On February 28, 2022 Legend Biotech Corporation (NASDAQ: LEGN) (Legend Biotech), a global biotechnology company developing, manufacturing and commercializing novel therapies to treat life-threatening diseases, reported that the U.S. Food and Drug Administration (FDA) has approved its first product, CARVYKTI (ciltacabtagene autoleucel; cilta-cel), for the treatment of adults with relapsed or refractory multiple myeloma (RRMM) who have received four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody (Press release, Legend Biotech, FEB 28, 2022, View Source [SID1234609171]). Legend Biotech entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc. (Janssen) to develop and commercialize cilta-cel in December 2017.

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CARVYKTI is a chimeric antigen receptor T-cell (CAR-T) therapy with two B-cell maturation antigen (BCMA)-targeting single domain antibodies and given as a one-time infusion with a recommended dose range of 0.5 to 1.0 x 106 CAR-positive viable T cells per kg of body weight. In the pivotal CARTITUDE-1 study, deep and durable responses were seen in patients with RRMM (n=97), with a high overall response rate (ORR) of 98 percent (95 percent confidence interval [CI]: 92.7-99.7) including 78 percent of the patients achieving stringent complete response (sCR, 95 percent CI: 68.8-86.1).1 At a median of 18 months follow-up, the median duration of response (DOR) was 21.8 months (95 percent CI 21.8-not estimable).1

CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS Program.1 The Safety Information for CARVYKTI includes a Boxed Warning regarding Cytokine Release Syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), Parkinsonism and Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), and prolonged and/or recurrent cytopenia.1 Warnings and Precautions include prolonged and recurrent cytopenias, infections, hypogammaglobulinemia, hypersensitivity reactions, secondary malignancies and effects on ability to drive and use machines.1 The most common adverse reactions (≥20 percent) are pyrexia, CRS, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections-pathogen unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting.1

"Multiple myeloma remains an incurable disease with heavily pretreated patients facing poor prognoses with limited treatment options," said Ying Huang, PhD, CEO and CFO of Legend Biotech. "Today’s approval of CARVYKTI is a pivotal moment for Legend Biotech because it is our first-ever marketing approval, but what really excites us is the drug’s potential to become an impactful therapy option for patients in need of long, treatment-free intervals. This is the first of many cell therapies we plan to bring to patients as we continue advancing our pipeline across disease states."

Multiple myeloma affects a type of white blood cell called plasma cells, which are found in the bone marrow.2 The majority of patients relapse after undergoing initial treatment and face poor prognoses after treatment with three major drug classes, including immunomodulatory agent, a proteasome inhibitor and anti-CD38 monoclonal antibody.3,4,5

"The treatment journey for the majority of patients living with multiple myeloma is a relentless cycle of remission and relapse with fewer patients achieving a deep response as they progress through later lines of therapy," said Dr. Sundar Jagannath, MBBS, Professor of Medicine, Hematology and Medical Oncology at Mount Sinai, and principal study investigator. "This is why I have been really excited about the results from the CARTITUDE-1 study, which has demonstrated that cilta-cel can provide deep and durable responses and long-term treatment-free intervals, even in this heavily pretreated multiple myeloma patient population. Today’s approval of CARVYKTI helps address a great unmet need for these patients."

As a personalized medicine, CARVYKTI’s administration requires extensive training, preparation, and certification to ensure a seamless experience for patients. Through a phased approach, Legend and Janssen will activate a limited network of certified treatment centers as they work to scale production capacity and increase the availability of CARVYKTI throughout the U.S. in 2022 and beyond, ensuring that the CARVYKTI treatment can be provided to oncologists and their patients in a reliable and timely manner.

About CARVYKTI (Ciltacabtagene autoleucel; cilta-cel)

CARVYKTI is a BCMA-directed, genetically modified autologous T-cell immunotherapy, which involves reprogramming a patient’s own T-cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA. BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B-cells and plasma cells. The CARVYKTI CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA. Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells.1

In December 2017, Legend Biotech Corporation entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc. to develop and commercialize cilta-cel.

In April 2021, Legend announced the submission of a Marketing Authorisation Application to the European Medicines Agency seeking approval of cilta-cel for the treatment of patients with relapsed and/or refractory multiple myeloma. In addition to U.S. Breakthrough Therapy Designation granted in December 2019, cilta-cel received a Breakthrough Therapy Designation in China in August 2020. Cilta-cel also received Orphan Drug Designation from the U.S. FDA in February 2019, and from the European Commission in February 2020.

