On February 24, 2022 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading genome editing company focused on developing potentially curative therapies leveraging CRISPR-based technologies, reported operational highlights and financial results for the fourth quarter and year ended December 31, 2021 (Press release, Intellia Therapeutics, FEB 24, 2022, View Source [SID1234608967]).

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"We began 2022 with strong momentum, executing against our strategic priorities for the advancement of our CRISPR-based pipeline and platform. We continued to make steady progress across our multiple clinical programs. In addition, we nominated two new development candidates – NTLA-2003 and NTLA-6001. Notably, we are looking forward to sharing additional data from the landmark study of NTLA-2001 next week," said Intellia President and Chief Executive Officer John Leonard, M.D. "In parallel, we continue to propel our own scientific innovation, as well as leverage external capabilities from across the industry to generate the next wave of clinical candidates. As part of this strategy, we completed several important transactions to further bolster our industry-leading genome editing toolbox and pipeline. Intellia is well-positioned to extend its leadership position as we aim to harness the full potential of genomic medicines."

Fourth Quarter 2021 and Recent Operational Highlights

In Vivo Program Updates

NTLA-2001 for ATTR amyloidosis: NTLA-2001 is the first investigational CRISPR-based therapy to be systemically delivered to edit genes inside the human body and has the potential to be the first single-dose treatment for transthyretin (ATTR) amyloidosis. Delivered with the Company’s in vivo lipid nanoparticle (LNP) technology, NTLA-2001 offers the possibility of halting and reversing the disease by driving a deep, potentially lifelong reduction in transthyretin (TTR) protein after a single dose. NTLA-2001 is part of a co-development/co-promotion agreement between Intellia, the lead party for this program, and Regeneron Pharmaceuticals, Inc. (Regeneron).
Intellia will be hosting a virtual investor event on February 28, 2022, at 4:30 p.m. ET to present additional interim clinical data from the ongoing Phase 1 study of NTLA-2001 in patients with hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN). Data to be presented will come from all four ATTRv-PN dose cohorts in Part 1, the single-ascending dose portion, and include safety and serum TTR reduction for Cohorts 3 and 4, as well as an early look at durability across all cohorts. The Company remains on track to initiate Part 2, a single-cohort expansion, in the polyneuropathy arm in the first quarter of 2022.
Intellia continues to dose patients in the cardiomyopathy arm of the Phase 1 study with NTLA-2001. In December 2021, Intellia initiated dosing in new dose-escalation cohorts in patients with ATTR amyloidosis with cardiomyopathy (ATTR-CM) as part of the expanded Phase 1 study. Enrollment across both ATTRv-PN and ATTR-CM patient populations is expected to complete in 2022.
NTLA-2002 for HAE: NTLA-2002 leverages Intellia’s proprietary in vivo LNP delivery technology to knock out the KLKB1 gene in the liver with the potential to permanently reduce total plasma kallikrein protein and activity, a key mediator of hereditary angioedema (HAE). This investigational approach aims to prevent attacks for people living with HAE by providing continuous suppression of plasma kallikrein activity following a single dose and to eliminate the significant treatment burden associated with currently available HAE therapies.
In December 2021, Intellia announced the first patient was dosed with NTLA-2002. The first-in-human study is expected to evaluate the safety, tolerability and activity of NTLA-2002 in adults with Type I or Type II HAE.
The Company anticipates presenting interim data from the Phase 1/2 study in the second half of 2022. The data are expected to characterize the emerging safety and activity profile of NTLA-2002, and to potentially demonstrate preliminary proof of concept.

NTLA-3001 for AATD-associated lung disease: NTLA-3001 is a wholly owned, first-in-class, CRISPR-mediated in vivo targeted gene insertion development candidate for the treatment of alpha-1 antitrypsin deficiency (AATD)-associated lung disease. It is designed with the aim to precisely insert a healthy copy of the SERPINA1 gene, which encodes the alpha-1 antitrypsin (A1AT) protein, with the potential to restore permanent expression of functional A1AT protein to therapeutic levels after a single dose. This approach seeks to eliminate the need for sub-optimal weekly IV infusions of A1AT augmentation therapy or lung transplant in severe cases.
Intellia continues to conduct Investigational New Drug (IND)-enabling activities for NTLA-3001, with plans to file an IND or IND-equivalent in 2023.
NTLA-2003 for AATD-associated liver disease: NTLA-2003 is a wholly owned in vivo knockout development candidate for the treatment of AATD-associated liver disease. It is designed to inactivate the SERPINA1 gene responsible for the production of abnormal A1AT protein in the liver. This approach aims to halt the progression of liver disease and eliminate the need for liver transplant in severe cases.
Today, Intellia announced the nomination of a new development candidate, NTLA-2003, for treatment of AATD-associated liver disease. The Company is advancing towards IND-enabling activities for this program.
Ex Vivo Program Updates

NTLA-5001 for AML: NTLA-5001 is an autologous T cell receptor (TCR)-T cell therapy engineered to target the Wilms’ Tumor 1 (WT1) antigen for the treatment of all genetic subtypes of acute myeloid leukemia (AML).
In the fourth quarter of 2021, Intellia initiated screening of patients in the Phase 1/2a study of NTLA-5001 for patients with AML. The Company has begun enrolling patients and expects to dose its first patient in the coming weeks. Later this year, the Company plans to provide guidance around timing of the first expected data readout, with the goal of demonstrating clinical proof of concept for its TCR-based platform.
NTLA-6001 for CD30+ Lymphomas: NTLA-6001 is Intellia’s wholly owned allogeneic CAR-T development candidate targeting CD30 for the treatment of CD30-expressing hematologic cancers, including relapsed or refractory classical Hodgkin’s Lymphoma (cHL).
Today, Intellia announced the nomination of its first ex vivo allogeneic development candidate, NTLA-6001, for CD30-expressing hematologic cancers, including cHL. NTLA-6001 is developed using Intellia’s proprietary allogeneic cell engineering platform, which leverages a novel combination of sequential gene edits. Preclinical data presented on its differentiated allogeneic engineering platform showed allogeneic T cells were shielded from immune rejection, both host T and natural killer (NK) cell attack.
Intellia is advancing towards IND-enabling activities and plans to present preclinical data leading to the development of NTLA-6001 at an upcoming scientific conference in 2022.
Research and Corporate Updates

Modular Platform and Pipeline Expansion: Intellia is expanding its industry-leading genome editing platform and scientific leadership through editing, delivery and cell engineering innovations that may enable broader in vivo and ex vivo applications.
Following the nomination of NTLA-2003, Intellia plans to advance at least one new in vivo development candidate by the end of 2022.
The Company plans to highlight additional advances to its proprietary technology capabilities, including both genome editing and delivery tools, at upcoming scientific conferences in 2022.
Collaboration Updates
In February, the Company executed a licensing and collaboration agreement with ONK Therapeutics Ltd. (ONK) for the development of allogeneic CRISPR-edited NK cell therapies for the treatment of cancer. The agreement grants ONK a non-exclusive license to Intellia’s proprietary ex vivo CRISPR/Cas9-based genome editing platform and its LNP-based delivery technologies and exclusive rights to certain guide RNAs for development of up to five NK cell therapies. ONK will be responsible for preclinical and clinical development for the engineered NK cell therapies covered under the agreement. In addition, the agreement grants Intellia options to co-develop and co-commercialize up to two products worldwide with rights to lead commercialization in the U.S.
In December 2021, the Company executed a licensing and collaboration agreement with Kyverna Therapeutics (Kyverna) for the development of KYV-201, an allogeneic CD19 CAR-T cell investigational candidate for the treatment of select autoimmune diseases. This is a novel approach aimed at targeting CD19 for inflammatory diseases as compared to traditional oncology indications. Kyverna will lead and fund preclinical and clinical development for KYV-201 and, as part of the agreement, Intellia granted Kyverna rights to use its proprietary ex vivo CRISPR/Cas9-based allogeneic platform in exchange for an equity stake in Kyverna. Intellia will be eligible to receive certain development and commercial milestone payments, as well as low- to mid-single-digit royalties on potential future sales and may choose to exercise an option to lead U.S. commercialization for KYV-201 under a co-development and co-commercialization agreement.
In October 2021, the Company executed a strategic collaboration with SparingVision to develop novel genomic medicines utilizing Intellia’s proprietary CRISPR/Cas9 technology for the treatment of ocular diseases. In addition, Intellia received an equity stake in SparingVision. As part of the collaboration, Intellia will receive an option for exclusive U.S. commercialization rights for product candidates arising from two of three collaboration targets, eligibility for development and commercial milestone payments, as well as royalties on potential future sales of products arising from the collaboration. The companies will additionally research and develop novel self-inactivating AAV vectors and LNP-based approaches to address delivery of CRISPR/Cas9 genome reagents to the retina.
Corporate Updates
In February, Intellia completed the acquisition of Rewrite Therapeutics, Inc. (Rewrite), a private biotechnology company focused on advancing novel DNA writing technologies. Rewrite’s DNA writing technology may enable a range of precise editing strategies. These include targeted corrections, insertions, deletions and the full range of single-nucleotide changes, which could provide new ways to edit disease-causing genes and broaden the therapeutic potential for genomic medicines.
In February, the Company announced a lease agreement to develop a 140,000-square-foot manufacturing facility in Waltham, Massachusetts, to support the manufacturing of key components for its CRISPR-based investigational therapies. The new manufacturing facility will be Good Manufacturing Practice (GMP) compliant and support both the preclinical through commercial supply for key components of Intellia’s CRISPR-based therapies. Additionally, this facility, in combination with existing capabilities and partnerships, will provide capacity and capabilities in support of Intellia’s expanding pipeline and commercial readiness.
Upcoming Events

