On February 6, 2020 University of Pennsylvania reported Genetically-edited immune cells can persist, thrive, and function months after a cancer patient receives them, according to new data published by researchers (Press release, University of Pennsylvania, FEB 6, 2020, View Source [SID1234553941]). The team showed cells removed from patients and brought back into the lab setting were able to kill cancer months after their original manufacturing and infusion. Further analysis of these cells confirmed they were successfully edited in three specific ways, marking the first-ever sanctioned investigational use of multiple edits to the human genome. This is the first U.S. clinical trial to test the gene editing approach in humans, and the publication of this new data today in Science follows on the initial report last year that researchers were able to use CRISPR/Cas9 technology to successfully edit three cancer patients’ immune cells. Penn is conducting the ongoing study in cooperation with the Parker Institute for Cancer Immunotherapy and Tmunity Therapeutics.

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"Our data from the first three patients enrolled in this clinical trial demonstrate two important things that, to our knowledge, no one has ever shown before. First, we can successfully perform multiple edits with precision during manufacturing, with the resulting cells surviving longer in the human body than any previously published data have shown. Second, thus far, these cells have shown a sustained ability to attack and kill tumors," said Carl June, MD, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies in the Abramson Cancer Center and director of the Parker Institute for Cancer Immunotherapy at the Perelman School of Medicine at the University of Pennsylvania and the study’s senior author.

The findings are the latest milestone in Penn’s history as cellular and gene therapy pioneers, including development of the first FDA-approved CAR T cell therapy, Kymriah, for pediatric and adult blood cancer patients.

Patients on this trial were treated by Edward A. Stadtmauer, MD, section chief of Hematologic Malignancies at Penn, who is the co-lead author on the study along with Joseph A. Fraietta, PhD, an assistant professor of Microbiology at Penn. The co-senior author is Simon F. Lacey, PhD, director of the Translational and Correlative Studies Laboratory in the Center for Cellular Immunotherapies.

The approach in this study is closely related to CAR T cell therapy, in which patient immune cells are engineered to fight cancer, but it has some key differences. Just like CAR T, researchers in this study began by collecting a patient’s T cells from blood. However, instead of arming these cells with a receptor against a protein such as CD19, the team first used CRISPR/Cas9 editing to remove three genes. The first two edits removed a T cell’s natural receptors so they can be reprogrammed to express a synthetic T cell receptor, allowing these cells to seek out and destroy tumors. The third edit removed PD-1, a natural checkpoint that sometimes blocks T cells from doing their job.

"This new analysis of the three patients has confirmed that the manufactured cells contained all three edits, providing proof of concept for this approach. This is the first confirmation of the ability of CRISPR/Cas9 technology to target multiple genes at the same time in humans and illustrates the potential of this technology to treat many diseases that were previously not able to be treated or cured," June said.

Once the three genes are knocked out, a fourth genetic modification was accomplished using a lentivirus to insert the cancer-specific synthetic T cell receptor, which tells the edited T cells to target an antigen called NY-ESO-1. Previously published data show these cells typically survive for less than a week, but this new analysis shows the edited cells used in this study persisted, with the longest follow up at nine months.

Several months after the infusion, researchers drew more blood and isolated the CRISPR-edited cells for study. When brought back into the lab setting, the cells were still able to kill tumors.

"Previous studies have shown these cells lose function within days, so the fact that the CRISPR-edited cells in this study retained anti-tumor function for a significantly longer period of time after a single infusion is very encouraging," June said.

The CRISPR-edited T cells used in this study are not active on their own like CAR T cells. Instead, they require the cooperation of a molecule known as HLA-A*02:01, which is only expressed in a subset of patients. This means that patients had to be screened ahead of time to make sure they were a match for the approach. Participants who met the requirements received other clinically-indicated therapy as needed while they waited for their cells to be manufactured. Once that process was completed, all three patients received the gene-edited cells in a single infusion after a short course of chemotherapy. Analysis of blood samples revealed that all three participants had the CRISPR-edited T cells take root and thrive in the patients. While none responded to the therapy, there were no treatment-related serious adverse events.

CRISPR technology has not previously been tested in humans in the U.S. Investigators at Penn have pioneered a number of other "first uses" of engineered T cells over the past decade. Even with that experience, moving this work into the clinic while ensuring appropriate patient safeguards meant the research team had to move through a comprehensive and rigorous series of institutional and federal regulatory approval steps, including approval by the National Institutes of Health’s Recombinant DNA Research Advisory Committee and review by the U.S. Food and Drug Administration, as well as Penn’s institutional review board and institutional biosafety committee. The entire process required more than two years. Researchers say these new data will open the door to later stage studies to investigate and extend this approach to a broader field beyond cancer, several of which are already planned at Penn.

On February 6, 2020 Ligand Pharmaceuticals Incorporated (NASDAQ: LGND) reported financial results for the three and 12 months ended December 31, 2019, and provided an operating forecast and program updates (Press release, Ligand, FEB 6, 2020, View Source [SID1234553957]). Ligand management will host a conference call and webcast with accompanying slides today beginning at 4:30 p.m. Eastern time to discuss this announcement and answer questions.

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"Ligand made tremendous progress during 2019 in areas that will drive our future success, including new license agreements, outstanding revenue performance driven by record revenue for Captisol and Kyprolis royalties, expansion of our proprietary technology platforms and continued investment in internal programs," said John Higgins, Chief Executive Officer of Ligand. "Last year we entered into nine OmniAb licensing transactions, reported positive Phase 1 results with Captisol-enabled Iohexol, bolstered our technology assets with the acquisition of an antigen design company, and advanced five internal immuno-oncology programs."

"Partners secured regulatory approvals during the year and we now have 13 partnered products contributing to royalty revenues, with as many as eight more potential approvals over the next three years. The first of 12 OmniAb programs currently in human trials entered pivotal testing in 2019."

"From a financial perspective, revenues exceeded the guidance we introduced last March after we monetized our Promacta assets for $827 million. That transaction was transformative for Ligand and provided significant cash for M&A activities and share repurchases. Over the past 18 months we have retired close to 25% of our outstanding shares through open-market repurchases which, all other things being equal, would result in future cash flow and profits per share increasing more than 30% given the new lower share count."

Higgins concluded, "As we move into 2020, we believe Ligand is well-positioned as a financial growth company driven by innovative technologies that enable partners to develop drugs. We are optimistic about our outlook, specifically in terms of EBITDA margin expansion, earnings growth and cash flow. For 2020 we forecast 14% organic revenue growth and 35% organic growth in adjusted diluted EPS, after factoring in the divestiture of Promacta in early 2019."

