UNITED STATES
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FORM
CURRENT REPORT
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| Item 7.01. | Regulation FD Disclosure. |
On November 2, 2023, Intellia Therapeutics, Inc. (“Intellia”) issued a press release titled “Intellia Presents New Interim Data from the Ongoing Phase 1 Study of NTLA-2001 at the 4th International ATTR Amyloidosis Meeting.” A copy of the press release is furnished as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference.
Additionally, Intellia presented clinical data from its ongoing Phase 1 Study of NTLA-2001 at the 4th International ATTR Amyloidosis Meeting. The presentation materials are attached to this Current Report on Form 8-K as Exhibit 99.2.
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 Securities Exchange Act of 1934, as amended (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. |
Updated Interim Clinical Data of NTLA-2001
On November 2, 2023, Intellia presented additional interim results from its ongoing Phase 1 study of NTLA-2001, an investigational, in vivo CRISPR/Cas9 genome editing therapy in development as a single-dose treatment for transthyretin (ATTR) amyloidosis, at the 4th International ATTR Amyloidosis Meeting in Madrid, Spain. The data presented today, with a cutoff date of May 11, 2023, are from the initial 65 out of 72 patients dosed in the Phase 1 study, which has now completed enrollment. In the newly reported dose-expansion portion, administration of NTLA-2001 at the 55 mg and 80 mg dose led to deep serum TTR reductions consistent with the results previously reported from patients in the dose-escalation portion who received the corresponding weight-based dose, 0.7 mg/kg and 1.0 mg/kg, respectively.
Across all patients who received a dose of 0.3 mg/kg or higher (n=62), the median serum TTR reduction was 91% and the median absolute residual serum TTR concentration was 17 µg/mL at day 28. The reduction of serum TTR compared to baseline was sustained through the latest follow-up. With 29 patients now reaching at least 12 months of follow-up, all patients continued to show a long-lasting response with no evidence of loss in activity over time.
NTLA-2001 was generally well tolerated across all patients and at all dose levels tested. The most commonly reported adverse events were infusion-related reactions, which occurred in 38% of patients. The majority of adverse events, including infusion-related reactions, were Grade 1 or 2 in severity, transient and resolved spontaneously. Other adverse events that were reported in greater than 10% of patients included headache, diarrhea and back pain, and were all Grade 1 or 2. All patients received a full dose of NTLA-2001 and remain on study. No dose-limiting toxicities were observed. Based on the safety and activity of NTLA-2001, the 55mg dose has now been selected to be evaluated in the upcoming pivotal Phase 3 study.
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 safety, efficacy and advancement of its clinical program for NTLA-2001 for the treatment of transthyretin (“ATTR”) amyloidosis pursuant to its clinical trial applications (“CTA”) and investigational new drug (“IND”) submissions, including the expected timing of data releases, regulatory filings, and the initiation and completion of clinical trials such as its ability to initiate a global pivotal Phase 3 trial by year-end; its ability to generate data to demonstrate NTLA-2001 as a potential single-dose treatment for ATTR amyloidosis; its ability to maintain and expand its related intellectual property portfolio, and avoid or acquire rights to valid intellectual property of third parties; and the timing of regulatory filings and clinical trial execution, including enrollment and dosing of patients.
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 the initiation and conduct of a global pivotal Phase 3 study for NTLA-2001 for the treatment of ATTR-CM and that the results of such Phase 3 study may not be positive; risks related to Intellia’s ability to protect and maintain its intellectual property position; risks related to the authorization, initiation and conduct of studies and other development requirements, including manufacturing, for NTLA-2001; the risk that any one or more of Intellia’s product candidates, including NTLA-2001, will not be successfully developed and commercialized; the risk that the results of preclinical studies or clinical studies, including for NTLA-2001, will not be predictive
of future results in connection with future studies; and the risk that Intellia will not be able to demonstrate its platform’s modularity and replicate or apply results achieved in preclinical studies to develop additional product candidates, including to apply its proprietary CRISPR/Cas9 technology platform successfully to additional 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 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 press release is as of the date of the release, and Intellia undertakes no duty to update this information unless required by law.