The Company will participate in the following events during the first quarter of 2022:

AAAAI Annual Meeting, February 25-28, Phoenix
Cowen Healthcare Conference, March 7, Virtual
Barclays Capital Global Healthcare Conference, March 15, Miami
Guggenheim Healthcare Talks Genomic Medicines and Rare Disease Day, March 31, Virtual
Upcoming Milestones

The Company has set forth the following for pipeline progression:

NTLA-2001 for ATTR amyloidosis:
Report additional interim data from Phase 1 study on February 28
Initiate Part 2, a single-dose expansion cohort, of the Phase 1 study of NTLA-2001 in Q1 2022
Complete enrollment of Phase 1 study for both ATTRv-PN and ATTR-CM subjects in 2022
NTLA-2002 for HAE: Present interim data from Phase 1/2 study in 2H 2022
NTLA-3001 for AATD: Plan to file an IND or IND-equivalent in 2023
NTLA-5001 for AML: Continue to enroll patients in Phase 1/2a study in 2022
NTLA-6001 for CD30+ Lymphomas: Plan to present preclinical data at an upcoming scientific conference in 2022
Pipeline Expansion:
Advance at least one new in vivo development candidate by the end of 2022
Advance additional novel platform capabilities in 2022

Fourth Quarter and Full-Year 2021 Financial Results

Cash Position: Cash, cash equivalents and marketable securities were $1,086.0 million as of December 31, 2021, compared to $597.4 million as of December 31, 2020. The increase was driven by net proceeds of $648.3 million from a follow-on offering in the third quarter of 2021, $45.3 million of net proceeds from the Company’s "At the Market" (ATM) agreement, $43.1 million in proceeds from employee-based stock plans, and $6.3 million of funding for cost-sharing agreements received from Regeneron. These increases were offset in part by cash used to fund operations of approximately $254.7 million.
Collaboration Revenue: Collaboration revenue increased by $6.3 million to $12.9 million during the fourth quarter of 2021, compared to $6.6 million during the fourth quarter of 2020. This increase was primarily driven by $5.8 million in revenue recorded in 2021 from our joint venture with AvenCell.
R&D Expenses: Research and development expenses increased by $32.9 million to $71.2 million during the fourth quarter of 2021, compared to $38.2 million during the fourth quarter of 2020. This increase was primarily driven by the advancement of our lead programs, research personnel growth to support these programs and expansion of the development organization.
G&A Expenses: General and administrative expenses increased by $11.3 million to $22.1 million during the fourth quarter of 2021, compared to $10.8 million during the fourth quarter of 2020. This increase was primarily related to employee related expenses, including stock-based compensation of $3.8 million.
Net Loss: The Company’s net loss was $81.2 million for the fourth quarter of 2021, compared to $42.2 million during the fourth quarter of 2020.

Conference Call to Discuss Fourth Quarter and Full-Year 2021 Results

The Company will discuss these results on a conference call today, Thursday, February 24, at 8:00 a.m. ET.

To join the call:

U.S. callers should dial 1-833-316-0545 and international callers should dial 1-412-317-5726, approximately five minutes before the call. All participants should ask to be connected to the Intellia Therapeutics conference call.
Please visit this link for a simultaneous live webcast of the call.
A replay of the call will be available through the Events and Presentations page of the Investors & Media section on Intellia’s website at intelliatx.com, beginning on February 24, at 12:00 p.m. ET.

On February 24, 2022 Genmab A/S (Nasdaq: GMAB) and Seagen Inc. (Nasdaq: SGEN) reported that it will present preliminary data from the innovaTV 207 global, open-label, multicenter phase 2 trial of tisotumab vedotin (TIVDAK) as a monotherapy in patients with squamous cell carcinoma of the head and neck (SCCHN) who experienced disease progression on or after a first-line platinum-containing regimen and a checkpoint inhibitor (Press release, Genmab, FEB 24, 2022, View Source [SID1234608965]). Early results showed tisotumab vedotin demonstrated a manageable safety profile and promising preliminary antitumor activity in this patient population with the primary endpoint of confirmed objective response rate (ORR) per investigator, achieved by 16 percent of patients (95% CI: 5.5 to 33.7). Findings will be presented as part of a plenary session at the American Society for Radiation Oncology (ASTRO) 2022 Multidisciplinary Head and Neck Cancers Symposium on February 25.

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"There is a significant unmet need for additional treatment options for patients diagnosed with squamous cell carcinoma of the head and neck that has progressed despite the use of chemotherapy," said David S. Hong, M.D., deputy chair of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center and lead investigator of the innovaTV 207 clinical trial. "These preliminary data provide important insight into the safety of tisotumab vedotin in this tumor type and demonstrate the value of exploring this potential use further in the innovaTV 207 trial."

The SCCHN cohort of the innovaTV 207 trial enrolled 31 patients with a median age of 65 (range 47 to 78) years whose disease progressed on or after systemic therapy. Patients received 2 milligrams (mg)/kilogram (kg) tisotumab vedotin (maximum dose: 200 mg per infusion) intravenously on day one of each 21-day cycle. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS) per investigator and overall survival (OS). DCR per investigator was 58.1 percent (95% CI: 39.1 to 75.5), median PFS was 4.2 months (95% CI: 2.7 to 4.8), median follow-up was 10.0 months (95% CI: 8.5 to 13.1) and median OS was 9.4 months (95% CI: 8.1 to 11.8). Adverse events were consistent with the known safety profile of tisotumab vedotin: twenty-one (67.7%) patients developed Grade ≥3 treatment-emergent adverse events (TEAEs); most commonly (≥10% of patients) anemia (16.1%), pneumonia (12.9%), and dyspnea (12.9%). Incidence of treatment-emergent serious adverse events (SAEs) was 51.6%, and incidence of treatment-related SAEs was 6.5% (grade 3 hemoptysis [n=1] and grade 3 post-procedural hemorrhage [n=1]).

See TIVDAK U.S. Important Safety Information, including Boxed Warning, below.

"We recognize the high medical need for additional treatment options for patients with head and neck cancers," said Jan van de Winkel, Ph.D., Chief Executive Officer, Genmab. "These initial data results are encouraging and underscore the importance of our ongoing clinical trial program that will assess the potential utility of tisotumab vedotin in various cancers."

For more information about the ongoing phase 2 innovaTV 207 clinical trial of tisotumab vedotin, please visit www.clinicaltrials.gov (Identifier: NCT03485209).

"The presentation of these preliminary data represents another step forward in our work to advance the tisotumab vedotin development program," said Roger Dansey, M.D., Chief Medical Officer, Seagen. "In partnership with Genmab, we will continue to recruit additional patients for trials to further investigate tisotumab vedotin in patients with squamous cell carcinoma of the head and neck, including its potential use as a combination therapy."

About the innovaTV 207 Trial
The phase 2 innovaTV 207 clinical trial evaluates the activity, safety, and tolerability of tisotumab vedotin in selected solid tumors with high tissue factor (TF) expression. The trial is a global, multicenter, open label basket trial which will enroll an estimated 532 adult patients with relapsed, locally-advanced or metastatic disease in separate tumor-specific cohorts. The primary endpoint of the trial is confirmed ORR per investigator, defined as the proportion of patients who achieve a confirmed complete or partial response. Key secondary endpoints include confirmed and unconfirmed ORR, DCR, duration of response, PFS, OS, safety and tolerability. For more information about the phase 2 innovaTV 207 clinical trial of tisotumab vedotin, please visit www.clinicaltrials.gov (Identifier: NCT03485209).