Fourth Quarter 2019 Financial Results

Total revenues for the fourth quarter of 2019 were $27.0 million, compared with $59.6 million for the same period in 2018. Royalties in the fourth quarter of 2019 were $11.0 million and primarily consisted of royalties from Kyprolis and EVOMELA. Royalties in the fourth quarter of 2018 were $40.2 million and included $31.0 million in royalties from Promacta, which was sold to Royalty Pharma as of March 6, 2019 for $827 million. Ligand did not receive any Promacta royalties in the fourth quarter of 2019 and will not receive any Promacta royalties going forward. Material sales were $7.1 million, compared with $10.1 million for the same period in 2018 due to the timing of Captisol purchases for use in clinical trials and commercial products. License fees, milestones and other revenues were $8.8 million, compared with $9.3 million for the same period in 2018.

Cost of material sales was $1.9 million for the fourth quarter of 2019, compared with $3.0 million for the same period in 2018. Amortization of intangibles was $6.3 million, compared with $3.5 million for the same period in 2018, with the increase due to accelerated amortization of the glucose receptor antagonist (GRA) asset. Research and development expense was $18.7 million, compared with $8.8 million for the same period of 2018, with the increase due to non-cash amortization of the upfront investments in the Palvella and Novan programs. General and administrative expense was $10.3 million, compared with $11.2 million for the same period in 2018, which included Vernalis acquisition-related expenses.

Net loss for the fourth quarter of 2019 was $(7.4) million, or $(0.43) per share, compared with net loss of $(42.5) million, or $(2.02) per share, for the same period in 2018. The net loss for both periods was impacted by a non-cash unrealized change in the value of Ligand’s investment in Viking Therapeutics of $8.5 million and $(74.0) million, respectively. Adjusted net income for the fourth quarter of 2019 was $12.9 million, or $0.71 per diluted share, compared with adjusted net income of $39.0 million, or $1.70 per diluted share, for the same period in 2018. See the table below for a reconciliation of net income (loss) to adjusted net income.

As of December 31, 2019, Ligand had cash, cash equivalents and short-term investments of approximately $1.0 billion. During the fourth quarter of 2019 Ligand used approximately $82 million in cash to repurchase approximately 760,000 shares.

Full Year 2019 Financial Results

Total revenues for 2019 were $120.3 million, compared with $251.5 million for 2018. Royalties were $47.0 million, compared with $128.6 million for 2018. Royalties for 2019 primarily consisted of royalties from Promacta, Kyprolis and EVOMELA and do not include contribution from Promacta after March 6, 2019, whereas 2018 royalties included the full year of Promacta royalties. Material sales were $31.5 million, compared with $29.1 million for 2018 due to the timing of Captisol purchases for use in clinical trials and commercial products. License fees, milestones and other revenues were $41.8 million, compared with $93.8 million for 2018, which included a $47 million payment from WuXi Biologics to amend its OmniAb platform license agreement as well as a $20 million upfront payment upon the licensing of Ligand’s GRA program.

Cost of material sales was $11.3 million for 2019, compared with $6.3 million for 2018, with the increase due primarily to higher sales and mix of Captisol sales in 2019. Amortization of intangibles was $16.9 million, compared with $15.8 million for 2018. Research and development expense was $55.9 million, compared with $27.9 million for 2018, with the increase due to costs associated with the VDP research team and non-cash amortization of the upfront investments in the Palvella and Novan programs. General and administrative expense was $41.9 million, compared with $37.7 million for 2018, with the increase due to costs associated with recent acquisitions and non-cash share-based compensation expense.

Net income for 2019 was $629.3 million, or $31.85 per diluted share, compared with net income of $143.3 million, or $5.96 per diluted share, for 2018. Net income for 2019 was impacted by an after-tax gain of approximately $642.6 million on the sale of Ligand’s Promacta license to Royalty Pharma. Adjusted net income for 2019 was $61.0 million, or $3.09 per diluted share, compared with adjusted net income of $166.9 million, or $7.15 per diluted share, for 2018.

2020 Financial Guidance

Ligand is providing guidance for 2020 with total revenues expected to be approximately $121 million, which includes royalties of approximately $38 million, material sales of approximately $35 million and license fees and milestones of approximately $48 million. Ligand notes that with total revenues of $121 million, adjusted earnings per diluted share would be approximately $3.40. This compares to 2019 adjusted revenue of $106.1 million and adjusted EPS of $2.52, excluding the impact of Promacta in 2019.

Fourth Quarter 2019 Highlights

Kyprolis (carfilzomib), an Amgen Product Utilizing Captisol

On December 10, Amgen announced additional results from the primary analysis of the Phase 3 CANDOR study evaluating Kyprolis in combination with dexamethasone and DARZALEX (daratumumab) compared to Kyprolis and dexamethasone alone in patients with relapsed or refractory multiple myeloma. The data were presented in a late-breaking abstract session at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (ASH) (Free ASH Whitepaper).
Additional Pipeline and Partner Developments

Viking Therapeutics, Inc. announced the initiation of a Phase 2b clinical trial of VK2809, its novel liver-selective thyroid hormone receptor beta agonist, in patients with biopsy-confirmed non-alcoholic steatohepatitis.
Palvella Therapeutics, Inc. announced that the Phase 3 pivotal portion of the seamless Phase 2/3 VALO study of PTX-022 (QTORIN 3.9% rapamycin anhydrous gel) for the treatment of patients with Pachyonychia congenita had commenced.
Sage Therapeutics launched ZULRESSO (brexanolone) Injection, the first and only treatment specifically indicated for postpartum depression. ZULRESSO utilizes Captisol in its formulation.
Sage announced the investigational new drug (IND) application for SAGE-689, a potential therapy for disorders associated with GABA hypofunction, was cleared by U.S. FDA and Sage expects to commence dosing in a Phase 1 clinical trial in healthy volunteers in 2020.
Retrophin, Inc. announced new data from the Phase 2 DUET study examining the impact of sparsentan on quality of life in patients with focal segmental glomerulosclerosis, at the American Society of Nephrology Kidney Week 2019.
Marinus Pharmaceuticals, Inc. announced that results from its Phase 2 trial of ganaxolone in refractory status epilepticus were presented at the Neurocritical Care Society 17th annual meeting.
Verona Pharma plc announced that it has randomized the last patient in its Phase 2b dose-ranging study evaluating the effect of nebulized ensifentrine as an add-on to treatment with a long-acting bronchodilator in patients with moderate-to-severe chronic obstructive pulmonary disease.
Aptevo announced that OmniAb-derived APVO436 is being evaluated in a Phase 1/1b clinical study in patients with acute myeloid leukemia and high-grade myelodysplastic syndrome. Aptevo expects to report ongoing progress from this study over the next several quarters as clinical data emerge.
Daiichi Sankyo announced positive results from the ESAX-DN Phase 3 study in Japan of esaxerenone in patients with diabetic nephropathy in a late-breaking poster presentation at the American Society of Nephrology Kidney Week 2019.
Immunovant announced that it initiated dosing in ASCEND-GO 2, a multicenter, randomized, masked, placebo-controlled Phase 2b clinical trial evaluating IMVT-1401 in patients with moderate-to-severe active Graves’ ophthalmopathy. IMVT-1401 is a fully human monoclonal antibody that selectively binds to and inhibits the neonatal Fc receptor, and is designed to be delivered by subcutaneous injection.
Aldeyra Therapeutics announced positive topline results from Part 1 of its Adaptive Phase 3 RENEW trial of topical ocular reproxalap in patients with dry eye disease.
Marinus Pharmaceuticals, Inc. announced additional data from its open-label, dose-finding Phase 2 study evaluating intravenous ganaxolone in patients with refractory status epilepticus. The results were presented at the American Epilepsy Society annual meeting.
CStone Pharmaceuticals announced that CS1001, its anti-PD-L1 antibody, demonstrated promising antitumor activity with a complete response rate of 33.3% and a good safety profile in patients with relapsed or refractory extranodal natural killer/T-cell lymphoma.
Sanofi presented pivotal data from its Phase 3 study of sutimlimab in patients with cold agglutinin disease at ASH (Free ASH Whitepaper) in a late-breaker session.
Business Development and Corporate Highlights

