding) Phase 3 Database 80 patients enrolled Multi-national trial with (original target: ?60) ~50% of enrolled patients Longest Phase 3 trial in U.S.; broad age range undertaken in HAE to date, All patients dosed within once completed nine months Population includes patients: With complete HAE control; Largest cohort of patients ~70% of patients washed partial control at entry receiving proposed label dose out of LTP to enroll (50 mg of lonvo-z) Who were on LTP and/or on-demand therapies at entry Lonvo-z: Unique Potential to Eliminate Attacks and Ongoing with One Treatment PHASE 3 CR OSS -T RIA L COM PARISO N* % of Patients Attack % Attack Reduction % of Patients Product & Therapy Free* vs. Placebo* Attack Free* Lifetime Dosing Burden lonvo-z 1x 62% 87% 62% (investigational) infusion 1 Daily berotralstat 0% 44% n/a therapies oral tablets 2 104 C1 est. inh. 0% 87% n/a (LTP) injections / year 3 7–13 donidalorsen 0% 55-81% 35-53% prophylaxis injections / year term 4 13—garadacimab 0% 89% 62% long injections / year 5 13–26 lanadelumab 0% 74-87% 31-44% Chronic injections / year For illustrative purposes only. Preparing for a Successful Launch in 1H 2027* Established core commercialization team Deployed field medical team Priorities ahead… Finalized overall launch strategy Complete BLA submission Commenced payer engagement Scale field sales and reimbursement teams Continued patient advocacy group/medical society engagements Finalize pricing Finalized distribution model for launch Finalize contracting strategy Identified potential treatment centers Initiated rolling BLA submission with FDA 2025 Accomplishment 2026 Accomplishment Summary #1 HAELO trial achieved Global first Intellia advancing its primary and all key for in vivo rapidly toward secondary endpoints gene editing potential approval with favorable safety and first planned and tolerability data launch in 1H 2027* Thank You! We extend our gratitude to the patients, caregivers, and families who have taken part in the HAELO clinical trial; a decision not taken lightly and rooted in trust and hope. A sincere thank you to the HAELO study investigators, site coordinators and staff whose commitment and hard work made this study possible. We also express our appreciation to the U.S. Hereditary Angioedema Association (HAEA) and HAE International (HAEi) for their invaluable support and partnership throughout this journey. This milestone is a shared achievement that we could not have achieved without the unwavering support of the HAE community.
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