About Tisotumab Vedotin
Tisotumab vedotin-tftv (TIVDAK) is an antibody-drug conjugate (ADC) composed of Genmab’s human monoclonal antibody directed to tissue factor (TF) and Seagen’s ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody. Nonclinical data suggests that the anticancer activity of tisotumab vedotin is due to the binding of the ADC to TF expressing cancer cells, followed by internalization of the ADC-TF complex, and release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. In vitro, tisotumab vedotin also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.

In September 2021, the U.S. Food and Drug Administration granted accelerated approval for tisotumab vedotin (TIVDAK) in patients with previously treated recurrent or metastatic cervical cancer. TIVDAK is the first and only approved ADC for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

Indication
TIVDAK is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information

BOXED WARNING: OCULAR TOXICITY
TIVDAK caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration. Conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care before, during, and after infusion. Withhold TIVDAK until improvement and resume, reduce the dose, or permanently discontinue, based on severity.

Warnings and Precautions
Ocular Adverse Reactions occurred in 60% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). Grade 3 ocular adverse reactions occurred in 3.8 % of patients, including severe ulcerative keratitis in 3.2% of patients. One patient experienced ulcerative keratitis with perforation requiring corneal transplantation. Cases of symblepharon were reported in patients with other tumor types treated with TIVDAK at the recommended dose. In innovaTV 204, 4% of patients experienced visual acuity changes to 20/50 or worse including 1% of patients who experienced a visual acuity change to 20/200. Of the patients who experienced decreased visual acuity to 20/50 or worse, 75% resolved, including the patient who experienced decreased visual acuity to 20/200.

Refer patients to an eye care provider for an ophthalmic exam including visual acuity and slit lamp exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care to reduce the risk of ocular adverse reactions. Promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms. Withhold dose, reduce the dose, or permanently discontinue TIVDAK based on the severity of the adverse reaction.

Peripheral Neuropathy (PN) occurred in 42% of cervical cancer patients treated with TIVDAK across clinical trials; 8% of patients experienced Grade 3 PN. PN adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (11%), peripheral sensorimotor neuropathy (5%), motor neuropathy (3%), muscular weakness (3%), and demyelinating peripheral polyneuropathy (1%). One patient with another tumor type treated with TIVDAK at the recommended dose developed Guillain- Barre syndrome. Monitor patients for signs and symptoms of neuropathy. For new or worsening PN, withhold, dose reduce, or permanently discontinue TIVDAK based on the severity of PN.

Hemorrhage occurred in 62% of cervical cancer patients treated with TIVDAK across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients. Monitor patients for signs and symptoms of hemorrhage. For patients experiencing pulmonary or CNS hemorrhage, permanently discontinue TIVDAK. For Grade ≥2 hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage recurrence. After resolution, either resume treatment or permanently discontinue TIVDAK.

Pneumonitis: Severe, life-threatening, or fatal pneumonitis can occur in patients treated with antibody-drug conjugates containing vedotin, including TIVDAK. Among patients with cervical cancer treated with TIVDAK across clinical trials, 2 patients (1.3%) experienced pneumonitis, including 1 patient who had a fatal outcome.

Monitor patients for pulmonary symptoms of pneumonitis. Infectious, neoplastic, and other causes for symptoms should be excluded through appropriate investigations.

Withhold TIVDAK for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue TIVDAK in all patients with Grade 3 or 4 pneumonitis.

Embryo-Fetal Toxicity: TIVDAK can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TIVDAK and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TIVDAK and for 4 months after the last dose.

Adverse Reactions
In the innovaTV 204 clinical trial (n=101), serious adverse reactions occurred in 43% of patients; the most common (≥3%) were ileus (6%), hemorrhage (5%), pneumonia (4%), PN, sepsis, constipation, and pyrexia (each 3%). Fatal adverse reactions occurred in 4% of patients who received TIVDAK, including septic shock, pneumonitis, sudden death, and multisystem organ failure (each 1%).

Adverse reactions leading to permanent discontinuation occurred in 13% of patients receiving TIVDAK; the most common (≥3%) were PN (5%) and corneal adverse reactions (4%). Adverse reactions leading to dose interruption occurred in 47% of patients; the most common (≥3%) were PN (8%), conjunctival adverse reactions (4%), and hemorrhage (4%). Adverse reactions leading to dose reduction occurred in 23% of patients; the most common (≥3%) were conjunctival adverse reactions (9%) and corneal adverse reactions (8%).

The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (52%), fatigue (50%), lymphocytes decreased (42%), nausea (41%), PN (39%), alopecia (39%), epistaxis (39%), conjunctival adverse reactions (37%), hemorrhage (32%), leukocytes decreased (30%), creatinine increased (29%), dry eye (29%), prothrombin international normalized ratio increased (26%), activated partial thromboplastin time prolonged (26%), diarrhea (25%), and rash (25%).

Drug interactions

Strong CYP3A4 Inhibitors: Concomitant use with strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the risk of TIVDAK adverse reactions. Closely monitor patients for TIVDAK adverse reactions.

Use in Specific Populations

Moderate or Severe Hepatic Impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Lactation: Advise lactating women not to breastfeed during TIVDAK treatment and for at least 3 weeks after the last dose.

On February 24, 2022 Galapagos NV (Euronext & NASDAQ: GLPG) reported that financial results 2021, reviews key events for the company, and provides outlook for 2022 (Press release, Galapagos, FEB 24, 2022, View Source [SID1234608964]).

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"2021 was a year of reflection, resulting in refocused R&D activities and resized spend, as well as commercial roll-out, with a major effort to launch Jyseleca throughout Europe," said Onno van de Stolpe, CEO of Galapagos. "We made excellent progress with Jyseleca and successfully completed the process of becoming Marketing Authorization Holder (MAH) in Europe for our first medicine. Improving patients’ lives is at the core of what we do, and completing our transition to a fully integrated, independent European biopharma is a major achievement to make that mission a reality for patients suffering from chronic debilitating conditions.

We received approval by the European Commission (EC), and most recently by the Medicines and Healthcare products Regulatory Agency (MHRA) in Great Britain, for a second indication for Jyseleca for patients suffering from UC, and we continue to roll out Jyseleca in RA and UC throughout Europe. Furthermore, following the completion of patient enrollment in the DIVERSITY Phase 3 program with filgotinib in CD, we anticipate topline results in the first half of 2023.

Also for filgotinib, we were pleased to report on the primary endpoint with the MANTA and MANTA-RAy studies investigating the effect on semen parameters, indicating that 8.3% patients on placebo and 6.7% patients on filgotinib had a 50% or more decline in sperm concentration at week 13.

In 2021, we also made important progress across our broader inflammation pipeline, most notably with our TYK2 and SIKi programs. We observed clinical activity with our TYK2 inhibitor GLPG3667 in a Phase 1b study in Pso, and we are currently finalizing a Phase 1 dose escalation study in healthy volunteers. We reported results from the first patient studies of our SIKi program with SIK2/3 inhibitor GLPG3970. The biological activity observed in the studies in Pso and UC highlights the pioneering role we are playing to unravel the role of SIKi in inflammation, and support further development of our SIKi portfolio. We are currently working on a set of follow-up SIKi compounds with improved pharmacology and selectivity profiles, and plan to select a preclinical candidate to move into a healthy volunteer study this year.

Beyond inflammation, we discontinued further development of ziritaxestat (GLPG1690) in IPF due to the unfavorable risk/benefit profile observed by an Independent Data Monitoring Committee (IDMC) in the Phase 3 trials. This not only was a major setback for Galapagos but most importantly for patients suffering from this debilitating disease for which current treatment options remain limited.

Finally, we completed the patient recruitment in our MANGROVE Phase 2 trial with our novel CFTR2 inhibitor GLPG2737 in patients with ADPKD3, with results expected in the first half of 2023.

I am very proud of our committed teams for working tirelessly to bring novel mode of action medicines to patients, and now that my tenure at the helm of this company is drawing to an end, I could not be more honored to hand over the baton to Paul. As a co-founder and board member in the early years, Paul has a keen understanding of our roots as well as who we are today. I strongly believe that Paul’s strategic and inspirational leadership, along with his deep knowledge of both the industry and Galapagos, make him the right next CEO to deliver tremendous value to all stakeholders."

Bart Filius, President, COO and CFO of Galapagos, added: "We ended 2021 with a very strong balance sheet, providing us with the foundations for future growth. One year after receiving approval for Jyseleca in RA in Europe and Great Britain, we secured reimbursement in 14 countries, covering the major markets of Germany, France, Spain, Italy, and Great Britain. We reported €14.8 million of Jyseleca sales in Europe out of a total in-market performance of €25.7 million.

Following a strategic operational review in March 2021, we implemented a cost savings program of €150 million on a full year basis, which will take full effect in the course of 2022. Our operational cash burni in 2021 was €564.8 million, within our reduced guidance. For 2022 we anticipate a further significant reduction of our cash burn and expect to land between €450 and €490 million. This includes sales for Jyseleca that we anticipate between €65 and €75 million."