Ligand presented positive results from its Phase 1 clinical trial of its Captisol-enabled (CE) Iohexol program at American Society of Nephrology Kidney Week 2019. The CE-Iohexol program was established in January 2018 to develop a Captisol-enabled, next-generation contrast agent for diagnostic imaging with a reduced risk of renal toxicity.
Ligand announced a worldwide OmniAb license agreement with Sanofi under which Sanofi will be able to use Ligand’s full OmniAb antibody discovery platform including OmniRat, OmniFlic, OmniMouse, OmniChicken and OmniClic, in addition to Ligand’s patented antigen technology.
Ligand acquired Ab Initio for $12 million. Ab Initio is an antigen-discovery company based in South San Francisco, California. Antigen design and preparation are the first steps necessary for the discovery of therapeutic antibodies.
Ligand announced that two members of its Board of Directors, Nancy Gray and Sarah Boyce, had been named to WomenInc. magazine’s 2019 Most Influential Corporate Directors list.
Ligand focused on adopting and implementing policies and practices aimed at improving its environmental sustainability, positively impacting its social community and maintaining and cultivating good corporate governance. By focusing on such environmental, social and governance (ESG) policies and practices, Ligand believes it can effect a meaningful, positive change in its community and maintain its open, collaborative corporate culture. Ligand expects to continue its proactive shareholder engagement and to refine its ESG policies and practices in 2020.
Use of Non-GAAP Adjusted Financial Measures

The Company reports adjusted net income and adjusted net income per diluted share in addition to, and not as a substitute for, or superior to, financial measures calculated in accordance with GAAP. The Company’s financial measures under GAAP include share-based compensation expense, amortization of debt-related costs, amortization related to acquisitions and intangible assets, amortization of commercial license and other economic rights, changes in contingent liabilities, acquisition and integration costs, mark-to-market adjustments for amounts relating to its equity investments in public companies, excess tax benefit from share-based compensation, unissued shares relating to its Senior Convertible Notes, gain on the sale of Promacta and others that are listed in the itemized reconciliations between GAAP and adjusted financial measures included at the end of this press release.

However, other than with respect to total revenues, the Company only provides financial guidance on an adjusted basis and does not provide reconciliations of such forward-looking adjusted measures to GAAP due to the inherent difficulty in forecasting and quantifying certain amounts that are necessary for such reconciliation, including adjustments that could be made for changes in contingent liabilities, changes in the market value of its investments in public companies, share-based compensation expense and effects of any discrete income tax items. Management has excluded the effects of these items in its adjusted measures to assist investors in analyzing and assessing the Company’s past and future core operating performance. Additionally, adjusted earnings per diluted share is a key component of the financial metrics utilized by the Company’s board of directors to measure, in part, management’s performance and determine significant elements of management’s compensation.

Conference Call and Webcast

Ligand management will host a conference call and webcast with accompanying slides today beginning at 4:30 p.m. Eastern time (1:30 p.m. Pacific time) to discuss this announcement and answer questions. To participate in the call via telephone, please dial (833) 591-4752 from the U.S. or (720) 405-1612 from outside the U.S., using the conference ID 1150048. To participate in the call via live or replay webcast, a link is available at www.ligand.com. The conference call slides are available here.

On February 6, 2020 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported financial results for the fourth quarter and full year 2019 and provided a business update (Press release, Regeneron, FEB 6, 2020, View Source [SID1234553973]).

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"Regeneron had a very productive 2019 marked by strong commercial growth for our core franchises, significant pipeline and regulatory progress, and positive financial results," said Leonard S. Schleifer, M.D., Ph.D., President and Chief Executive Officer of Regeneron. "In 2020, we are focused on driving continued growth with EYLEA, Dupixent, and Libtayo and anticipate several new regulatory approvals and submissions across our portfolio. Our expanding pipeline of innovative and complementary immuno-oncology therapies continues to advance, and we feel confident that we are positioned to bring new breakthroughs to cancer patients and be a leader in this rapidly evolving field."

"We continue to work constructively with Sanofi to finalize our modified antibody agreement for Praluent and Kevzara, which we expect to be accretive in 2020," said Robert E. Landry, Executive Vice President, Finance and Chief Financial Officer of Regeneron. "We will provide financial guidance for full year 2020 by no later than the end of the first quarter."

Financial Highlights

Business Highlights

Key Pipeline Progress
Regeneron has 22 product candidates in clinical development, including five of the Company’s U.S. Food and Drug Administration (FDA) approved products for which it is investigating additional indications. Updates from the clinical pipeline include:

EYLEA (aflibercept) Injection

In December 2019, the Company launched the EYLEA pre-filled syringe in the United States.
Dupixent (dupilumab)

In October 2019, the European Commission (EC) approved Dupixent in chronic rhinosinusitis with nasal polyposis (CRSwNP).
The FDA accepted for priority review the supplemental Biologics License Application (sBLA) for children aged 6 to 11 years with moderate-to-severe atopic dermatitis, with a target action date of May 26, 2020. In addition, a Marketing Authorization Application (MAA) for children aged 6 to 11 years with moderate-to-severe atopic dermatitis was recently submitted in the European Union.
A Phase 2/3 study in bullous pemphigoid and Phase 3 studies in prurigo nodularis and chronic spontaneous urticaria were initiated.
Libtayo (cemiplimab)

A Phase 2 neoadjuvant study in cutaneous squamous cell carcinoma (CSCC) was initiated.
REGN1979, a bispecific antibody targeting CD20 and CD3

In December 2019, the Company reported updated results from the initial clinical trial in patients with non-Hodgkin lymphoma.
The potentially pivotal Phase 2 study has been expanded to include patients with diffuse large B-cell lymphoma (DLBCL) and other non-Hodgkin lymphomas.
REGN5458, a bispecific antibody targeting BCMA and CD3

In December 2019, the Company announced positive preliminary results from an initial clinical trial in patients with relapsed or refractory multiple myeloma.
Pozelimab, an antibody to C5

