On May 2, 2019 Intellia Therapeutics, Inc. (NASDAQ:NTLA), reported operational highlights and financial results for the first quarter ended March 31, 2019 (Press release, Intellia Therapeutics, MAY 2, 2019, View Source [SID1234535544]). Additionally, the Company highlighted important corporate milestones for 2019.

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"2019 is off to a productive start in support of our mission to advance genome editing to treat a range of severe and life-threatening diseases. We are excited by our achievements in gene knockout and insertion across both our in vivo and engineered cell therapy efforts. In particular, we presented data at the 22nd Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) (Free ASGCT Whitepaper) showing unprecedented CRISPR-mediated, targeted gene insertion in the liver of non-human primates, achieving normal circulating human levels of protein production," said Intellia President and Chief Executive Officer John Leonard, M.D. "These achievements highlight Intellia’s leadership in CRISPR/Cas9 genome editing as we advance our pipeline towards the clinic. Looking ahead, we remain on track to file an IND application next year for NTLA-2001, our lead in vivo candidate for the treatment of transthyretin amyloidosis, and expect to nominate a development candidate in our first engineered cell therapy program for acute myeloid leukemia by year-end."

First Quarter 2019 and More Recent Operational Highlights

ATTR Program: Intellia’s lead candidate for the treatment of transthyretin amyloidosis (ATTR), which demonstrated an average of >95% reduction in circulating transthyretin (TTR) protein in non-human primates (NHPs), has been nominated as the Company’s first in vivo development candidate to advance into Investigational New Drug (IND)-enabling toxicology studies. Preliminary results from substantially completed dose-range finding (DRF) studies showed a favorable tolerability profile; and data from multiple studies in NHPs demonstrated durable liver editing with sustained reduction of circulating TTR through 10 months of observation following a single dose.

Today, Intellia announced plans to begin IND-enabling toxicology studies of NTLA-2001 in mid-2019 and that it remains on track to submit an IND application in 2020. NTLA-2001 is being co-developed with Regeneron Pharmaceuticals, Inc. (Regeneron), with Intellia as the lead development and commercialization party.
AML Program: Intellia and its research collaborators at IRCCS Ospedale San Raffaele presented new in vitro data at the 22nd Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) (Free ASGCT Whitepaper), showing that CRISPR/Cas9 editing resulted in >98% knockout of endogenous T cell receptors (TCRs) followed by insertion of Wilms’ Tumor 1 (WT1)-specific TCRs into >95% of isolated T cells. In addition, the engineered T cells were functional and capable of specifically killing high levels of a panel of leukemic blasts from patients that expressed the WT1 epitope. Based on these results, Intellia has identified multiple lead TCRs restricted to the HLA-A*02:01 allele to move into functional testing in patient-derived xenograft models for an autologous TCR-based therapy targeting WT1 for the treatment of acute myeloid leukemia (AML). These studies are expected to begin in mid-2019 and will inform the nomination of the Company’s first engineered cell therapy development candidate by the end of 2019.

In Vivo Insertion in NHPs: At the 2019 ASGCT (Free ASGCT Whitepaper) Meeting, Intellia presented data demonstrating the first CRISPR-mediated, targeted transgene insertion in the liver of NHPs, using Factor 9 (F9) as a model gene. F9 is a gene that encodes for Factor IX (FIX) protein, a blood-clotting protein that is missing or defective in hemophilia B patients. In a collaboration between Intellia and Regeneron, researchers combined Intellia’s lipid nanoparticle (LNP) delivery system of CRISPR/Cas9 with an adeno-associated virus (AAV) containing a proprietary bi-directional insertion template. NHP data showed that a single administration achieved ~3-4 μg/mL of circulating human FIX protein at day 14 and was sustained through 28 days (~3-5 μg/mL) of completed observation in an ongoing study. The levels of circulating human FIX protein demonstrated in NHPs correspond with the normal 3-5 μg/mL range of human FIX protein levels (source: Amiral et al, Clin. Chem., 1984). The NHP data shared also incorporates the improved CRISPR/Cas9 LNP identified from the ATTR program and demonstrates the modularity of Intellia’s platform to apply learnings to other programs. This data expands on the clinically relevant human FIX protein levels achieved in mice, first reported in October, which have remained stable through 10 months of observation.

Modular In Vivo Knockout Update: Today, at the 2019 ASGCT (Free ASGCT Whitepaper) Meeting, Intellia will present new data demonstrating that independent CRISPR-mediated knockout of each of two targets of interest, either lactate dehydrogenase A (Ldha) or hydroxyacid oxidase 1 (Hao1), via the Company’s proprietary LNP delivery technology, results in a durable, therapeutically relevant reduction of oxalate excretion in a disease mouse model of primary hyperoxaluria type 1 (PH1).