| Item 9.01. | Financial Statements and Exhibits. |
(d) Exhibits.
| Exhibit |
Description | |
| 99.1 | Press Release, dated November 2, 2023. | |
| 99.2 | Clinical Data Presentation at 4th International ATTR Amyloidosis Meeting on November 2, 2023. | |
| 104 | 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: November 2, 2023 | By: | /s/ John M. Leonard | ||||
| Name: | John M. Leonard | |||||
| Title: | Chief Executive Officer and President | |||||
Exhibit 99.1
Intellia Presents New Interim Data from the Ongoing Phase 1 Study of NTLA-2001 at the 4th International ATTR Amyloidosis Meeting
| • | Updated data from over 60 patients showed consistent, deep and durable serum TTR reduction achieved with a single dose of NTLA-2001, including in 29 patients who have now reached 12 months or more of follow-up |
| • | NTLA-2001 was generally well-tolerated across both polyneuropathy and cardiomyopathy arms at all dose levels tested |
| • | 55 mg dose of NTLA-2001 selected for further evaluation in the global pivotal Phase 3 trial expected to begin by year-end |
CAMBRIDGE, Mass., Nov. 2, 2023 – Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading clinical-stage genome editing company focused on developing potentially curative therapies leveraging CRISPR-based technologies, today presented additional interim results from its ongoing Phase 1 study of NTLA-2001, an investigational, in vivo CRISPR/Cas9 genome editing therapy in development as a single-dose treatment for transthyretin (ATTR) amyloidosis. Results were presented in an oral presentation at the 4th International ATTR Amyloidosis Meeting, held Nov. 2–3 in Madrid, Spain.
“With 65 patients reported from the Phase 1 study, this update represents the largest clinical dataset for an in vivo CRISPR-based investigational therapy. These positive interim results add to the growing body of data that demonstrates deep and durable reductions of serum TTR after a single dose of NTLA-2001. The consistent and profound levels of reduction in all patients bolster our confidence that NTLA-2001 could potentially reset the standard of care for ATTR amyloidosis — both for treating the disease and how response is evaluated,” said Intellia President and Chief Executive Officer John Leonard, M.D. “We have also observed early signals of clinical activity in the initial cohorts and look forward to presenting the first clinical data beyond serum TTR levels once we have longer follow-up across all cohorts.”
The Phase 1 trial is a two-part study evaluating NTLA-2001 in patients with either ATTR amyloidosis with cardiomyopathy (ATTR-CM) or hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN). The data presented today, with a cutoff date of May 11, 2023, are from the initial 65 out of 72 patients dosed in the Phase 1 study, which has now completed enrollment. The results from the final seven patients dosed, who were enrolled after the data cutoff, will be reported at a future date.
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In the newly reported dose-expansion portion, administration of NTLA-2001 at the 55 mg and 80 mg dose led to deep serum TTR reductions consistent with the results previously reported from patients in the dose-escalation portion who received the corresponding weight-based dose, 0.7 mg/kg and 1.0 mg/kg, respectively.
Across all patients who received a dose of 0.3 mg/kg or higher (n=62), the median serum TTR reduction was 91% and the median absolute residual serum TTR concentration was 17 µg/mL at day 28. The persistently low levels of TTR concentration are expected to reduce the rate of ongoing amyloid formation and hold the possibility for amyloid clearance to reverse the symptoms of the disease. If clinically validated, the use of absolute residual TTR concentration levels could become a new benchmark for evaluating ATTR amyloidosis.
The reduction of serum TTR compared to baseline was sustained through the latest follow-up. With 29 patients now reaching at least 12 months of follow-up, all patients continued to show a long-lasting response with no evidence of loss in activity over time.