In December 2019, the Company announced positive top-line results from a Phase 2 trial in paroxysmal nocturnal hemoglobinuria (PNH).
Garetosmab, an antibody to Activin A

In January 2020, the Company announced encouraging results from a Phase 2 trial in fibrodysplasia ossificans progressiva (FOP).
REGN-EB3, a multi-antibody therapy to Ebola virus infection

The New England Journal of Medicine published results from the randomized, controlled PALM trial showing that Regeneron’s REGN-EB3 and another agent provided the highest overall survival rates among four investigational treatments for Ebola.
Business Development Update

The Company and Sanofi announced their intent to restructure their antibody collaboration for Kevzara and Praluent and enter into a royalty-based arrangement. Under the proposed terms of the agreement, Sanofi is expected to gain sole global rights to Kevzara and sole rights to Praluent outside of the United States. Regeneron is expected to gain sole U.S. rights to Praluent. Under the proposed terms, each party will be solely responsible for funding development and commercialization expenses in their respective territories. The proposed agreement, which is expected to be finalized in the first quarter of 2020, will not impact the companies’ existing collaboration relating to Dupixent and REGN3500.
The Company entered into a research collaboration and option licensing agreement with Vyriad, Inc. to discover and develop new oncolytic (cancer-killing) virus-based treatments for various forms of cancer.
Select 2020 Milestones

Programs

Milestones

Dupixent

–

FDA decision (target action date of May 26, 2020) on sBLA and EC decision for expanded atopic dermatitis indication in pediatric patients (6–11 years of age)

–

Report results from Phase 3 study for asthma in pediatric patients (6–11 years of age)

–

Report results from Phase 2 portion of Phase 2/3 study in eosinophilic esophagitis (EOE)

Libtayo

–

Interim analysis of overall survival in Phase 3 non-small cell lung cancer (NSCLC) monotherapy study in patients with high PD-L1 expression

–

Report results from potentially pivotal Phase 2 study in basal cell carcinoma (BCC)

REGN1979 (CD20 and CD3 Antibody)

–

Report updated results from initial study in certain B-cell malignancies

–

Continue to expand potentially pivotal Phase 2 study

REGN5458 (BCMA and CD3 Antibody)

–

Report updated results from initial study in multiple myeloma

Evinacumab (ANGPTL3 Antibody)

–

Submit BLA and MAA for homozygous familial hypercholesterolemia (HoFH)

Pozelimab (C5 Antibody)

–

Initiate Phase 3 program in PNH

–

Initiate combination program with Alnylam’s cemdisiran

Garetosmab (Activin A Antibody)

–

Discuss regulatory submission for FOP with regulatory authorities

Fasinumab (NGF Antibody)

–

Report results from Phase 3 studies in osteoarthritis pain of the knee or hip

REGN-EB3 (Multi-antibody therapy to Ebola)

–

Complete rolling BLA submission for Ebola

Fourth Quarter and Full Year 2019 Financial Results

Total Revenues: Total revenues increased by 13% to $2.170 billion in the fourth quarter of 2019, compared to $1.928 billion in the fourth quarter of 2018. Full year 2019 total revenues increased 17% to $7.863 billion, compared to $6.711 billion for the full year 2018.

Net product sales were $1.286 billion in the fourth quarter and $4.834 billion for the full year 2019, compared to $1.096 billion in the fourth quarter and $4.106 billion for the full year 2018. EYLEA net product sales in the United States were $1.222 billion in the fourth quarter and $4.644 billion for the full year 2019, compared to $1.079 billion in the fourth quarter and $4.077 billion for the full year 2018. Overall distributor inventory levels for EYLEA in the United States remained within the Company’s one-to-two-week targeted range.

Total revenues also include Sanofi and Bayer collaboration revenues(2) of $748 million in the fourth quarter and $2.616 billion for the full year 2019, compared to $729 million in the fourth quarter and $2.188 billion for the full year 2018. Sanofi collaboration revenue in the fourth quarter and full year 2019 included the Company’s share of profits from collaboration antibodies (Dupixent, Praluent, and Kevzara) of $104 million and $209 million, respectively, while Sanofi collaboration revenue in the fourth quarter and full year 2018 included the Company’s share of losses from collaboration antibodies of $(44) million and $(227) million, respectively. The increase in the Company’s share of profits from collaboration antibodies was primarily driven by higher Dupixent profits. Sanofi collaboration revenue in the fourth quarter of 2018 also included the recognition of a cumulative catch-up adjustment of $149 million arising from a change in the estimate of the stage of completion of the collaborations’ immuno-oncology programs primarily in connection with the Amended IO Discovery Agreement.

Refer to Table 4 for a summary of collaboration and other revenue.

Research and Development (R&D) Expenses: GAAP R&D expenses were $683 million in the fourth quarter and $3.037 billion for the full year 2019, compared to $601 million in the fourth quarter and $2.186 billion for the full year 2018. The higher R&D expenses in the fourth quarter of 2019 were principally due to additional costs incurred in connection with our earlier-stage pipeline and dupilumab, and higher headcount and headcount-related costs. The higher R&D expenses for the full year 2019 were principally due to a $400 million up-front payment to Alnylam, additional costs incurred in connection with our earlier-stage pipeline, and higher headcount and headcount-related costs. R&D-related non-cash share-based compensation expense was $72 million in the fourth quarter and $250 million for the full year 2019, compared to $68 million in the fourth quarter and $229 million for the full year 2018.

Selling, General, and Administrative (SG&A) Expenses: GAAP SG&A expenses were $587 million in the fourth quarter and $1.835 billion for the full year 2019, compared to $491 million in the fourth quarter and $1.556 billion for the full year 2018. The higher SG&A expenses in the fourth quarter and full year 2019 were primarily due to higher headcount and headcount-related costs, an increase in commercialization-related expenses for Dupixent and EYLEA, additional accruals for loss contingencies associated with ongoing litigation, and higher contributions to independent not-for-profit patient assistance organizations. In addition, in the fourth quarter of 2019, the Company recorded a charge for restructuring-related costs, primarily related to employee separation costs, as the Company has eliminated certain commercialization activities and related headcount in connection with the proposed restructuring of the antibody agreement with Sanofi (as described above). SG&A-related non-cash share-based compensation expense was $45 million in the fourth quarter and $168 million for the full year 2019, compared to $51 million in the fourth quarter and $169 million for the full year 2018.

Cost of Goods Sold (COGS): GAAP COGS was $109 million in the fourth quarter and $362 million for the full year 2019, compared to $44 million in the fourth quarter and $180 million for the full year 2018. The increase in COGS was primarily due to our obligation to pay Sanofi its share of Libtayo U.S. gross profits, third-party royalties on Libtayo U.S. sales, and higher inventory write-downs and reserves.

Cost of Collaboration and Contract Manufacturing (COCM): GAAP COCM was $115 million in the fourth quarter and $420 million for the full year 2019, compared to $73 million in the fourth quarter and $254 million for the full year 2018. The increase in COCM for the full year 2019 was primarily due to the recognition of manufacturing costs associated with higher sales of Dupixent.