About the CARTITUDE-1 Study
CARTITUDE-1 (NCT03548207) is an ongoing Phase 1b/2, open-label, single arm, multi-center trial evaluating cilta-cel for the treatment of adult patients with relapsed or refractory multiple myeloma, who previously received at least three prior lines of therapy including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and an anti-CD38 monoclonal antibody. Of the 97 patients enrolled in the trial, 99 percent were refractory to the last line of treatment and 88 percent were triple-class refractory, meaning their cancer did not respond, or no longer responds, to an IMiD, a PI and an anti-CD38 monoclonal antibody.1

The longer-term efficacy and safety profile of cilta-cel is being assessed in the ongoing CARTITUDE-1 study, with two-year follow-up results recently presented at ASH (Free ASH Whitepaper) 2021.6

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excessive proliferation of plasma cells.2 In 2022, it is estimated that more than 34,000 people will be diagnosed with multiple myeloma, and more than 12,000 people will die from the disease in the U.S.7 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.8 Although treatment may result in remission, unfortunately, patients will most likely relapse.3 Patients who relapse after treatment with standard therapies, including protease inhibitors, immunomodulatory agents, and an anti-CD38 monoclonal antibody, have poor prognoses and few treatment options available.4,5

CARVYKTI Important Safety Information

INDICATIONS AND USAGE
CARVYKTI (ciltacabtagene autoleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma, after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, and PROLONGED and RECURRENT CYTOPENIA

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with CARVYKTI. Do not administer CARVYKTI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which may be fatal or life-threatening, occurred following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with CARVYKTI. Provide supportive care and/or corticosteroids as needed.
Parkinsonism and Guillain-Barré syndrome and their associated complications resulting in fatal or life-threatening reactions have occurred following treatment with CARVYKTI.
Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including fatal and life-threatening reactions, occurred in patients following treatment with CARVYKTI. HLH/MAS can occur with CRS or neurologic toxicities.
Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for hematopoietic recovery occurred following treatment with CARVYKTI.
CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS Program.
WARNINGS AND PRECAUTIONS

Cytokine Release Syndrome (CRS) including fatal or life-threatening reactions, occurred following treatment with CARVYKTI in 95% (92/97) of patients receiving ciltacabtagene autoleucel. Grade 3 or higher CRS (2019 ASTCT grade)1 occurred in 5% (5/97) of patients, with Grade 5 CRS reported in 1 patient. The median time to onset of CRS was 7 days (range: 1-12 days). The most common manifestations of CRS included pyrexia (100%), hypotension (43%), increased aspartate aminotransferase (AST) (22%), chills (15%), increased alanine aminotransferase (14%) and sinus tachycardia (11%). Grade 3 or higher events associated with CRS included increased AST and ALT, hyperbilirubinemia, hypotension, pyrexia, hypoxia, respiratory failure, acute kidney injury, disseminated intravascular coagulation, HLH/MAS, angina pectoris, supraventricular and ventricular tachycardia, malaise, myalgias, increased C-reactive protein, ferritin, blood alkaline phosphatase and gamma-glutamyl transferase.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS.

Sixty-nine of 97 (71%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of ciltacabtagene autoleucel. Forty-four (45%) patients received only tocilizumab, of whom 33 (34%) received a single dose and 11 (11%) received more than one dose; 24 patients (25%) received tocilizumab and a corticosteroid, and one patient (1%) received only corticosteroids. Ensure that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI.

Monitor patients at least daily for 10 days following CARVYKTI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurologic toxicities, which may be severe, life-threatening or fatal, occurred following treatment with CARVYKTI. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of parkinsonism, Guillain-Barré Syndrome, peripheral neuropathies, and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time.

Overall, one or more subtypes of neurologic toxicity described below occurred following ciltacabtagene autoleucel in 26% (25/97) of patients, of which 11% (11/97) of patients experienced Grade 3 or higher events. These subtypes of neurologic toxicities were also observed in two ongoing studies.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): ICANS occurred in 23% (22/97) of patients receiving ciltacabtagene autoleucel including Grade 3 or 4 events in 3% (3/97) and Grade 5 (fatal) events in 2% (2/97). The median time to onset of ICANS was 8 days (range 1-28 days). All 22 patients with ICANS had CRS. The most frequent (≥5%) manifestation of ICANS included encephalopathy (23%), aphasia (8%) and headache (6%).