NTLA-2001 was generally well tolerated across all patients and at all dose levels tested. The most commonly reported adverse events were infusion-related reactions, which occurred in 38% of patients. The majority of adverse events, including infusion-related reactions, were Grade 1 or 2 in severity, transient and resolved spontaneously. Other adverse events that were reported in greater than 10% of patients included headache, diarrhea and back pain, and were all Grade 1 or 2. All patients received a full dose of NTLA-2001 and remain on study. No dose-limiting toxicities were observed. Based on the safety and activity of NTLA-2001, the 55mg dose has now been selected to be evaluated in the upcoming pivotal Phase 3 study.
These data support NTLA-2001’s continued development as a potential one-time treatment to permanently inactivate the TTR gene and reduce the disease-causing protein in people living with ATTR amyloidosis. As previously announced, Intellia recently received IND clearance from the FDA to begin a Phase 3 trial of NTLA-2001 for ATTR-CM and expects to initiate the global pivotal trial by the end of this year. Additionally, the Company is actively preparing for a Phase 3 trial for ATTRv-PN.
About NTLA-2001
Based on Nobel Prize-winning CRISPR/Cas9 technology, NTLA-2001 could potentially be the first single-dose treatment for ATTR amyloidosis. NTLA-2001 is the first investigational CRISPR therapy candidate to be administered systemically, or through a vein, to edit genes inside the human body. Intellia’s proprietary non-viral platform deploys lipid nanoparticles to deliver to the liver a two-part genome editing system: guide RNA specific to the disease-causing gene and messenger RNA that encodes the Cas9 enzyme, which carries out the precision editing. Robust preclinical and clinical data, showing deep and long-lasting transthyretin (TTR) reduction following in vivo inactivation of the target gene, supports NTLA-2001’s potential as a single-administration therapeutic. Intellia leads development and commercialization of NTLA-2001 as part of a multi-target discovery, development and commercialization collaboration with Regeneron. The global Phase 1 trial is
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an open-label, multi-center, two-part study of NTLA-2001 in adults with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) or transthyretin amyloidosis with cardiomyopathy (ATTR-CM). The Phase 1 trial is now closed for enrollment. Visit clinicaltrials.gov (NCT04601051) for more details.
About Transthyretin (ATTR) Amyloidosis
Transthyretin amyloidosis, or ATTR amyloidosis, is a rare, 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.
About Intellia Therapeutics
Intellia Therapeutics, a leading clinical-stage genome editing company, is developing novel, potentially curative therapeutics leveraging CRISPR-based technologies. To fully realize the transformative potential of CRISPR-based technologies, Intellia is pursuing two primary approaches. The company’s in vivo programs use intravenously administered CRISPR as the therapy, in which proprietary delivery technology enables highly precise editing of disease-causing genes directly within specific target tissues. Intellia’s ex vivo programs use CRISPR to create the therapy by using engineered human cells to treat cancer and autoimmune diseases. Intellia’s deep scientific, technical and clinical development experience, along with its robust intellectual property portfolio, have enabled the company to take a leadership role in harnessing the full potential of genome editing to create new classes of genetic medicine. Learn more at intelliatx.com. Follow us on X (formerly known as Twitter) @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 and advancement of its clinical program for NTLA-2001 for the treatment of transthyretin (“ATTR”) amyloidosis pursuant to its clinical trial applications (“CTA”) and investigational new drug (“IND”) submissions, including the expected timing of data releases, regulatory filings, and the initiation and completion of clinical trials such as its ability to initiate a global pivotal Phase 3 trial by year-end; its ability to generate data to demonstrate NTLA-2001 as a potential single-dose treatment for ATTR amyloidosis to permanently inactivate the TTR gene and reduce the disease-causing protein in people living with ATTR amyloidosis; its beliefs concerning observed early signals of clinical activity in the initial cohorts; its
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belief that NTLA-2001 may reduce the rate of ongoing amyloid formation, reverse the symptoms of ATTR amyloidosis, including possible amyloid clearance, and reset the standard of care for ATTR amyloidosis; its belief that the use of absolute residual TTR concentration levels could become a new benchmark for evaluating ATTR amyloidosis, if clinically validated; its ability to develop its modular platform and full-spectrum approach to advance its complex genome editing capabilities, including to apply its proprietary CRISPR/Cas9 technology platform to additional product candidates; its ability to maintain and expand its related intellectual property portfolio, and avoid or acquire rights to valid intellectual property of third parties; its ability to demonstrate its platform’s modularity and replicate or apply results achieved in preclinical studies and clinical studies, including those in its NTLA-2001 program, in any future studies, including human clinical trials; and the timing of regulatory filings and clinical trial execution, including enrollment and dosing of patients.