Details of the financial results
After the sale of our fee-for-service business (Fidelta) to Selvita on 4 January 2021, we only have one remaining reporting segment. The results of Fidelta, including the impact of the 2021 sale, are presented as "Net profit from discontinued operations" in our consolidated income statements for the years 2021 and 2020.

Revenues from continuing operations
Our net revenues from continuing operations in 2021 amounted to €484.8 million compared to €478.1 million in 2020.

We reported net sales of Jyseleca in 2021 amounting to €14.8 million, which reflects the sales booked by Galapagos after the country-by-country transition from Gilead.

Collaboration revenues amounted to €470.1 million in 2021, compared to €478.1 million last year. The revenue recognition linked to the upfront consideration and milestone payments in the scope of the collaboration with Gilead for filgotinib, amounted to €235.7 million in 2021 (€228.1 million in 2020). The revenue recognition related to the exclusive access rights for Gilead to our drug discovery platform amounted to €230.6 million in 2021 (€229.6 million last year). Additionally we have recognized royalty income from Gilead for Jyseleca for €3.8 million in 2021 (compared to €16.2 million in 2020, which was mainly from income related to upfront payments from a distribution agreement for the commercial launch of filgotinib in Japan).

Our deferred income balance at 31 December 2021 includes €1.8 billion allocated to our drug discovery platform that is recognized linearly over 10 years, and €0.6 billion allocated to the filgotinib development that is recognized over time until the end of the development period.

Results from continuing operations

We realized a net loss from continuing operations of €125.4 million in 2021, compared to a net loss of €311.0 million in 2020.

We reported an operating loss amounting to €165.6 million in 2021, compared to an operating loss of €178.6 million in 2020.

Cost of sales related to Jyseleca net sales in 2021 amounted to €1.6 million.

Our R&D expenditure in 2021 amounted to €491.7 million, compared to €523.7 million in 2020. This decrease was primarily due to the winding down of the programs with ziritaxestat (IPF), MOR106 (atopic dermatitis), and GLPG1972 (OA), and reduced spend on our other programs. This was partly offset by cost increases for our filgotinib and Toledo (SIKi) programs, on a yearly comparison basis.

Our S&M and G&A expenses were respectively €70.0 million and €140.9 million in 2021, compared to respectively €66.5 million and €118.8 million in 2020. This increase was primarily due to an increase in personnel costs resulting from an increase in headcount and other operating expenses mainly driven by the commercial launch of filgotinib in Europe. This increase was partly offset by higher cost recharges from us to Gilead in the scope of our commercial cost sharing for filgotinib in Europe.

Other operating income (€53.7 million in 2021 vs €52.2 million last year) slightly increased, mainly driven by higher grant income.

We reported a non-cash fair value gain from the re-measurement of initial warrant B issued to Gilead, amounting to €3.0 million in 2021 (€3.0 million in 2020), mainly due to the decreased implied volatility of the Galapagos share price and its evolution between 31 December 2020 and 31 December 2021.

Net other financial income in 2021 amounted to €39.6 million, compared to net other financial loss of €134.2 million in 2020. Net other financial income in 2021 was primarily attributable to €57.2 million of currency exchange gains on our cash and cash equivalents in U.S. dollars, and to €8.8 million of net interest expenses. The other financial expenses also contained the effect of discounting our long term deferred income of €9.3 million.

Results from discontinued operations
The net profit from discontinued operations in 2021 consisted of the gain on the sale of Fidelta, our fee-for-services business, for €22.2 million.

Group net results
We reported a group net loss in 2021 of €103.2 million, compared to a group net loss of €305.4 million in 2020.

Cash position
Current financial investments and cash and cash equivalents totaled €4,703.2 million on 31 December 2021, as compared to €5,169.3 million on 31 December 2020 (including the cash and cash equivalents included in the assets as classified as held for sale).

Total net decrease in cash and cash equivalents and current financial investments amounted to €466.1 million in 2021, compared to a net decrease of €611.5 million in 2020. This net decrease was composed of (i) €564.8 million of operational cash burn, offset by (ii) €6.8 million positive changes in (fair) value of current financial investments and €59.9 million of mainly positive exchange rate differences, (iii) €3.3 million of cash proceeds from capital and share premium increase from exercise of subscription rights in 2021, and (iv) €28.7 million cash in from disposal of subsidiaries.

Our balance sheet on 31 December 2021 included R&D incentives receivables from the French government (Crédit d’Impôt Rechercheiv) and from the Belgian government, for a total of €144.0 million.

Outlook 2022

Early in 2022, we announced the appointment of Dr. Paul Stoffels as successor to our co-founder and current CEO Onno van de Stolpe, effective 1 April 2022. Paul is widely recognized as an inspirational industry leader with exceptional R&D and global executive experience, with an outstanding track record of accelerated product development in biotech and pharma through insightful acquisitions and strategic partnerships.

In 2022, we expect reimbursement decisions in most key European markets for Jyseleca in UC. In Japan, collaboration partner Gilead expects a decision on the potential approval for Jyseleca in UC in the first half of 2022, which potentially could add a second indication for Jyseleca in this market.

Early this year, the EMA announced that its Pharmacovigilance Risk Assessment Committee (PRAC) started an Article 20 specific pharmacovigilance procedure to investigate the safety data for all JAK inhibitors following recent results from the ORAL Surveillance study with tofacitinib4 as well as the data from an observational study with baricitinib5. Following initiation of this procedure, all JAKi MAHs will be invited to submit evidence and we will continue to work with the EMA. The European Commission has asked the EMA to give its opinion by 30 September 2022.

Within our broader inflammation portfolio, we expect the read out from a Phase 1b trial with JAK1 inhibitor GLPG0555 in osteoarthritis and from multiple Phase 1 trials in healthy volunteers. We aim to progress our TYK2 inhibitor GLPG3667 into a Phase 2 program, following the dose escalation Phase 1 study currently being finalized, also taking into account the current regulatory and competitive landscape for TYK2 as a class. We aim to advance selected compounds with optimized pharmacology and selectivity from our SIKi portfolio into the clinic. Within our fibrosis portfolio, we anticipate starting a Phase 2 trial with chitinase inhibitor GLPG4716 in IPF.

For 2022 we anticipate a further significant reduction of our cash burn and expect to land between €450 and €490 million. This includes sales for Jyseleca that we anticipate between €65 and €75 million.

We believe our strong cash balance affords us the opportunity to develop our pipeline through internal as well as externally sourced assets. We expect our scientific expertise, strong leadership, and growing commercial Jyseleca franchise to propel us forward as we rebuild a differentiated pipeline of novel mode of action drug candidates to help patients in need of new treatment options.

Annual report 2021

Galapagos is currently finalizing its financial statements for the year ended 31 December 2021. Our independent auditor has confirmed that its audit procedures, which are substantially completed, have not revealed any material corrections required to be made to the financial information included in this press release. Should any material changes arise during the audit finalization, an additional press release will be issued. Galapagos expects to be able to publish its fully audited annual report for the full year 2021 on or around 24 March 2022.

Conference call and webcast presentation

Galapagos will conduct a conference call open to the public tomorrow, 25 February 2022, at 14:00 CET / 8 AM ET, which will also be webcasted. To participate in the conference call, please call one of the following numbers ten minutes prior to commencement:

CODE: 5438549

A question and answer session will follow the presentation of the results. Go to www.glpg.com to access the live audio webcast. The archived webcast will also be available for replay shortly after the close of the call.

Financial calendar

24 March 2022 Publication Annual Report 2021 and 20-F 2021
26 April 2022 Annual Shareholders’ meeting
5 May 2022 First quarter 2022 results (webcast 6 May 2022)
4 August 2022 Half Year 2022 results (webcast 5 August 2022)
3 November 2022 Third quarter 2022 results (webcast 4 November 2022)
23 February 2023 Full year 2022 results (webcast 24 February 2023)

On February 24, 2022 MilliporeSigma, the U.S. and Canada Life Science business sector of Merck KGaA, Darmstadt, Germany, a leading science and technology company, reported the closing of the transaction to acquire Exelead, following regulatory clearances and the fulfillment of other customary closing conditions, for approximately USD 780 million in cash (Press release, MilliporeSigma, FEB 24, 2022, View Source [SID1234608963]). The business combination is expected to enable the Life Science business to provide its customers with comprehensive end-to-end contract development and manufacturing organization (CDMO) services across the mRNA value chain. The Life Science business plans to further invest over € 500 million to scale up Exelead’s technology over the next ten years.