Other Income (Expense): GAAP other income (expense), net, includes the recognition of net gains on equity securities of $189 million in the fourth quarter and $118 million for the full year 2019, compared to net losses of $(63) million in the fourth quarter and $(42) million for the full year 2018.

Income Taxes: GAAP income tax expense was $98 million and the effective tax rate was 11.0% in the fourth quarter of 2019, compared to a GAAP income tax benefit of $(144) million and (21.3%) in the fourth quarter of 2018. GAAP income tax expense was $313 million and the effective tax rate was 12.9% for the full year 2019, compared to $109 million and 4.3% for the full year 2018. The effective tax rate for the fourth quarter and full year 2019 was positively impacted, compared to the U.S. federal statutory rate, primarily by stock-based compensation, income earned in foreign jurisdictions with tax rates lower than the U.S. federal statutory rate, and federal tax credits for research activities. The Company’s effective tax rate for the fourth quarter and full year 2018 was positively impacted, compared to the U.S. federal statutory rate, primarily by the Company’s fourth quarter sale of non-inventory related assets between foreign subsidiaries, which had a net impact on the rate by 24.0% and 6.3% for the fourth quarter and full year 2018, respectively. During the fourth quarter and full year 2018, the Company also recorded an income tax benefit of $56 million and $68 million, respectively, as an adjustment to the provisional amount recorded as of December 31, 2017 for the U.S. Tax Reform Act.

GAAP and Non-GAAP Net Income(1): GAAP net income was $792 million, or $6.93 per diluted share, in the fourth quarter of 2019, compared to GAAP net income of $820 million, or $7.15 per diluted share, in the fourth quarter of 2018. GAAP net income was $2.116 billion, or $18.46 per diluted share, for the full year 2019, compared to GAAP net income of $2.444 billion, or $21.29 per diluted share, for the full year 2018.

Non-GAAP net income was $858 million, or $7.50 per diluted share, in the fourth quarter of 2019, compared to non-GAAP net income of $786 million, or $6.84 per diluted share, in the fourth quarter of 2018. Non-GAAP net income was $2.827 billion, or $24.67 per diluted share, for the full year 2019, compared to non-GAAP net income of $2.622 billion, or $22.84 per diluted share, for the full year 2018.

A reconciliation of the Company’s GAAP to non-GAAP results is included in Table 3 of this press release.

2020 Financial Guidance

Given the announcement regarding the intent to restructure the antibody collaboration for Kevzara and Praluent with Sanofi, Regeneron will provide financial guidance for full year 2020 by the end of the first quarter of 2020.

This press release uses non-GAAP net income and non-GAAP net income per share, which are financial measures that are not calculated in accordance with U.S. Generally Accepted Accounting Principles (GAAP). These non-GAAP financial measures are computed by excluding certain non-cash and other items from the related GAAP financial measure. Non-GAAP adjustments also include the estimated income tax effect of reconciling items.

The Company makes such adjustments for items the Company does not view as useful in evaluating its operating performance. For example, adjustments may be made for items that fluctuate from period to period based on factors that are not within the Company’s control (such as the Company’s stock price on the dates share-based grants are issued or changes in the fair value of the Company’s equity investments) or items that are not associated with normal, recurring operations (such as restructuring-related expenses, including employee separation costs). Management uses these non-GAAP measures for planning, budgeting, forecasting, assessing historical performance, and making financial and operational decisions, and also provides forecasts to investors on this basis. Additionally, such non-GAAP measures provide investors with an enhanced understanding of the financial performance of the Company’s core business operations. However, there are limitations in the use of these and other non-GAAP financial measures as they exclude certain expenses that are recurring in nature. Furthermore, the Company’s non-GAAP financial measures may not be comparable with non-GAAP information provided by other companies. Any non-GAAP financial measure presented by Regeneron should be considered supplemental to, and not a substitute for, measures of financial performance prepared in accordance with GAAP. A reconciliation of the Company’s historical GAAP to non-GAAP results is included in Table 3 of this press release.

The Company’s collaborators provide it with estimates of the collaborators’ respective sales and the Company’s share of the profits or losses from commercialization of products for the most recent fiscal quarter. The Company’s estimates for such quarter are reconciled to actual results in the subsequent fiscal quarter, and the Company’s share of the profit or loss is adjusted on a prospective basis accordingly, if necessary.

Conference Call Information

Regeneron will host a conference call and simultaneous webcast to discuss its fourth quarter and full year 2019 financial and operating results on Thursday, February 6, 2020, at 8:00 AM. To access this call, dial (800) 708-4540 (U.S.) or (847) 619-6397 (International). A link to the webcast may be accessed from the "Investors and Media" page of Regeneron’s website at www.regeneron.com. A replay of the conference call and webcast will be archived on the Company’s website and will be available for at least 30 days.

On February 6, 2020 Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, reported its consolidated financial results for the fourth quarter and full year ended December 31, 2019 and reviewed recent business highlights (Press release, Alnylam, FEB 6, 2020, View Source [SID1234553926]).

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"In 2019 we saw continued and steady growth of patients on ONPATTRO, and we expect growth to continue in 2020, driven by new patient finding, geographic expansion, and evidence-generating activities. We also believe that our ongoing APOLLO-B Phase 3 study, if positive, can potentially enable future label expansion for patisiran to treat the cardiomyopathy of hereditary and wild-type ATTR amyloidosis. With the early U.S. approval of GIVLAARI in the fourth quarter, Alnylam became a multi-product commercial company, and we are pleased with the strong initial interest from patients, physicians, and payers in the short period since the drug’s approval by the FDA," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "Also in the fourth quarter, we reported positive topline Phase 3 results with lumasiran, Alnylam’s third program in 2019 to achieve positive Phase 3 results, and we’ve initiated the rolling submission of an NDA, setting us up for a potential approval later this year. In addition, in 2020 we look forward to advancing additional late-stage programs closer to the market, namely vutrisiran – with the HELIOS-A and -B studies in ATTR amyloidosis – and, inclisiran and fitusiran with our partners at Novartis and Sanofi, respectively. With continued execution across these and other programs we are confident that by year-end we’ll achieve our Alnylam 2020 goals of building a multi-product, global biopharma company with a deep clinical pipeline to fuel future growth and a robust product engine for sustainable and organic innovation, a profile rarely achieved in our industry."