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 the initiation and conduct of a global pivotal Phase 3 study for NTLA-2001 for the treatment of ATTR-CM and that the results of such Phase 3 study may not be positive; risks related to Intellia’s ability to protect and maintain its intellectual property position; risks related to the authorization, initiation and conduct of studies and other development requirements, including manufacturing, for NTLA-2001; the risk that any one or more of Intellia’s product candidates, including NTLA-2001, will not be successfully developed and commercialized; the risk that the results of preclinical studies or clinical studies, including for NTLA-2001, will not be predictive of future results in connection with future studies; and the risk that Intellia will not be able to demonstrate its platform’s modularity and replicate or apply results achieved in preclinical studies to develop additional product candidates, including to apply its proprietary CRISPR/Cas9 technology platform successfully to additional 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 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 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 Karp
Senior Vice President, Investor Relations and Corporate Communications
ian.karp@intelliatx.com
Lina Li
Senior Director, Investor Relations and Corporate Communications
lina.li@intelliatx.com
Media:
Matt Crenson
Ten Bridge Communications
media@intelliatx.com
mcrenson@tenbridgecommunications.com
# # #
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Exhibit 99.2 Enabling the development of November 2-3, 2023 • MADRID serum [TTR] as a biomarker for treatment of ATTR amyloidosis Julian D. Gillmore National Amyloidosis Centre, Division of Medicine, University College London on behalf of: 2 3 4 5 5 Jörg Täubel, Ed Gane, Björn Pilebro, Michael L. Maitland, Ricardo Rocha, 5 5 5 5 5 Joy Olbertz, Adia Leung, Derek Smith, Michael D. Pickard, Carri Boiselle, 5 5 6 5 7 Yuanxin Xu, Peijuan Zhu, David Gutstein, Liron Walsh, David Adams 2 Richmond Pharmacology, St. George’s University of London, London, UK 3 New Zealand Clinical Research, Auckland, New Zealand 4 Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden 5 Intellia Therapeutics, Cambridge, MA, USA 6 Regeneron Pharmaceuticals, Tarrytown, NY, USA 7 Department of Neurology, CHU Bicetre, University Paris Saclay, AP-HP, Le Ktremin-Bicetre, France
Disclosures • Adviser for Alnylam, AstraZeneca, Attralus, BridgeBio, Ionis, Pfizer, and Intellia
Treatment outcomes in systemic amyloidosis associate with 1,2 the residual concentration of the amyloid precursor protein 1 AA Amyloidosis Median SAA values >50 mg/L • More amyloid = worse outcomes Less amyloid = better outcomes • “Natural” clearance of in vivo amyloid deposits occurs slowly Baseline 3-year follow-up • Clearance of amyloid occurs at Unresponsive to methotrexate and steroids a different rates in different organs AL Amyloidosis Liver vs heart • The rate of amyloid clearance varies between individuals A 75% reduction in fibril precursor protein concentrations may be sufficient to permit amyloid regression in one patient but may 2016 2019 2022 result in amyloid accumulation in another Hematologic response Hematologic relapse AA, amyloid A; AL, amyloid light chain; SAA, serum amyloid A. Reprinted from The Lancet, Gillmore JD, et al, volume 358, Amyloid load and clinical outcome 1. Gillmore JD, et al. Lancet. 2001;358(9275):24-29. in AA amyloidosis in relation to circulating concentration of serum amyloid A protein, pages 24- a Unpublished. 29, copyright 2001, with permission from Elsevier. 2. Lachmann HJ, et al. Br J Haematol. 2003;122(1):78-84.