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MilliporeSigma Announces Close of Exelead Acquisition

"With the addition of Exelead’s leading capabilities and highly experienced team, our Life Science business achieves an important milestone in becoming one of the leading CDMO players in mRNA vaccines and therapeutics, offering an integrated CDMO across the mRNA value chain from pre-clinical to commercial," said Matthias Heinzel, Member of the Executive Board of Merck KGaA, Darmstadt, Germany, and CEO Life Science. "mRNA holds much promise as a treatment well beyond Covid-19 and we will further invest in this technology to help realize its potential."

Exelead, a biopharmaceutical CDMO, specializes in PEGylated products and complex injectable formulations, including Lipid Nanoparticle (LNP) based drug delivery technology, which is key in mRNA vaccines and therapeutics for use in Covid-19 and many other indications. The company has experience in all development phases from pre-clinical development to commercial contract manufacturing for LNP formulations, including fill and finish. Exelead will complement the Life Science business sector’s more than 20 years’ experience in producing lipids as well as its mRNA manufacturing capabilities acquired through AmpTec in 2020. This integrated offering will accelerate the Life Science business sector’s ability to bring life-enhancing vaccines and treatments to patients faster by simplifying supply chain complexity and enhancing speed to market through its end-to-end portfolio.

Over the past two years, the Life Science business sector has made significant investments to advance traditional and novel modalities (mAb, ADC, HP-API, viral vector, and mRNA) through acquisitions and expansions. The acquisition of Exelead is another milestone to accelerate innovation in the company’s Process Solutions and Life Science Services businesses, one of the company’s three growth engines ("Big 3"), through targeted smaller to medium-sized acquisitions with high impact.

Follow MilliporeSigma on Twitter @MilliporeSigma, on Facebook @MilliporeSigma and on LinkedIn.

All Merck KGaA, Darmstadt, Germany news releases are distributed by email at the same time they become available on the EMD Group website. In case you are a resident of the U.S. or Canada please go to www.emdgroup.com/subscribe to register again for your online subscription of this service as our newly introduced geo-targeting requires new links in the email. You may later change your selection or discontinue this service.

On February 24, 2022 Moderna, Inc. (NASDAQ:MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines, reported financial results and provided business updates for the fourth quarter of fiscal year 2021 (Press release, Moderna Therapeutics, FEB 24, 2022, View Source [SID1234608962]).

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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"Spikevax is now approved in more than 70 countries around the world protecting hundreds of millions of people and real-world evidence from multiple independent studies has confirmed its strong effectiveness," said Stéphane Bancel, Chief Executive Officer of Moderna. "In 2021, we delivered 807 million doses with approximately 25% of those doses going to low- and middle-income countries, and we will continue to scale in 2022 to help end the COVID-19 pandemic. Moderna has experienced exponential growth and we have more than doubled the size of our team over the last year with a global team of 3,000. We also have announced plans to scale to 21 commercial subsidiaries across the world, including four new locations in Asia and six new locations in Europe. We continue to expand and advance our industry-leading mRNA pipeline with 44 programs in development. We look forward to clinical readouts from our therapeutics development candidates later in 2022 in rare genetic diseases and oncology. We are entering 2022 with a remarkable team and strategic priorities to continue advancing mRNA vaccines and therapeutics to impact human health."

Updates and recent progress include:

COVID-19 Vaccine Development

Therapeutic Goods Administration (TGA) in Australia has granted provisional registration for the use of Spikevax in a 50 µg dose, two-dose series, for active immunization to prevent COVID-19 caused by SARS-CoV-2 in children aged 6-11 years
U.S. Food and Drug Administration (U.S. FDA) approved the Biologics License Application (BLA) for Spikevax (COVID-19 Vaccine, mRNA-1273) to prevent COVID-19 in individuals in the U.S. 18 years of age and older; Spikevax approved or authorized in more than 70 countries
Pivotal studies are underway for Omicron-specific booster candidate (mRNA-1273.529)
Moderna announces bivalent booster candidate (mRNA-1273.214) combining mRNA-1273.529 and the Moderna COVID-19 vaccine (mRNA-1273)
Respiratory Vaccines

Pivotal Phase 3 study of respiratory syncytial virus (RSV) vaccine candidate (mRNA-1345) has begun
Seasonal flu vaccine candidate (mRNA-1010) successfully boosted hemagglutination inhibition (HAI) assay geometric mean titers against all strains 29 days after vaccination at all doses tested in younger and older adults in Phase 1 study and no significant safety concerns were observed through day 29; Phase 2 study of mRNA-1010 is fully enrolled; preparation for the Phase 3 study is underway
Latent Vaccines

Announcing new Herpes simplex virus (HSV) therapeutic vaccine candidate (mRNA-1608), a vaccine candidate to prevent incidence of herpes lesions due to HSV-2
Announcing a new Varicella-zoster virus (VZV) vaccine candidate (mRNA-1468)designed to reduce the rate of herpes zoster (shingles)
Enrollment in Phase 1 study of Epstein-Barr virus (EBV) vaccine candidate (mRNA-1189) is ongoing
Enrollment in Phase 3 pivotal registration study of cytomegalovirus (CMV) vaccine candidate (mRNA-1647) is ongoing
Cancer Vaccines

Announcing new checkpoint cancer vaccine (mRNA-4359) to expand naturally occurring T cells that counteract the impact of immune checkpoints Indoleamine 2,3 -dioxygenase (IDO) and programmed death-ligand 1 (PD-L1)
Moderna has regained all rights to mutant KRAS vaccine (mRNA-5671) from Merck; Moderna is evaluating next steps for the program
Therapeutics

Enrollment of the first cohort in Phase 1/2 Paramount study of Propionic Acidemia candidate (mRNA-3927) is complete; enrollment in additional dose level cohorts is continuing
Enrollment of the first cohort in Phase 1/2 Landmark study of Methylmalonic Acidemia candidate (mRNA-3705) is complete; enrollment for additional cohorts expected to begin soon
Moderna now has 44 programs in development across 41 development candidates 1, of which 25 are currently in active clinical trials. The Company’s updated pipeline can be found at www.modernatx.com/pipeline. Moderna and collaborators have published more than 100 peer reviewed manuscripts.

Summary of Program Highlights by Modality 2

Core Modalities

Prophylactic Vaccines: Moderna is developing vaccines against viral diseases where there is an unmet medical need, including vaccines against respiratory infections and vaccines against latent viruses.

Vaccines against acute respiratory infections

COVID-19 vaccine development

Moderna COVID-19 Vaccine (mRNA-1273 3 , Spikevax ): The U.S. Food and Drug Administration (FDA) has approved the Biologics License Application (BLA) for SPIKEVAX (COVID-19 Vaccine, mRNA) to prevent COVID-19 in individuals 18 years of age and older. 807 million doses of Moderna’s COVID-19 vaccine shipped globally in 2021; approximately 25% of those doses shipped to low- and middle-income countries.
Booster Dose of mRNA-1273: The U.S. FDA, European Medicines Agency (EMA), Swissmedic and other health agencies around the world have authorized a booster dose of the Moderna COVID-19 vaccine at the 50 µg dose level for adults ages 18 years and older.
Omicron-specific booster candidate (mRNA-1273.529): Moderna’s Omicron-specific booster candidate is being studied to evaluate the immunogenicity, safety, and reactogenicity of mRNA-1273.529 as a single booster dose in adults aged 18 years and older in two cohorts: individuals who previously received the two-dose primary series of mRNA-1273 with the second dose being at least six months ago (cohort 1), or who have received the two-dose primary series and a 50 µg booster dose of mRNA-1273 with the booster dose being at least three months ago (cohort 2). Participants in both cohorts will receive a single booster dose of mRNA-1273.529.
Bivalent booster candidate (mRNA-1273.214): Today, Moderna is announcing a new bivalent candidate that combines Moderna’s Omicron-specific candidate and mRNA-1273.
Moderna COVID-19 Vaccine for adolescents and children: Moderna has received regulatory authorizations for the use of the 100 µg Moderna COVID-19 vaccine primary series for adolescents 12 to 17 years of age in the European Union, UK, Australia, Canada, Switzerland and other countries. At this point, the U.S. FDA has not concluded on the benefit-risk profile of the 100 µg primary series for adolescents 12 to 17 years of age. Moderna made the decision to evaluate the potential of a 50 µg two-dose primary series to meet regulatory guidance for immunogenicity in adolescents and children ages 6 to 11 years. The Company is also evaluating a heterologous booster dose in adolescents after a two-dose primary series of 50 µg, 100 µg, or BNT162b2 and is preparing to submit data to regulators. The Company received authorization for a two-dose 50 µg primary series of the Moderna COVID-19 vaccine in children ages 6 to 11 in Australia and has submitted additional applications for the 6 to 11 age group. In the U.S., Moderna is also studying a two-dose 25 µg primary series for the 6 to 11 age group. In the 6 months to 5 years age group, Moderna is studying a two-dose 25 µg primary series, and expects data in the first quarter of 2022. The Company plans to submit these data to regulators. Additionally, the Company is evaluating lower doses in the U.S. for this age group.
Next-generation vaccine candidate against COVID-19 (mRNA-1283): The Phase 1 study of mRNA-1283 is fully enrolled and ongoing. The Phase 2 study of a booster dose of mRNA-1283 is ongoing.mRNA-1283 is a next-generation vaccine candidate against COVID-19 that encodes for the portions of the SARS-CoV-2 spike protein critical for neutralization, specifically the Receptor Binding Domain (RBD) and N-terminal Domain (NTD). The encoded mRNA-1283 antigen is shorter than mRNA-1273 and is being developed as a potential refrigerator-stable mRNA vaccine that will facilitate easier distribution and administration by healthcare providers.
Additional vaccines against respiratory infections