LDHA and HAO1 are enzymes involved in oxalate production. In people with PH1, mutations in a specific liver enzyme cause the production of a surplus of oxalate, which can combine with calcium to form insoluble deposits in the kidney and throughout the body, leading to damage of the kidneys, heart, eyes and skeletal system. An approximate 30% reduction in urinary oxalate in patients with PH1 is considered to be therapeutically relevant (source: Nephrology Dialysis Transplantation 1999; 14:2556-2558). In collaboration with the University of Alabama at Birmingham, Intellia researchers found that a CRISPR-mediated knockout of the Ldha gene in a PH1 mouse model disrupts LDHA protein production and reduces urinary oxalate levels by 63%. Researchers also observed that a CRISPR-mediated knockout of the Hao1 gene disrupts glycolate-to-glyoxylate conversion, resulting in a urinary oxalate level reduction of 57% in a PH1 mouse model. In each individual knockout approach, these reduced levels of urinary oxalate were sustained for at least 15 weeks.

Today’s presentation, titled "CRISPR/Cas9-Mediated Gene Knockout to Address Primary Hyperoxaluria," is accessible through the Events and Presentations page of the Investor Relations section of Intellia’s website.
Upcoming Milestones

The Company has set forth the following for 2019 pipeline progression:

ATTR:
Initiate IND-enabling toxicology studies in mid-2019
Commence manufacturing of NTLA-2001 Phase 1 materials
AML:
Initiate functional testing in patient-derived xenograft models of multiple lead TCRs in mid-2019
Nominate first engineered cell therapy development candidate by the end of 2019
First Quarter 2019 Financial Results

Cash Position: Cash, cash equivalents and marketable securities were $296.6 million as of March 31, 2019, compared to $314.1 million as of December 31, 2018. The decrease was driven by cash used to fund operations of approximately $29 million, which was offset in part by $6.0 million of funding received under the Novartis collaboration, $3.6 million of net equity proceeds raised from the Company’s "At the Market" (ATM) agreement, $1.5 million of ATTR cost reimbursements made by Regeneron, and $0.4 million in proceeds from employee-based stock plans.
Collaboration Revenue: Collaboration revenue increased by approximately $3.0 million to $10.4 million during the first quarter of 2019, compared to $7.5 million during the first quarter of 2018. The increase in collaboration revenue in 2019 was primarily driven by amounts recognized from the expansion of the existing collaboration with Novartis, as well as by amounts recognized under the Company’s ATTR Co/Co agreement with Regeneron. As previously disclosed, Regeneron is obligated to fund approximately 50% of the development costs for the ATTR program.
R&D Expenses: Research and development expenses increased by $1.2 million to $23.7 million during the first quarter of 2019, compared to $22.5 million during the first quarter of 2018. This increase was driven primarily by the advancement of Intellia’s research programs, research personnel growth to support these programs, as well as the expansion of the development organization.
G&A Expenses: General and administrative expenses increased by $3.1 million to $10.5 million during the first quarter of 2019, compared to $7.4 million during the first quarter of 2018. This increase was driven primarily by employee and intellectual property (IP)-related expenses to support Intellia’s growing research and development efforts.
Net Loss: The Company’s net loss was $21.9 million for the first quarter of 2019, compared to $21.4 million during the first quarter of 2018.
Financial Guidance

Intellia expects that its cash, cash equivalents and marketable securities as of March 31, 2019, as well as technology access and funding from Novartis and Regeneron, will enable Intellia to fund its anticipated operating expenses and capital expenditure requirements into the first half of 2021. This expectation excludes any potential milestone payments or extension fees that could be earned and distributed under the collaboration agreements with Novartis and Regeneron or any strategic use of capital not currently in the Company’s base-case planning assumptions.

Conference Call to Discuss First Quarter 2019 Earnings

The Company will discuss these results on a conference call today, May 2, 2019, at 8 a.m. ET. The investor presentation may be downloaded starting at 7:30 a.m. ET from the Events and Presentations page of the Investor Relations section of Intellia’s website at intelliatx.com.

To join the call:

U.S. callers should dial 800-458-4148 and use conference ID# 7725705, approximately five minutes before the call.
International callers should click here to access dial-in information and use conference ID# 7725705, approximately five minutes before the call.
A replay of the call will be available on Intellia’s website, beginning on May 2, 2019 at 12 p.m. ET.