Our community has incorporated this information to advance therapy in AA and AL amyloidosis Specific concentration thresholds inform outcomes 1 AA amyloidosis 2 Unadjusted relative risk of death associated with the most recent AL amyloidosis a median annual SAA concentration during follow-up SAA Octile (mg/L) P value 1.0 <4 - <10 mg/L 3.9 0.007 ≥4 to <9 5.1 <40 mg/L 0.003 ≥9 to <16.7 7.0 0.07 ≥16.7 to <28 9.1 0.008 ≥38 to <45.6 12.1 <0.001 ≥45.6 to <87 17 <0.001 ≥87 to <155 17.7 0 ≥155 <0.001 0.5 1.0 5 50 1. Lachmann HJ, et al. N Engl J Med. 2007;356(23):2361-2371. Relative risk (95% CI) 2. Palladini G, et al. J Clin Oncol. 2012;30(36):4541-4549. a The SAA value is the median concentration within each 12-month period and From Palladini G, et al, New criteria for response to treatment in was incorporated into the Cox regression model as a time-dependent covariate. immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes, Journal of Clinical Oncology, volume 30, issue 36, pages 4541-4549, DOI: AA, amyloid A; aCR, amyloidosis complete response; AL, amyloid light chain; CI, confidence interval; NR, no response; 10.1200/JCO.2011.37.7614, with permission from Wolters Kluwer Health. PR, partial response; py, person years;SAA, serum amyloid A; VGPR, very good partial response.
There is an equilibTherape rium bet utic str ween ategies cir in cu am lat yloing idos amyl is oid fibril precursor protein Therapeutic strategies in amyloidosis concentration and change in amyloid burden Pr Precu ecur rso sor r p pr ro ote teiin n A Amyl mylo oiid d Precursor protein Amyloid Precursor protein Amyloid Reversion to normally folded protein Reversion to normally folded protein Precursor protein Amyloid Amyloid clearance Fibril formation Fibril formation F Fiib br riill fo for rma mati tio on n Amyloid formation Stabilise amyloid- Stabilise amyloid- forming proteins forming proteins ▪β sheet breakers ▪β sheet breakers Enhance removal of Stabilise amyloid- Enhance removal of existing amyloid Reduce supply of existing amyloid forming proteins Reduce supply of Reduce supply of Reduce supply of amyloid amyloid precursor • β sheet breakers amyloid ▪ Immunotherapy amyloid ▪ Immunotherapy precursor protein protein precursor ▪ SAP depletion precursor ▪ SAP depletion • Immunotherapy protein protein • SAP depletion • Chemotherapy in AL • Anti-inflammatory therapy in AA • Gene “silencers” and gene editing in ATTR AA, amyloid A; AL, amyloid light chain; ATTR, transthyretin amyloidosis; SAP, serum amyloid P component.
Percent reduction in serum [TTR] is associated with clinical benefit in ATTR amyloidosis Pharmacodynamics: Primary endpoint: 1 1 % change in serum TTR over 18 months mNIS+7 neuropathy score Worse Better Median reduction in serum TTR in the patisiran group was 56% vs 4% 81% (range, -38% to 95%) and was similar across age, of patisiran- and placebo-treated patients, 1 respectively, experienced a sex, or genotype halting or reversal of disease progression 1 (change <0 point mNIS+7) In a post hoc analysis of the cardiac subpopulation (n=126), there was an approximate 45% 2 reduction in the composite rate of cardiac hospitalization and all-cause mortaility 1. Adams D, et al. N Engl J Med. 2018;379(1):11-21. 2. Solomon SD, et al. Circulation. 2019;139(4):431-443. Graphs from The New England Journal of Medicine, Adams D, et al, Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis, volume 379, pages 11-21, copyright 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. ATTR, transthyretin amyloidosis; mNIS+7, modified neuropathy impairment score +7; TTR, transthyretin.