Seasonal influenza vaccine (mRNA-1010): On December 10, 2021, Moderna announced positive interim data from the Phase 1 study of mRNA-1010. mRNA-1010 successfully boosted hemagglutination inhibition (HAI) assay geometric mean titers against all strains 29 days after vaccination at all doses tested in both younger and older adults and no significant safety concerns were observed through day 29. The Phase 2 study of mRNA-1010 is fully enrolled and preparation for the Phase 3 study is underway. mRNA-1010 encodes for hemagglutinin (HA) glycoproteins of four flu strains and targets lineages recommended by the World Health Organization (WHO) for the prevention of influenza, including seasonal influenza A H1N1, H3N2 and influenza B Yamagata and Victoria.
Seasonal Influenza vaccines with expanded coverage (mRNA-1011 and mRNA-1012) and broader immunologic coverage (mRNA-1020 and mRNA-1030): On December 10, 2021, Moderna announced two development candidates which the Company believes may expand coverage against seasonal influenza strains. mRNA-1011 will have one additional hemagglutinin (HA) antigen and mRNA-1012 will have two additional HA antigens. Moderna is also developing two next-generation flu candidates that incorporate neuraminidase antigens to potentially improve immunity by increasing immunologic breadth targeting more conserved antigens (mRNA-1020, mRNA-1030).
COVID-19 and flu combination vaccine (mRNA-1073): mRNA-1073 encodes for the COVID-19 spike protein and the Flu HA glycoproteins.
Respiratory syncytial virus (RSV) vaccine (mRNA-1345): The pivotal Phase 3 study of RSV in older adults (ages older than 60 years) is ongoing. This is a global study conducted in locations influenced by the epidemiology of RSV and the Company expects to enroll approximately 34,000 participants. The FDA has granted Fast Track designation for mRNA-1345 in adults older than 60 years of age. RSV is the leading cause of severe respiratory illness in young children and older adults (65+). The Phase 1 study of mRNA-1345 to evaluate the tolerability and reactogenicity of mRNA-1345 in younger adults, women of child-bearing potential, older adults and seropositive toddlers is ongoing. All four cohorts of younger adults (ages 18-49 years) and all four cohorts of older adults (ages 65-79 years) are fully enrolled.
Human metapneumovirus (hMPV) and parainfluenza type 3 (PIV3) vaccine (mRNA-1653): The Phase 1 study of mRNA-1653 in children 12-59 months of age is fully enrolled.
Pediatric RSV and hMPV combination vaccine (mRNA-1365): mRNA-1365 encodes for the RSV prefusion F glycoprotein and the hMPV F protein.
Vaccines against latent viruses

Cytomegalovirus (CMV) vaccine (mRNA-1647): The Phase 3 pivotal registration study of mRNA-1647, known as CMVictory, is ongoing. The study is evaluating the safety and efficacy of mRNA-1647 against primary CMV infection in women ages 16-40 years. The Company will seek to enroll up to 6,900 women of child-bearing age, at approximately 150 sites globally, beginning in the U.S. Moderna has set a goal of enrolling a diverse group of U.S. participants into the study, including approximately 42% of participants who are Persons of Color. The ClinicalTrials.gov identifier is NCT05085366. To learn more about eligibility, visit www.CMVictory.com.
Epstein-Barr virus (EBV) vaccine (mRNA-1189): The Phase 1 study of mRNA-1189 ongoing. EBV is spread through bodily fluids (e.g., saliva) and contracted primarily by young children and adolescents. It is a major cause of infectious mononucleosis (IM), and associated risks to other long-term medical conditions, including an increased risk of developing multiple sclerosis, certain lymphoproliferative disorders and cancers, and autoimmune diseases 4,5 . Similar to Moderna’s CMV vaccine (mRNA-1647), mRNA-1189 contains four mRNAs that encode EBV envelope glycoproteins (gH, gL, gp42, gp220). There is currently no approved vaccine for EBV or IM.
Epstein-Barr virus (EBV) therapeutic vaccine candidate (mRNA-1195): mRNA-1195 is being developed to prevent longer term sequelae of EBV infection, which are associated with loss of immune control of EBV latent infection, creating longer-term complications. mRNA-1195 is in pre-clinical development and encodes for additional antigens than mRNA-1189. The Company expects to initially test the vaccine in post-transplant lymphoproliferative disorder (PTLD) because 60-80% of PTLD cases are associated with EBV infection. The Company expects to also pursue other longer-term potential indications for this vaccine, including multiple sclerosis.
HIV vaccine (mRNA-1644 & mRNA-1574): The first participant has been dosed in the ongoing Phase 1 study of mRNA-1644, which is using iterative human testing to validate the approach and antigens and multiple novel antigens will be used for germline-targeting and immuno-focusing. mRNA-1644, a collaboration with the International AIDS Vaccine Initiative (IAVI) and the Bill & Melinda Gates Foundation, is a novel approach to HIV vaccine strategy in humans designed to elicit broadly neutralizing HIV-1 antibodies (bNAbs). A second approach, mRNA-1574, is being evaluated in collaboration with the National Institutes of Health (NIH) and includes multiple native-like trimer antigens.
Herpes simplex virus (HSV) therapeutic vaccine candidate (mRNA-1608): Moderna recently announced a new development candidate, mRNA-1608, a vaccine candidate against herpes. In the U.S., approximately 18.6 million adults ages 18 to 49 years are living with HSV-2. Moderna is developing mRNA-1608 to reduce the burden of HSV lesions.
Varicella-zoster virus (VZV) vaccine candidate (mRNA-1468): Moderna recently announced a new mRNA vaccine candidate (mRNA-1468) designed to express varicella-zoster virus (VZV) glycoprotein E (gE) to reduce the rate of herpes zoster (shingles). Herpes zoster occurs in one of three adults in their lifetime and incidence dramatically increases at approximately 50 years of age. Declining immunity in older adults decreases cell-mediated immunity against VZV, allowing reactivation of the virus from latently infected neurons, causing painful and itchy lesions. Serious herpes zoster complications include postherpetic neuralgia (10-13% of herpes zoster cases), bacterial coinfections, and cranial and peripheral palsies; 1-4% of herpes zoster cases are hospitalized for complications.
Public health vaccines

Zika virus vaccine (mRNA-1893): The Phase 2 study of mRNA-1893 is ongoing in the U.S. and Puerto Rico. mRNA-1893 is being developed in collaboration with BARDA.
Nipah virus (NiV) Vaccine (mRNA-1215): NiV is a zoonotic virus transmitted to humans from animals, contaminated food, or through direct human-to-human transmission and causes a range of illnesses including fatal encephalitis. Severe respiratory and neurologic complications of NiV have no treatment other than intensive supportive care. NiV has been identified as the cause of isolated outbreaks in India, Bangladesh, Malaysia, and Singapore since 2000 and is included on the WHO R&D Blueprint list of epidemic threats needing urgent R&D action. mRNA-1215 was co-developed by Moderna and the NIH’s Vaccine Research Center (VRC).
Systemic Secreted & Cell Surface Therapeutics: In this modality, mRNA is delivered systemically to create proteins that are either secreted or expressed on the cell surface.

IL-2 (mRNA-6231): mRNA-6231 is an mRNA encoding for a long-acting tolerizing IL-2. This autoimmune development candidate is designed to preferentially activate and expand the regulatory T cell population. The Phase 1 study of mRNA-6231 in healthy adult participants (between 18 and 50 years of age) is ongoing.
PD-L1 (mRNA-6981): mRNA-6981 is an mRNA encoding for PD-L1. This autoimmune development candidate is designed to augment cell surface expression of PD-L1 on myeloid cells to provide co-inhibitory signals to self-reactive lymphocytes.
Relaxin (mRNA-0184): mRNA-0184 encodes for the relaxin protein which has been engineered to increase expression and prolong half-life. Moderna is planning for a Phase 1 study in participants with chronic heart failure. The Company expects that mRNA-0184 will be administered after heart failure decompensation to bridge patients through the vulnerable period.
Exploratory Modalities

Cancer Vaccines: These programs focus on stimulating a patient’s immune system with antigens derived from tumor-specific mutations to enable the immune system to elicit a more effective anti-tumor response.