Monitor patients at least daily for 10 days following CARVYKTI infusion at the REMS-certified healthcare facility for signs and symptoms of ICANS. Rule out other causes of ICANS symptoms. Monitor patients for signs or symptoms of ICANS for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

Parkinsonism: Of the 25 patients in the CARTITUDE-1 study experiencing any neurotoxicity, five male patients had neurologic toxicity with several signs and symptoms of parkinsonism, distinct from immune effector cell-associated neurotoxicity syndrome (ICANS). Neurologic toxicity with parkinsonism has been reported in other ongoing trials of ciltacabtagene autoleucel. Patients had parkinsonian and non-parkinsonian symptoms that included tremor, bradykinesia, involuntary movements, stereotypy, loss of spontaneous movements, masked facies, apathy, flat affect, fatigue, rigidity, psychomotor retardation, micrographia, dysgraphia, apraxia, lethargy, confusion, somnolence, loss of consciousness, delayed reflexes, hyperreflexia, memory loss, difficulty swallowing, bowel incontinence, falls, stooped posture, shuffling gait, muscle weakness and wasting, motor dysfunction, motor and sensory loss, akinetic mutism, and frontal lobe release signs. The median onset of parkinsonism in the 5 patients in CARTITUDE-1 was 43 days (range 15-108) from infusion of ciltacabtagene autoleucel.

Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson’s disease, for the improvement or resolution of parkinsonism symptoms following CARVYKTI treatment.

Guillain-Barré Syndrome: A fatal outcome following Guillain-Barré Syndrome (GBS) has occurred in another ongoing study of ciltacabtagene autoleucel despite treatment with intravenous immunoglobulins. Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances and polyradiculoneuritis.

Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulins and plasma exchange, depending on severity of GBS.

Peripheral Neuropathy: Six patients in CARTITUDE-1 developed peripheral neuropathy. These neuropathies presented as sensory, motor or sensorimotor neuropathies. Median time of onset of symptoms was 62 days (range 4-136 days), median duration of peripheral neuropathies was 256 days (range 2-465 days) including those with ongoing neuropathy. Patients who experienced peripheral neuropathy also experienced cranial nerve palsies or GBS in other ongoing trials of ciltacabtagene autoleucel.

Cranial Nerve Palsies: Three patients (3.1%) experienced cranial nerve palsies in CARTITUDE-1. All three patients had 7th cranial nerve palsy; one patient had 5th cranial nerve palsy as well. Median time to onset was 26 days (range 21-101 days) following infusion of ciltacabtagene autoleucel. Occurrence of 3rd and 6th cranial nerve palsy, bilateral 7th cranial nerve palsy, worsening of cranial nerve palsy after improvement, and occurrence of peripheral neuropathy in patients with cranial nerve palsy have also been reported in ongoing trials of ciltacabtagene autoleucel. Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): Fatal HLH occurred in one patient (1%), 99 days after ciltacabtagene autoleucel. The HLH event was preceded by prolonged CRS lasting 97 days. The manifestations of HLH/MAS include hypotension, hypoxia with diffuse alveolar damage, coagulopathy, cytopenia, and multi-organ dysfunction, including renal dysfunction. HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards.

CARVYKTI REMS: Because of the risk of CRS and neurologic toxicities, CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS.

Further information is available at www.CARVYKTIrems.com or 1-844-672-0067.

Prolonged and Recurrent Cytopenias: Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI infusion. One patient underwent autologous stem cell therapy for hematopoietic reconstitution due to prolonged thrombocytopenia.

In CARTITUDE-1, 30% (29/97) of patients experienced prolonged Grade 3 or 4 neutropenia and 41% (40/97) of patients experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Day 30 following ciltacabtagene autoleucel infusion.

Recurrent Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia and anemia were seen in 63% (61/97), 18% (17/97), 60% (58/97), and 37% (36/97) after recovery from initial Grade 3 or 4 cytopenia following infusion. After Day 60 following ciltacabtagene autoleucel infusion, 31%, 12% and 6% of patients had a recurrence of Grade 3 or higher lymphopenia, neutropenia and thrombocytopenia, respectively, after initial recovery of their Grade 3 or 4 cytopenia. Eighty-seven percent (84/97) of patients had one, two, or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Six and 11 patients had Grade 3 or 4 neutropenia and thrombocytopenia, respectively, at the time of death.

Monitor blood counts prior to and after CARVYKTI infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines.

Infections: CARVYKTI should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening or fatal infections occurred in patients after CARVYKTI infusion.