Serum [TTR] is typically expressed as % reduction from baseline – should we be using residual absolute serum [TTR] instead? % serum TTR reduction vs ΔmNIS+7 by Same % serum TTR reduction can mean nonile in APOLLO A different risk for ongoing fibril formation At the population level, ≈80% TTR lowering is associated with improved score 80% knockdown Patient 1 Patient 2 Predose [TTR] (µg/mL) 350 150 Postdose [TTR] (µg/mL) 70 30 Both represent 80% knockdown, but >2× available substrate for ongoing amyloid formation in Patient 1 post-treatment Should we be using residual absolute serum [TTR] instead? Polydefkis M, et al. Presented at ISA. Mar 26-29, 2018; Kumamoto, Japan. Graph used with permissions from first author. ΔmNIS+7, change in modified neuropathy impairment score +7; TTR, transthyretin.
The NTLA-2001 phase 1 study in ATTR amyloidosis has completed enrollment (N=72) Two-part, open-label, multicenter study in adults with hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN) or ATTR amyloidosis with cardiomyopathy (ATTR-CM) PART I: Single-Ascending Dose Escalation PART II: Dose Expansion 0.1 mg/kg (n=3) ATTRv-PN 55 mg (n=16) 0.3 mg/kg (n=3) patients n=15 n=21 Intervention: 0.7 mg/kg (n=3) (n=36) 80 mg (n=5) Single dose 1.0 mg/kg (n=6) CRISPR/Cas9- N=72 based gene editing 0.7 mg/kg NYHA Class I/II (n=3) 55 mg NYHA Class I/II (n=12) ATTR-CM therapy administered 1.0 mg/kg patients via an intravenous 0.7 mg/kg NYHA Class III (n=6) n=12 n=24 (IV) infusion (n=36) 55 mg NYHA Class III (n=12) 1.0 mg/kg NYHA Class I/II (n=3) PRIMARY OBJECTIVES SECONDARY OBJECTIVES Evaluate safety, tolerability, PK, and PD Evaluate efficacy on clinical measures of: ▪ Measure serum TTR levels▪ Neurologic function in patients with ATTRv-PN ▪ Cardiac disease in patients with ATTR-CM Clinicaltrials.gov ID: NCT0460105. ATTR, transthyretin amyloidosis; Cas, CRISPR-associated protein; CRISPR, clustered regularly interspaced short palindromic repeats; NYHA, New York Heart Association; PD, pharmacodynamics; PK, pharmacokinetics.
Patient demographics and characteristics Characteristic PN Patients (N=36) CM Patients (N=29) All Patients (N=65) Age, years Median (min, max) 61 (19, 75) 78 (46, 86) 68 (19, 86) Sex, n (%) Male 26 (72) 28 (97) 54 (83) Weight, kg Median (min, max) 77 (55, 117) 82 (63, 115) 81 (55, 117) p.V50M 11 (31) 0 11 (17) p.V142I 1 (3) 6 (21) 7 (11) p.T80A 7 (19) 1 (3) 8 (12) TTR genotype, n (%) p.S97Y 7 (19) 0 7 (11) p.E62D 4 (11) 0 4 (6) Other 6 (17) 2 (7) 8 (12) WT 0 20 (69) 20 (31) No diagnosis of heart failure 12 (33) 0 12 (18) I 19 (53) 3 (10) 22 (34) NYHA Class, n (%) II 5 (14) 14 (48) 19 (29) III 0 12 (41) 12 (18) NT-proBNP, ng/L Median (min, max) 127 (<50, 1878) 1845 (851, 19,624) 757 (<50, 19,624) Data cutoff May 11, 2023. Interim data presented are for the first 65 (dosed and reached at least 28 days post-infusion by the data cutoff) of 72 patients dosed. Results from the final 7 patients will be reported at a future date. CM, cardiomyopathy; NT-proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, New York Heart Association; PN, polyneuropathy; TTR, transthyretin.