Personalized cancer vaccine (PCV) (mRNA-4157): The randomized, placebo-controlled Phase 2 study investigating a 1 mg dose of mRNA-4157 in combination with Merck’s pembrolizumab (KEYTRUDA), compared to pembrolizumab alone, for the adjuvant treatment of high-risk resected melanoma is fully enrolled (n=150). The Company expects the Phase 2 data readout to occur in the fourth quarter of 2022. The primary endpoint of the Phase 2 study is recurrence-free survival at 12 months. The Phase 1 in multiple cohorts is ongoing including in the expanded head and neck cohort. Moderna shares worldwide commercial rights to mRNA-4157 with Merck.
Mutant KRAS vaccine (mRNA-5671 or V941): Moderna has regained all rights to mutant KRAS vaccine (mRNA-5671) from Merck and Moderna is evaluating next steps for the program.The Phase 1 open-label, multi-center study to evaluate the safety and tolerability of mRNA-5671 both as a monotherapy and in combination with pembrolizumab, led by Merck, is ongoing.
Checkpoint cancer vaccine (mRNA-4359): Moderna recently announced a new checkpoint cancer vaccine (mRNA-4359) expresses Indoleamine 2,3 -dioxygenase (IDO) and programmed death-ligand 1 (PD-L1) antigens. Moderna designed mRNA-4359 with the goal of stimulating effector T-cells that target and kill suppressive immune and tumor cells that express these checkpoints. Moderna is planning to explore initial indications for advanced or metastatic cutaneous melanoma and non-small cell lung carcinoma (NSCLC).
Intratumoral Immuno-Oncology : These programs aim to drive anti-cancer T cell responses by injecting mRNA therapies directly into tumors.

OX40L/IL-23/IL-36γ (Triplet) (mRNA-2752): The Phase 1 trial evaluating mRNA-2752 as a single agent and in combination with durvalumab in patients with advanced solid tumor malignancies and lymphoma is fully enrolled. Enrollment in additional cohorts is ongoing.
IL-12 (MEDI1191): The Phase 1 open-label, multi-center study of intratumoral injections of MEDI1191 alone and in combination with durvalumab in patients with advanced solid tumors, led by AstraZeneca, is ongoing. MEDI1191 is an mRNA encoding for IL-12, a potent immunomodulatory cytokine. Moderna shares worldwide commercial rights to MEDI1191 with AstraZeneca.
Localized Regenerative Therapeutics: Localized production of proteins has the potential to be used as a regenerative medicine for damaged tissues.

VEGF-A (AZD8601): Positive data from the AstraZeneca-led Phase 2 (EPICCURE) study evaluating the use of VEGF-A (AZD8601) in patients undergoing coronary artery bypass grafting (CABG) were presented at the American Heart Association’s Scientific Sessions 2021 annual meeting. The Phase 2 study met the primary endpoint of safety and tolerability of AZD8601. In the study of 11 patients, seven were treated with AZD8601 VEGF-A mRNA and four received placebo injections. Numerical trends were observed in endpoints in the heart failure efficacy domains compared with placebo, including increase in left ventricular ejection fraction (LVEF) and patient reported outcomes. In addition, all seven patients treated with AZD8601 had NT-proBNP levels below heart failure (HF) limit at 6 months follow-up compared to one of four patients treated with placebo. These results support further investigation of AZD8601 for efficacy and safety in future studies.
Systemic Intracellular Therapeutics: These programs aim to deliver mRNA into cells within target organs as a therapeutic approach for diseases caused by a missing or defective protein.

Propionic acidemia (PA) (mRNA-3927): The Phase 1/2 Paramount study of mRNA-3927 is ongoing and the first cohort is fully enrolled. Moderna is enrolling participants into additional cohorts.
Methylmalonic acidemia (MMA) (mRNA-3705): The Phase 1/2 Landmark study to evaluate the safety and pharmacology of mRNA-3705 in patients 1 year of age and older with MMA is ongoing. Moderna received rare pediatric designation for mRNA-3705.
Glycogen storage disease type 1a (GSD1a) (mRNA-3745): The U.S. FDA has granted mRNA-3745 Orphan Drug Designation and completed its review of the IND application allowing it to proceed to clinic. Individuals with GSD1a have a deficiency in glucose-6-phosphatase resulting in pathological blood glucose imbalance. mRNA-3745 is an IV-administered mRNA encoding human G6Pase enzyme, designed to restore the deficient or defective intracellular enzyme activity in patients with GSD1a.
Phenylketonuria (PKU) (mRNA-3283): Individuals with PKU have a deficiency in phenylalanine hydroxylase (PAH) resulting in a reduced or complete inability to metabolize the essential amino acid phenylalanine into tyrosine. mRNA-3283 encodes human PAH to restore the deficient or defective intracellular enzyme activity in patients with PKU. mRNA-3283 is in preclinical development.
Crigler-Najjar Syndrome Type 1 (CN-1) (mRNA-3351): mRNA-3351 encodes for the human UGT1A1 and is designed to restore the missing or dysfunctional proteins that causes Crigler-Najjar Syndrome Type 1. mRNA-3351 has been granted Rare Pediatric Disease designation by the U.S. FDA. Moderna will provide investigational mRNA-3351 to the nonprofit Institute for Life Changing Medicines (ILCM) free of charge. ILCM will be responsible for the clinical development of mRNA-3351 and plans to initiate clinical studies of mRNA-3351.
Inhaled Pulmonary Therapeutics

Cystic Fibrosis (CF) (VXc-522): VXc-522 is an mRNA therapeutic being designed in collaboration with Vertex Pharmaceuticals. It is designed to treat the underlying cause of CF by enabling cells in the lungs to produce functional cystic fibrosis transmembrane conductance regulator (CFTR) protein for the treatment of the 10% of patients who do not produce any CFTR protein. IND-enabling studies are underway, and Vertex expects to submit an IND for this program in 2022. VXc-522 is being advanced by Vertex.
Information about each development candidate in Moderna’s pipeline can be found at investors.modernatx.com .

Fourth Quarter and Full Year 2021 Financial Results

Fourth Quarter 2021

Revenue: Total revenue was $7.2 billion for the fourth quarter of 2021, compared to $571 million for the same period in 2020. The increase in 2021 was driven by increased product sales. Product sales for the fourth quarter of 2021 were $6.9 billion from sales of 297 million doses of the Company’s COVID-19 vaccine, compared to $200 million in the fourth quarter of 2020 from sales of 13 million doses of the Company’s COVID-19 vaccine. The Company began to record product sales for the Company’s COVID-19 vaccine subsequent to its authorization for emergency use by the FDA and Health Canada in December 2020.
Cost of Sales: Cost of sales was $952 million, or 14% of the product sales for the fourth quarter of 2021, including third-party royalties of $241 million. Cost of sales was $8 million, or 4% of product sales, for the fourth quarter of 2020, comprised of third-party royalties and shipping and handling costs only as the associated inventory costs were expensed previously as pre-launch inventory.
Research and Development Expenses: Research and development expenses were $648 million for the fourth quarter of 2021, compared to $759 million for the same period in 2020. The decrease in spending in 2021 was mainly due to a decrease in pre-launch inventory costs, partially offset by an increase in clinical trial expenses.
Selling, General and Administrative Expenses: Selling, general and administrative expenses were $201 million for the fourth quarter of 2021, compared to $79 million for the same period in 2020. The growth in spending was driven by the commercialization of our COVID-19 vaccine globally with continued investments in personnel and outside services in support of the accelerated company buildout.
Provision for Income Taxes: The effective tax rate was 10.0% for the fourth quarter of 2021, which included tax benefits from the utilization of the cumulative net operating loss carry-forward of $2.3 billion, the foreign-derived intangible income deduction and stock-based compensation. Income taxes were $542 million for the fourth quarter of 2021, compared to $1 million for the same period in 2020. The increase was due to pre-tax income recognized in 2021, compared to a loss in 2020.
Net Income (Loss): Net income was $4.9 billion for the fourth quarter of 2021, compared to a net loss of $(272) million for the same period in 2020.
Earnings (Loss) Per Share: Diluted EPS was $11.29 for the fourth quarter of 2021, compared to $(0.69) for the same period in 2020.
Full Year 2021