Fourth Quarter 2019 and Recent Significant Corporate Highlights

Commercial Performance

ONPATTRO

Achieved global net product revenues for the fourth quarter and full year 2019 of $55.8 million and $166.4 million, respectively.
As of year-end 2019, over 750 patients worldwide were receiving commercial ONPATTRO, and over 1,000 total patients worldwide were being treated with patisiran, when also including those patients in clinical studies and in the Company’s global Expanded Access Program (EAP).
Significant ONPATTRO new patient growth in the fourth quarter was seen in the U.S. and EU, along with a strong launch in Japan.
In the U.S., 44% of Start Forms submitted in 2019 came from cardiologists, 38% from neurologists, and 18% from other physician specialties.
In the U.S., Alnylam has now completed definitive value-based agreements (VBAs) with 15 commercial payers, including each of the top 5 commercial payers and 8 of the top 10, with signed VBAs now covering over 130 million U.S. lives in the aggregate.
Continued progress with market access efforts across the Canada, Europe, Middle East, and Africa (CEMEA) region, with a recent launch in the United Kingdom and reimbursement approvals in Belgium, Israel, and Italy.
GIVLAARI

A total of 13 Start Forms were submitted for the period following approval of GIVLAARI in the U.S. on November 20, 2019 through year-end 2019.
Net product revenues for the fourth quarter of 2019 were $0.2 million representing initial channel stocking.
The Company has made significant progress toward establishing VBAs, including a Prevalence-Based Adjustment feature, with multiple ongoing discussions with payers.
R&D Highlights

Continued to apply for marketing authorization of patisiran (the non-proprietary name for ONPATTRO) in additional countries for the treatment of hATTR amyloidosis patients with polyneuropathy and to advance the development of patisiran for the potential treatment of the cardiomyopathy of both hereditary and wild type ATTR amyloidosis.
Continued enrollment in the APOLLO-B Phase 3 study in ATTR amyloidosis patients with cardiomyopathy.
Filed a marketing authorization application with the Brazilian Health Regulatory Agency (ANVISA) for patisiran for the treatment of hATTR amyloidosis patients with polyneuropathy.
Achieved the second-ever regulatory approval of an RNAi therapeutic with the approval of GIVLAARI (givosiran) in the U.S.
Received FDA approval of GIVLAARI for the treatment of adults with AHP.
Received a positive opinion for givosiran for the treatment of AHP in adolescents and adults from the Committee for Medicinal Products for Human Use (CHMP) in the EU.
Filed a marketing authorization application for givosiran with the Brazilian Health Regulatory Agency (ANVISA).
Advanced lumasiran, an investigational RNAi therapeutic in development for the treatment of primary hyperoxaluria type 1 (PH1).
Reported positive topline results from ILLUMINATE-A Phase 3 study of lumasiran for the treatment of PH1.
Initiated NDA rolling submission to the FDA, with remaining sections expected to be submitted in early 2020.
The Company announces today that it has completed enrollment in the ILLUMINATE-B Phase 3 study of lumasiran in PH1 patients less than six years of age with preserved renal function, and remains on track to report topline results in mid-2020.
Initiated the ILLUMINATE-C Phase 3 study of lumasiran for the treatment of advanced PH1 in patients of all ages with advanced renal disease.
Received a pediatric rare disease designation from the FDA for lumasiran for the treatment of PH1.
Announced positive efficacy results from the ongoing Phase 2 open-label extension (OLE) study of lumasiran at the American Society of Nephrology (ASN) 2019 Annual Meeting.
Advanced vutrisiran, a subcutaneously administered investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis.
Initiated the HELIOS-B Phase 3 study in patients with hereditary and wild-type ATTR amyloidosis with cardiomyopathy.
Continued enrollment in the HELIOS-A Phase 3 study in hereditary ATTR amyloidosis with polyneuropathy, with the study over 85% enrolled.
Alnylam’s partner, The Medicines Company, acquired by Novartis in January 2020, advanced inclisiran, an investigational RNAi therapeutic in development for the treatment of hypercholesterolemia.
Reported positive complete results from the ORION-9 and -10 Phase 3 studies of inclisiran in patients with heterozygous familial hypercholesterolemia (HeFH) and atherosclerotic cardiovascular disease (ASCVD).
Submitted an NDA and an MAA for inclisiran to the FDA and the EMA, respectively.
Novartis announced a groundbreaking agreement with the UK National Health Service (NHS) to study inclisiran in UK patients as part of a large-scale NHS clinical trial expected to start later this year. As part of the agreement, inclisiran is also expected to be available to UK patients through a population-level agreement, if approved and reimbursed.
Alnylam’s partner, Sanofi, continues enrollment in the ATLAS Phase 3 program for fitusiran in patients with hemophilia A or B with and without inhibitors.
Advanced early-stage RNAi pipeline programs.
Announced initial positive clinical results with ALN-AAT02 and ALN-HBV02 (VIR-2218), providing initial human proof of concept for "Enhanced Stabilization Chemistry Plus" (ESC+) GalNAc conjugate delivery technology.
Presented initial positive clinical results, namely knockdown of serum angiotensinogen levels, from Phase 1 trial of ALN-AGT, an investigational RNAi therapeutic for hypertension, expanding potential opportunities for RNAi therapeutics in highly prevalent chronic diseases.
Reported strong progress in CNS and ocular delivery of RNAi therapeutics with seven initial programs selected as part of Regeneron collaboration, including ALN-APP, in development for the treatment of cerebral amyloid angiopathy and potentially other neurodegenerative diseases, and ALN-HTT, in development for the treatment of Huntington’s disease.
Additional Business Updates

Alnylam announces today that it ranked #3 in gender parity and #1 in fair representation for Women of Color at the leadership level among the top 25 employers in Massachusetts by the Eos Foundation’s inaugural Women’s Power Gap in Corporate Massachusetts Survey and Rankings.
Received recognition as the world’s #1 biopharma employer from Science magazine based on more than 7,500 responses to its annual survey of the biotech and pharmaceutical industry.
Upcoming Events

Alnylam announces today that it intends to present multiple new study results with patisiran at the XVII International Symposium on Amyloidosis on March 1-5, 2020 in Tarragona, Spain.
The Company also intends to report full results from the ILLUMINATE-A Phase 3 study of lumasiran at the OxalEurope International Congress on March 31, 2020 in Amsterdam.
In addition, in early 2020, Alnylam intends to:

Continue global commercialization of ONPATTRO.
Continue global launch of GIVLAARI, including launch in Europe following expected approval from the European Medicines Agency (EMA).
Complete enrollment in the HELIOS-A Phase 3 study of vutrisiran.
Complete rolling submission of the lumasiran NDA and file MAA with the EMA.
Financial Results for the Quarter and Year Ended December 31, 2019

"We believe our fourth quarter and full year 2019 results reflect strong ONPATTRO patient demand and excellent execution by our commercial teams around the world. Notably, we saw significant ONPATTRO new patient growth in the U.S. and EU, and strong initial demand in Japan, together resulting in over 20 percent quarter-on-quarter growth in net product revenues. We expect growth to continue in 2020 and are guiding that we expect to achieve between $285 million and $315 million in ONPATTRO net product revenues for the year. We also look forward to now leveraging our global commercial capabilities for the launch of GIVLAARI," said Jeff Poulton, Chief Financial Officer of Alnylam. "Our balance sheet remains strong with $1.55B in cash and investments at year-end, enabling continued investments in R&D and commercial execution. Looking forward, we are now focused on achieving a self-sustainable financial profile. The key elements of this transition include top line revenue growth from currently two marketed products – and in the not-too-distant future, potentially up to six marketed products – as well as disciplined investment in our operations."