Most frequent treatment emergent adverse events TEAEs by Maximum Toxicity Grade and Preferred Term Reported in >5% of All ATTRv-PN and ATTR-CM Patients (N=65) • This includes all reported events, AE, Preferred Term, n (%) Any Grade Grade 1 Grade 2 Grade ≥3 including those unrelated to NTLA-2001 Infusion-related reaction 25 (38) 10 (15) 14 (22) 1 (2) (e.g., atrial flutter and cardiac failure Headache 12 (18) 12 (18) hospitalizations) Diarrhea 11 (17) 10 (15) 1 (2) • Infusion-related reactions were most Back pain 7 (11) 7 (11) common; nearly all were considered COVID-19 infection 6 (9) 5 (8) 1 (2) mild and resolved without sequelae, and Cardiac failure 6 (9) 2 (3) 2 (3) 2 (3) all patients received the complete, Upper respiratory tract infection 6 (9) 6 (9) planned dose 5 (8) 3 (5) 1 (2) 1 (2) AST increased • Any liver enzyme elevations resolved Dizziness 5 (8) 5 (8) spontaneously, were asymptomatic, and Fatigue 5 (8) 5 (8) required no intervention (e.g., steroids) or hospitalization Muscle spasms 5 (8) 4 (6) 1 (2) Vision blurred 5 (8) 5 (8) Atrial flutter 4 (6) 1 (2) 3 (5) Constipation 4 (6) 2 (3) 2 (3) Rash 4 (6) 4 (6) Data cutoff May 11, 2023. Patients reporting more than one AE related to NTLA-2001 are counted only once using the maximum toxicity grade. AEs coded to preferred term using Medical Dictionary for Regulatory Activities (MedDRA), version 23.0 for PN and version 24.0 for CM. Interim data presented are from the initial 65 of 72 patients dosed. Results from the final 7 patients enrolled after the data cutoff will be reported at a future date. AE, adverse event; AST, aspartate transaminase; CM, cardiomyopathy; PN, polyneuropathy; TEAE, treatment-emergent adverse event.
Regardless of baseline TTR levels, NTLA-2001 led to consistently low and sustained absolute serum [TTR] in all patients 350 350 ATTR-CM ATTRv-PN NYHA I-II 0.7 mg/kg (N=3) 0.3 mg/kg (N=3) 300 300 NYHA III 0.7 mg/kg (N=6) 0.7 mg/kg (N=3) NYHA I-II 1.0 mg/kg (N=3) 1.0 mg/kg (N=6) Baseline IQR: Baseline IQR: NYHA I-II 55 mg (N=11) 55 mg (N=16) 250 250 155 to 234 µg/mL 160 to 300 µg/mL NYHA III 55 mg (N=6) 80 mg (N=5) 200 200 150 150 100 100 50 50 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months Months Median (IQR) Residual absolute TTR concentration at day 28 17 µg/mL (11 to 24) Serum [TTR] at % Change from baseline in serum TTR at day 28 -91% (-88 to -94) Day 28 (n=62) Data cutoff May 11, 2023. Figure notes: Results for each dose level are shown out to the last time point with complete follow-up for the entire cohort. Interim data presented excludes the 0.1 mg/kg cohort from the dose-escalation of the polyneuropathy arm. The three patients in the 0.1 mg/kg cohort have been re-dosed at 55 mg and results will be shared in a future presentation. The 55 mg and 80 mg doses are the fixed doses corresponding to 0.7 mg/kg and 1.0 mg/kg, respectively. ATTR-CM, transthyretin amyloidosis with cardiomyopathy; ATTRv-PN, hereditary transthyretin amyloidosis with polyneuropathy; IQR, interquartile range; NYHA, New York Heart Association; SD, standard deviation; TTR, transthyretin. Serum [TTR] (µg/mL) Mean ± SD Serum [TTR] (µg/mL) Mean ± SD