Revenue: Total revenue was $18.5 billion for the full year 2021, compared to $803 million in 2020. Total revenue increased in 2021, primarily due to commercial sales of the Company’s COVID-19 vaccine. Product sales for the full year 2021 were $17.7 billion from sales of 807 million doses of the Company’s COVID-19 vaccine.
Cost of Sales: Cost of sales was $2.6 billion, or 15% of the product sales for full year 2021, including third-party royalties of $641 million. A portion of the inventory costs associated with the Company’s product sales for the full year 2021 was expensed as pre-launch inventory costs in 2020. The Company’s pre-launch inventory was fully utilized in the first half of 2021. If inventory sold for the full year 2021 was valued at cost, the Company’s cost of sales for the period would have been $2.8 billion, or 16% of product sales.
Research and Development Expenses: Research and development expenses were $2.0 billion for the full year 2021, compared to $1.4 billion in 2020. The growth in spending in 2021 was mainly due to increases in clinical trial expenses, personnel-related costs, and consulting and outside services, largely driven by increased mRNA-1273 clinical development and headcount.
Selling, General and Administrative Expenses: Selling, general and administrative expenses were $567 million for the full year 2021, compared to $188 million in 2020. The growth in spending in 2021 was mainly due to increases in consulting and outside services, personnel-related costs, marketing expense and distributor fees, primarily attributable to the Company’s COVID-19 vaccine commercialization-related activities and increased headcount.
Provision for Income Taxes: The effective tax rate was 8.1% for the full year 2021 which included tax benefits from the utilization of the cumulative net operating loss carry-forward of $2.3 billion, the foreign-derived intangible income deduction and stock-based compensation. Income taxes were $1.1 billion for the full year 2021, compared to $3 million in 2020. The increase was due to pre-tax income recognized in 2021, compared to a loss in 2020.
Net Income (Loss): Net income was $12.2 billion for the full year 2021, compared to a net loss of $(747) million in 2020.
Earnings (Loss) Per Share: Diluted EPS was $28.29 for the full year 2021, compared to $(1.96) in 2020.
Cash Position: Cash, cash equivalents and investments as of December 31, 2021 and December 31, 2020 were $17.6 billion and $5.2 billion, respectively.
Net Cash Provided by Operating Activities: Net cash provided by operating activities was $13.6 billion for the full year 2021, compared to $2.0 billion in 2020. Net cash provided by operating activities increased significantly in 2021, mainly due to net income of $12.2 billion and additional customer deposits received during the period for the Company’s future COVID-19 vaccine supply.
Cash Used for Purchases of Property and Equipment: Cash used for purchases of property and equipment was $284 million for the full year 2021, compared to $68 million in 2020. The increase was primarily driven by the Company’s business expansion.
2022 Financial Framework

Advanced Purchase Agreements (APAs): Moderna has signed 2022 APAs for product sales of approximately $19 billion and approximately $3 billion in options (probabilized) including for any potential updated COVID-19 vaccine booster candidates. The Company is currently in active discussions for additional orders in 2022. Moderna believes that the SARS-CoV-2 virus will evolve to an endemic phase in 2022 and as a result, the Company expects sales to be larger in the second half of 2022 than in the first half.
Cost of Sales: Cost of sales as percentage of product sales are expected to be in the low-to-mid 20s percentage range.
Research & Development (R&D) and Selling, General & Administrative (SG&A) Expenses: Full year expenses expected to be approximately $4 billion.
Tax Rate: The Company expects an Effective Tax Rate for the full year in the mid-teen percentage range.
Capital Expenditures: Expect capital investments for 2022 in the range of $0.6-$0.8 billion.
Share Repurchase Program: The Board of Directors has authorized a new share repurchase program for $3 billion to return excess capital to shareholders. The previous program of $1 billion announced in August 2021 has been fully utilized as of the end of January 2022.
Commercial Outlook in 2023 & Beyond

Spikevax 2023 commercial outlook: Moderna has received firm orders for delivery in 2023 from the United Kingdom, Canada, Taiwan, and Kuwait. The Company is currently in active discussions for additional orders in 2023.
Supply agreements with strategic countries: Moderna is committed to expanding its partnerships with governments to equip countries with access to innovative vaccines against respiratory viruses, and domestic access to rapid pandemic response capabilities. To date, Moderna has announced in principle agreements with Australia and Canada and the Company is in discussions with additional countries for similar partnerships.
Moderna’s Capital Allocation Priorities

Reinvest in the base business and accelerating investments in R&D, manufacturing infrastructure, digital, automation, and our global commercial operations.
Seek attractive external investment and collaboration opportunities (licenses and/or M&A) to further expand the reach of Moderna’s technology and capabilities.
After evaluating internal and external investment opportunities, return excess capital to shareholders through share repurchases.
2021 Commercial Network

Moderna is building a global commercial network to enable Moderna’s entire portfolio, which will facilitate the commercialization of its pipeline without a large pharmaceutical partner. The Company now has active commercial subsidiaries in the following geographies – in the Americas: Canada, the United States; Europe: France, Germany, Italy, Spain, Switzerland, and the United Kingdom; Asia Pacific: Australia, Japan, and South Korea. In addition, Moderna works with distributors or partners in other geographies.

2022 New Commercial Networks

In 2022, the Company plans to further expand its commercial network to enable Moderna’s entire portfolio by establishing or activating commercial subsidiaries in the following geographies – in Asia: Hong Kong, Malaysia, Singapore and, Taiwan; and in Europe: Belgium, Denmark, Netherlands, Norway, Poland, and Sweden. In addition, Moderna will continue to work with distributors or partners in other geographies.

Corporate Social Responsibility

Global Access: Approximately 807 million doses of the Moderna COVID-19 vaccine were shipped around the world during 2021 6 ; approximately 25% of all doses delivered in 2021 went to low- and middle-income countries through direct sales by Moderna and facilitated donations from high-income countries. The more than 200 million doses delivered to low- and middle-income countries in 2021 are more than Moderna delivered to any other country or multinational group last year, other than the United States. Gavi has exercised its option to purchase 293 million doses for delivery in 2022 under the agreement to purchase up to 650 million doses across 2021 and 2022, in addition to the 34 million doses delivered in 2021.
mRNA Facility in Africa: Moderna announced that it will build a state-of-the-art mRNA facility in Africa, in part to ensure future access to mRNA vaccines in future pandemics, and is in the final stages of country selection with assistance from the United States government.
Sustainability: Moderna announced a pledge to achieve net-zero carbon emissions globally by 2030.
Moderna Charitable Foundation: Moderna announced it is establishing a new charitable foundation to promote public health, healthcare and educational opportunities, particularly in underserved populations.
Corporate Updates

Continued Growth: Moderna now has approximately 3,000 full time employees. Moderna ended 2020 with approximately 1,300 full time employees.
Expanding Manufacturing Partnerships: Moderna announced an expanded long-term collaboration with Rovi for the manufacture of mRNA medicines over the next ten years in Madrid, Spain. Moderna announced an expanded long-term collaboration with Thermo Fisher for the manufacture of mRNA vaccines over the next 15 years in the U.S.
AI Academy: In December 2020, Moderna launched its Artificial Intelligence (AI) Academy, an innovative initiative that will bring to life an immersive learning experience for Moderna employees, in partnership with Carnegie Mellon University (CMU).
Shareholder Letter: Moderna CEO Stéphane Bancel published a letter to shareholders on January 4, 2022.
Company Recognition: Moderna was named a top employer by Science and Science Careers for the seventh consecutive year and was ranked the number one employer in BioSpace’s 2022 Best Places to Work in Biopharma report.
Juan Andres Elected to the National Academy of Engineering: Juan Andres, Chief Technical Operations and Quality Officer has been elected to the National Academy of Engineering. Moderna’s Co-founder and Chairman, Noubar Afeyan, was also elected to the Academy.
Annual Meeting of Shareholders: The Moderna Annual Meeting of Shareholders will be held on Thursday, April 28, 2022 at 8:00 a.m. ET. The meeting will be held virtually at www.virtualshareholdermeeting.com/MRNA2022 . The record date for voting or attendance as a stockholder is 4:00 p.m. ET on March 1, 2022.
Key 2022 Investor and Analyst Event Dates

Vaccines Day: March 24
Science Day: May 17
R&D Day: September 8
ESG Day: November 10
Investor Call and Webcast Information

Moderna will host a live conference call and webcast at 8:00 a.m. ET on Thursday, February 24, 2022. To access the live conference call, please dial 866-922-5184 (domestic) or 409-937-8950 (international) and refer to conference ID 5682797. A webcast of the call will also be available under "Events and Presentations" in the Investors section of the Moderna website at investors.modernatx.com. The archived webcast will be available on Moderna’s website approximately two hours after the conference call and will be available for one year following the call.