Financial Highlights

Net Product Revenues

Net product revenues were $55.9 million in the fourth quarter 2019 representing 21% growth from the third quarter 2019 primarily driven by the addition of new patients on therapy and expansion into new markets.
Net product revenues grew from $12.5 million in 2018 to $166.5 million in 2019 primarily driven by the continued global launch of ONPATTRO during its first full-year on the market.
Net Revenues from Collaborators

Net revenues from collaborators were $15.7 million in the fourth quarter 2019, an increase from $9.0 million in the fourth quarter 2018 primarily due to revenues from the Regeneron collaboration.
Net revenues from collaborators were $53.2 million in 2019, a decrease from $62.4 million in 2018 primarily due to a decline in reimbursable activities from the Sanofi Genzyme collaboration, offset by revenues from the Regeneron collaboration.
Research & Development (R&D) and Selling, General & Administrative (SG&A) Expenses

R&D expenses increased in the fourth quarter and full year 2019 compared to the same periods in 2018 on a GAAP and non-GAAP basis primarily due to increased activity related to the advancement of the Company’s late stage programs.
SG&A expenses increased in the fourth quarter and full year 2019 compared to the same periods in 2018 on a GAAP and non-GAAP basis primarily due to increases in commercial and medical affairs activities supporting continued investment in the ongoing ONPATTRO launch and the launch of GIVLAARI in late 2019.
R&D and SG&A expenses on a GAAP basis also increased in the fourth quarter 2019 compared to the same period in 2018 due to an increase in stock-based compensation primarily due to the probability of or achievement of certain performance-based vesting events under outstanding equity awards.
Cash and Investments

Cash and investments were $1.55 billion at the end of 2019 compared to $1.13 billion at the end of 2018. The increase was due to proceeds received under the Company’s equity offering in the first quarter of 2019 and proceeds received under the collaboration and equity agreements with Regeneron offset by cash used in the Company’s operations.
A reconciliation of GAAP to non-GAAP results is included in the tables of this press release.

2020 Financial Guidance

Full year 2020 financial guidance consists of the following:

ONPATTRO net product revenues of $285 million – $315 million
Net revenues from collaborators of $100 million – $150 million
GAAP R&D and SG&A expenses of $1,180 million – $1,300 million
Non-GAAP R&D and SG&A expenses of $1,025 million – $1,125 million*
The Company expects that its current cash, cash equivalents, and marketable debt and equity securities will support company operations for multiple years based on its current operating plans.
*Excludes $155 million – $175 million of stock-based compensation from GAAP R&D and SG&A expenses.

Use of Non-GAAP Financial Measures
This press release contains non-GAAP financial measures, including expenses adjusted to exclude certain non-cash expenses and non-recurring gains outside the ordinary course of the Company’s business. These measures are not in accordance with, or an alternative to, GAAP, and may be different from non-GAAP financial measures used by other companies.

The items included in GAAP presentations but excluded for purposes of determining non-GAAP financial measures for the periods presented in the press release are stock-based compensation expense, a gain on equity securities, a gain on the change in fair value of a liability obligation, and a gain on litigation settlement. The Company has excluded the impact of stock-based compensation expense, which may fluctuate from period to period based on factors including the variability associated with performance-based grants for stock options and restricted stock units and changes in the Company’s stock price, which impacts the fair value of these awards. The Company has excluded the impact of the gain on equity securities, the change in fair value of liability obligation and the gain on litigation settlement because the Company believes these items are one-time events occurring outside the ordinary course of the Company’s business.

The Company believes the presentation of non-GAAP financial measures provides useful information to management and investors regarding the Company’s financial condition and results of operations. When GAAP financial measures are viewed in conjunction with non-GAAP financial measures, investors are provided with a more meaningful understanding of the Company’s ongoing operating performance and are better able to compare the Company’s performance between periods. In addition, these non-GAAP financial measures are among those indicators the Company uses as a basis for evaluating performance, allocating resources and planning and forecasting future periods. Non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between GAAP and non-GAAP measures is provided later in this press release.

Conference Call Information
Management will provide an update on the Company and discuss fourth quarter and year-end 2019 results as well as expectations for the future via conference call on Thursday, February 6, 2020 at 8:30 am ET. To access the call, please dial 800-239-9838 (domestic) or +1-323-794-2551 (international) five minutes prior to the start time and refer to conference ID 6976021. A replay of the call will be available beginning at 11:30 am ET on the day of the call. To access the replay, please dial 888-203-1112 (domestic) or +1-719-457-0820 (international) and refer to conference ID 6976021.

A live audio webcast of the call will be available on the Investors section of the Company’s website at www.alnylam.com/events. An archived webcast will be available on the Alnylam website approximately two hours after the event.

About ONPATTRO (patisiran)
ONPATTRO is an RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. ONPATTRO is also approved in the European Union and Switzerland for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy. Based on Nobel Prize-winning science, ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, thereby blocking the production of TTR protein before it is made. ONPATTRO blocks the production of TTR in the liver, reducing its accumulation in the body’s tissues in order to halt or slow down the progression of the polyneuropathy associated with the disease. For more information about ONPATTRO, visit ONPATTRO.com.

ONPATTRO Important Safety Information
Infusion-Related Reactions
Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO. In a controlled clinical study, 19 percent of ONPATTRO-treated patients experienced IRRs, compared to 9 percent of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache.

To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.

Reduced Serum Vitamin A Levels and Recommended Supplementation
ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body.

Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness).

Adverse Reactions
The most common adverse reactions that occurred in patients treated with ONPATTRO were upper respiratory-tract infections (29 percent) and infusion-related reactions (19 percent).

For additional information about ONPATTRO, please see the full Prescribing Information.

About GIVLAARI (givosiran)
GIVLAARI is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) that is approved in the U.S. for the treatment of adults with acute hepatic porphyria (AHP). In the pivotal study, GIVLAARI was shown to significantly reduce the rate of porphyria attacks that required hospitalizations, urgent healthcare visits or IV hemin administration at home compared to placebo. GIVLAARI is Alnylam’s first commercially available therapeutic based on its Enhanced Stabilization Chemistry (ESC) GalNAc conjugate technology to increase potency and durability. GIVLAARI is administered via subcutaneous injection once monthly at a dose based on actual body weight and should be administered by a healthcare professional. GIVLAARI works by specifically reducing elevated levels of ALAS1 messenger RNA (mRNA), leading to reduction of toxins associated with attacks and other disease manifestations of AHP. For more information about GIVLAARI, visit GIVLAARI.com.

GIVLAARI Important Safety Information
Contraindications
GIVLAARI is contraindicated in patients with known severe hypersensitivity to givosiran. Reactions have included anaphylaxis.