Infections (all grades) occurred in 57 (59%) patients. Grade 3 or 4 infections occurred in 23% (22/97) of patients; Grade 3 or 4 infections with an unspecified pathogen occurred in 17%, viral infections in 7%, bacterial infections in 1%, and fungal infections in 1% of patients. Overall, four patients had Grade 5 infections: lung abscess (n=1), sepsis (n=2) and pneumonia (n=1).

Monitor patients for signs and symptoms of infection before and after CARVYKTI infusion and treat patients appropriately. Administer prophylactic, pre-emptive and/or therapeutic antimicrobials according to the standard institutional guidelines. Febrile neutropenia was observed in 10% of patients after ciltacabtagene autoleucel infusion, and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated.

Viral Reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients with hypogammaglobulinemia. Perform screening for Cytomegalovirus (CMV), HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV), or any other infectious agents if clinically indicated in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.

Hypogammaglobulinemia was reported as an adverse event in 12% (12/97) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 92% (89/97) of patients. Monitor immunoglobulin levels after treatment with CARVYKTI and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

Use of Live Vaccines: The safety of immunization with live viral vaccines during or following CARVYKTI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during CARVYKTI treatment, and until immune recovery following treatment with CARVYKTI.

Hypersensitivity Reactions have occurred in 5% (5/97) of patients following ciltacabtagene autoleucel infusion. Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage appropriately according to the severity of the hypersensitivity reaction.

Secondary Malignancies: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc., at 1-800-526-7736 for reporting and to obtain instructions on collection of patient samples for testing of secondary malignancy of T cell origin.

Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status, seizures, neurocognitive decline, or neuropathy, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery during this initial period, and in the event of new onset of any neurologic toxicities.

ADVERSE REACTIONS
The most common non-laboratory adverse reactions (incidence greater than 20%) are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections of unspecified pathogen, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. The most common laboratory adverse reactions (incidence greater than or equal to 50%) include thrombocytopenia, neutropenia, anemia, aminotransferase elevation, and hypoalbuminemia.

Please read full Prescribing Information including Boxed Warning for CARVYKTI.

On February 28, 2022 Clarity Pharmaceuticals (ASX: CU6) ("Clarity"), a clinical-stage radiopharmaceutical company developing next-generation products to address the growing needs in oncology, reported an update regarding the Company’s negotiations with China Grand Pharmaceutical and Healthcare Holdings Limited (China Grand) (Press release, Clarity Pharmaceuticals, FEB 28, 2022, View Source [SID1234609197]).

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As noted in the Company’s Prospectus, Clarity and China Grand agreed to enter exclusive discussions for the grant of a licence to permit China Grand to develop, manufacture and commercialise one or more of the Company’s products in the Greater China territory. In connection with those discussions, and in consideration for exclusivity, the Company and China Grand entered into an Option Deed on 1 July 2021, with an expiration date on the earlier of a number of events including a period of six months from the date of the Company listing on the ASX.

Under the Deed, the Company issued 25,543,912 options to China Grand to acquire shares at an exercise price of A$1.75. Those options lapsed and were cancelled at 5pm on 25 February 2022 (Expiry Date), being six months from Clarity’s listing date, and the exclusivity period for the licencing negotiations also expired at that time. Clarity continues to progress strategic discussions in relation to its pipeline and technology globally and is now clear to negotiate the Greater China territory on a non-exclusive basis.

Clarity’s Executive Chairman, Dr Alan Taylor, commented, "We consider China Grand to be a quality pharmaceutical group who could be a potential future partner. We welcome the interest they have shown in our entire platform, products and technology as well as the opportunity to discuss collaborative opportunities in the Greater China territory. The Clarity Board of Directors is committed to ensuring that any collaborative agreement provides maximum value for Clarity shareholders and reflects the long-term potential returns to all parties.

"Clarity has rapidly expanded its clinical program and manufacturing and supply capabilities in the past 12 months, clearly differentiating itself as an effective and sustainable player in the radiopharmaceutical market, a market that is undergoing rapid growth. The Company is currently recruiting in four clinical trials in the US and Australia with plans to open a number of additional trials across all our products over the next 12 months. This provides a broad range of strategic partnering opportunities globally, which we continue to explore.

"With our continued clinical momentum in a range of products in rare and large indications, it is an exciting time for the Company as we look to create substantial value for shareholders while we progress towards our ultimate goal of better treating children and adults with cancer."

This announcement has been authorised for release by the Executive Chairman.