Regardless of baseline TTR levels, NTLA-2001 led to consistently low and sustained absolute serum [TTR] in all patients The median (IQR) maximum change from day 28 onward (measure of fluctuations) = -1.4 µg/mL (-4.7 to 1.7) 350 350 ATTR-CM ATTRv-PN 300 NYHA I-II 0.7 mg/kg (N=3) 300 0.3 mg/kg (N=3) NYHA III 0.7 mg/kg (N=6) 0.7 mg/kg (N=3) NYHA I-II 1.0 mg/kg (N=3) 1.0 mg/kg (N=6) 250 250 NYHA I-II 55 mg (N=11) 55 mg (N=16) NYHA III 55 mg (N=6) 80 mg (N=5) 200 200 150 150 100 100 50 50 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months Months Data cutoff May 11, 2023. Figure notes: Mean depicted only when there are two or more data points. Subsequent points connected by a dashed line denotes less than full group follow-up. Interim data presented excludes the 0.1 mg/kg cohort from the dose-escalation of the polyneuropathy arm. The three patients in the 0.1 mg/kg cohort have been re-dosed at 55 mg and results will be shared in a future presentation. The 55 mg and 80 mg doses are the fixed doses corresponding to 0.7 mg/kg and 1.0 mg/kg, respectively. ATTR-CM, transthyretin amyloidosis with cardiomyopathy; ATTRv-PN, hereditary transthyretin amyloidosis with polyneuropathy; IQR, interquartile range; NYHA, New York Heart Association; SD, standard deviation; TTR, transthyretin. Serum [TTR] (µg/mL) Mean ± SD Serum [TTR] (µg/mL) Mean ± SD
Summary • In other systemic amyloidoses, the residual, absolute concentration of the amyloid precursor protein is closely associated with clinical outcomes • Interim data from 62 patients with ATTR amyloidosis treated with NTLA-2001 continue to show a favorable safety and tolerability profile, with rapid, consistent, and durable reductions of serum [TTR] to low levels in all patients • For treatments that reduce total serum [TTR], with nonfluctuating steady state measures, the residual absolute serum [TTR] could be a robust biomarker of ATTR amyloidosis therapy outcomes • With collaboration, this approach to biomarker development has facilitated progress in care and better outcomes in AA and AL amyloidosis AA, amyloid A; AL, amyloid light chain; ATTR, transthyretin amyloidosis; TTR, transthyretin.
Acknowledgments We extend our gratitude to the patients who United Kingdom participated in the NTLA-2001 Phase 1 study National Amyloidosis Centre and their family and caregiver networks Physicians Histology Staff executing the study on behalf of: Prof. Mariana Janet Gilbertson Richmond Pharmacology, London Fontana New Zealand Clinical Research, Auckland Prof. Philip Hawkins Imaging Umea University, Sweden CHU Bicetre, University of Paris-Saclay Laboratory Dorota Rowczenio Intellia Therapeutics Regeneron Pharmaceuticals Prof. Paul Simons Genetics Guglielmo Verona David Hutt Editorial support was provided by James Banigan, PhD, and Shannon Davis of Apollo Medical Communications, part of Helios Global Group, and funded by Intellia Therapeutics
Appendix
Dose-responsive rapid and deep serum TTR reduction sustained across all patients 0.1 mg/kg (N=3) NYHA I-II 0.7 mg/kg (N=3) ATTR-CM ATTRv-PN 0.3 mg/kg (N=3) 0 0 NYHA III 0.7 mg/kg (N=6) 0.7 mg/kg (N=3) NYHA I-II 1.0 mg/kg (N=3) -10 -10 1.0 mg/kg (N=6) NYHA I-II 55 mg (N=11) 55 mg (N=16) NYHA III 55 mg (N=6) -20 -20 80 mg (N=5) -30 -30 -40 -40 -50 -50 -60 -60 -70 -70 -80 -80 -90 -90 -100 -100 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months Months % Change from baseline in serum TTR at Day 28 (n=62, excludes the 0.1 mg/kg cohort) Mean (SE) serum [TTR] -90% (0.86) Median (IQR) serum [TTR] -91% (-88 to -94) Data cutoff May 11, 2023. Figure notes: Results for each dose level are shown out to the last time point with complete follow-up for the entire cohort. ATTR-CM, transthyretin amyloidosis with cardiomyopathy; ATTRv-PN, hereditary transthyretin amyloidosis with polyneuropathy; NYHA, New York Heart Association; SE, standard error; TTR, transthyretin. Change from baseline in serum TTR (%) Mean ± SE Change from baseline in serum TTR (%) Mean ± SE