Anaphylactic Reaction
Anaphylaxis has occurred with GIVLAARI treatment (<1% of patients in clinical trials). Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI. Monitor for signs and symptoms of anaphylaxis. If anaphylaxis occurs, immediately discontinue administration of GIVLAARI and institute appropriate medical treatment.

Hepatic Toxicity
Transaminase elevations (ALT) of at least 3 times the upper limit of normal (ULN) were observed in 15% of patients receiving GIVLAARI in the placebo-controlled trial. Transaminase elevations primarily occurred between 3 to 5 months following initiation of treatment.

Measure liver function tests prior to initiating treatment with GIVLAARI, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter. Interrupt or discontinue treatment with GIVLAARI for severe or clinically significant transaminase elevations. In patients who have dose interruption and subsequent improvement, reduce the dose to 1.25 mg/kg once monthly. The dose may be increased to the recommended dose of 2.5 mg/kg once monthly if there is no recurrence of severe or clinically significant transaminase elevations at the 1.25 mg/kg dose.

Renal Toxicity
Increases in serum creatinine levels and decreases in estimated glomerular filtration rate (eGFR) have been reported during treatment with GIVLAARI. In the placebo-controlled study, 15% of patients receiving GIVLAARI experienced a renally-related adverse reaction. The median increase in creatinine at Month 3 was 0.07 mg/dL. Monitor renal function during treatment with GIVLAARI as clinically indicated.

Injection Site Reactions
Injection site reactions were reported in 25% of patients receiving GIVLAARI in the placebo-controlled trial. Symptoms included erythema, pain, pruritus, rash, discoloration, or swelling around the injection site. One (2%) patient experienced a single, transient, recall reaction of erythema at a prior injection site with a subsequent dose administration.

Drug Interactions
Concomitant use of GIVLAARI increases the concentration of CYP1A2 or CYP2D6 substrates, which may increase adverse reactions of these substrates. Avoid concomitant use of GIVLAARI with CYP1A2 or CYP2D6 substrates for which minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP1A2 or CYP2D6 substrate dosage in accordance with approved product labeling.

Adverse Reactions
The most common adverse reactions that occurred in patients receiving GIVLAARI were nausea (27%) and injection site reactions (25%).

For additional information about GIVLAARI, please see full Prescribing Information.

About LNP Technology
Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using LNP technology.

About RNAi
RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

On February 6, 2020 On Target Laboratories Inc., a privately held biotechnology company developing the use of Purdue University-discovered fluorescent markers to target and illuminate cancer during surgery, reported that it has announced the results of a multi-institutional Phase 2 clinical trial in which outcomes were improved for 26% of patients undergoing pulmonary resection for non-small-cell lung cancer (NSCLC) (Press release, On Target Laboratories, FEB 6, 2020, View Source,-improve-outcomes,-receives-fda-fast-track-as-phase-3-clinical-trials-begin.html [SID1234553942]).

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The results of the treatment, called OTL38, were presented at the 56th annual Meeting of the Society of Thoracic Surgeons (STS), held last month in New Orleans, and were featured in a plenary session as a J. Maxwell Chamberlain Memorial Paper for General Thoracic Surgery, considered to be among the top-rated abstracts at STS. The treatment was developed in the Purdue laboratory of Philip Low in the Purdue Institute of Drug Discovery. Low is the Presidential Scholar for Drug Discovery and Ralph C. Corley Distinguished Professor of Chemistry-Biochemistry in the Department of Chemistry. Currently, there are 288 clinical trials performed or in process using Purdue-developed medical treatments at 4,841 sites across the globe.

"Our goal is to provide surgeons with new technology to help them provide a more complete resection to more patients. This gives patients the best chance of improved outcomes after surgery," said Christopher Barys, president and CEO of On Target Laboratories.

Lung cancer is the leading cause of cancer-related deaths in the United States. Pulmonary resection, either a wedge resection, segmentectomy, or lobectomy, is recommended for most patients who have operable stage I-II non-small cell lung cancer. Intraoperative molecular imaging (IMI) — also referred to as fluorescence-guided surgery — may increase the likelihood of a more complete surgical resection, which could translate into increased survival for patients and reduced re-operations or adjuvant treatment for hospitals.

Conducted over 18 months, the study included 92 patients eligible for analysis. There were no drug-related serious adverse events and 24 patients, or 26%, were impacted during pulmonary resection, with 8% of patients having a change in their stage due to the use of IMI.

The study showed that IMI improved localization of small and peripheral lesions, which can be difficult for surgeons to identify visually or through manual palpitation, and enabled localization of otherwise unlocalizable lesions in 11 patients, or 12%. Further, 10 additional cancers were found in seven patients, or 8%. During the Specimen Check Phase, when the surgeon confirms that the nodule is in the specimen and analyzes the margins, surgeons thought all margins were adequate, yet back-table inspection using IMI revealed inadequate margins in eight patients, or 9%.

"OTL38 is the first technique that is specific to imaging adenocarcinomas of the lung, which is one of the most common types of invasive lung cancer," said Dr. Inderpal (Netu) S. Sarkaria of the Department of Cardiothoracic Surgery at the University of Pittsburgh Medical Center. "Near-infrared imaging with OTL38 may be a powerful tool to help surgeons significantly improve the quality of lung cancer surgery by more clearly identifying tumors and allowing the surgeon to better see and completely remove them — one of the most vital components in the overall care of patients with this disease."

OTL38 is under development in two Phase 3 clinical trials for lung and ovarian cancer indications. Both trials are being conducted under a special protocol agreement with the U.S. Food and Drug Administration. OTL38 also has received a fast-track designation for both the lung and ovarian cancer indications and an orphan designation for ovarian cancer from the FDA.

Low is a co-founder of On Target and the technology is licensed through the Purdue Research Foundation Office of Technology of Commercialization. The Purdue Institute of Drug Discovery is situated near Discovery Park District, a $1 billion-plus long-term enterprise to support a transformational center of innovation on the western edge of the Purdue University campus. The district includes the Convergence Center for Innovation and Collaboration, where startups, entrepreneurs, innovators and companies can collaborate with Purdue to address global challenges in health, sustainability, IT and space. The district already includes a public airport with a 7,000-foot runway, and partnerships with international companies including Rolls-Royce, Schweitzer Engineering Laboratories and Saab. Visit Discovery Park District.

About Intraoperative Molecular Imaging

To date, there have been limited ways for surgeons to confidently assess the location and full extent of cancerous tissue while operating. On Target Laboratories’ fluorescent markers are composed of a near-infrared dye and a targeting molecule, or ligand, that binds to receptors overexpressed on cancer cells. These markers illuminate the cancerous lesions, lighting the way for the resection of malignant tissue and enabling surgeons to see and remove more diseased tissue. On Target’s first novel compound, OTL38, targets folate receptors commonly found on many cancers, including lung and ovarian cancers. A small single dose of the compound is administered via IV infusion one to 24 hours before surgery, allowing the surgeon to identify malignant tissue during the procedure using the near-infrared camera.