On March 28, 2022 Merus N.V. (Nasdaq: MRUS) ("Merus", "we", or "our"), a clinical-stage oncology company developing innovative, full-length multispecific antibodies (Biclonics and Triclonics), reported financial results for the fourth quarter and full year ended December 31, 2021 and provided a business update (Press release, Merus, FEB 28, 2022, View Source [SID1234609296]).

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"We made significant progress in 2021, advancing our clinical programs, further developing our discovery and research pipeline and strengthening our balance sheet," said Bill Lundberg, M.D., President and Chief Executive Officer of Merus. "Our most advanced product candidate, zenocutuzumab remains on track for a clinical update on the eNRGy trial in the first half of 2022, and, if the rate of enrollment and efficacy remain consistent, we believe a sufficient number of patients will be enrolled in the eNRGy trial and Early Access Program, with sufficient follow up, by mid-2022, that could form the basis of a potential registrational data set. We also plan to provide clinical updates on our second most-advanced candidate, petosemtamab, and on MCLA-129 in the second half of this year."

Clinical Programs and Business Update

Zenocutuzumab, or "Zeno" (MCLA-128: HER3 x HER2 Biclonics)
NRG1+ Cancer: Phase 1/2 eNRGy trial clinical data and program update planned for first half of 2022

Zeno is currently being investigated in the phase 1/2 eNRGy trial to assess the safety and anti-tumor activity of Zeno monotherapy in NRG1+ cancer.

As of February 2022, more than 100 patients with NRG1+ cancer have been treated with Zeno monotherapy in our phase 1/2 eNRGy trial and Early Access Program ("EAP"). Merus plans to provide a clinical program update in the first half of 2022. In June 2021, Merus shared interim clinical data from an April 2021 data cutoff, demonstrating encouraging early clinical activity, with confirmed partial response rates observed to be 42% in NRG1+ pancreatic cancer (5 of 12), and 29% across all NRG1+ tumor types treated (13 of 45).

In November 2021, Merus reported that it met with the U.S. Food and Drug Administration (FDA) in an end-of-phase Type B meeting to discuss interim results from the ongoing phase 1/2 eNRGy trial and EAP in NRG1+ cancer, and to discuss the development plan for Zeno. Based on feedback received from the FDA, Merus believes that the trial design and planned enrollment will be appropriate to potentially support a Biologics License Application ("BLA") submission seeking a tumor agnostic indication for Zeno in patients with previously treated NRG1+ cancer.

In January 2021, the FDA granted Fast Track Designation to Zeno for the treatment of patients with metastatic solid tumors harboring NRG1 gene fusions (NRG1+ cancers) that have progressed on standard of care therapy.

Details of the eNRGy trial, including current trial sites, can be found at clinicaltrials.gov and Merus’ trial website at www.nrg1.com, or by calling 1-833-NRG-1234.

Petosemtamab, or "Peto" (MCLA-158: Lgr5 x EGFR Biclonics): Solid Tumors
Dose expansion continues in the phase 1 trial: update planned for second half of 2022

Peto is currently enrolling in a phase 1 open-label, multicenter study, and is in the expansion phase, in patients with solid tumors.

In October 2021, Merus reported early interim clinical data of our Peto program in patients with advanced head and neck squamous cell carcinoma (HNSCC) at the 2021 AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper). Among 10 patients with previously treated advanced HNSCC, as of the August 9, 2021 safety and efficacy data cutoff, the median age was 65 and the median number of prior lines of therapy was two. Seven patients were evaluable for an interim efficacy analysis by investigator assessment (three patients were enrolled <8 weeks before the data cutoff date). Three of seven patients achieved a partial response, with one of these three achieving complete response after the data cutoff date. Tumor reduction was observed in the target lesions of all seven patients. The safety results presented for Peto were based on 29 patients with advanced solid tumors who were treated at the recommended phase 2 dose across the phase 1 trial, and, as of the data cutoff, the most frequent adverse events (AEs) were infusion related reactions with 72% any grade and 7% grade 3 or greater. Mild to moderate skin toxicity (3% grade ≥3) was also observed.

MCLA-145 (CD137 x PD-L1 Biclonics): Solid Tumors
Phase 1 trial continues

MCLA-145 is currently enrolling a global, phase 1, open-label, single-agent clinical trial evaluating MCLA-145 in patients with solid tumors. In December 2021, Merus reported interim clinical data on MCLA-145 from the phase 1 trial in patients with solid tumors at the ESMO (Free ESMO Whitepaper) Immuno-Oncology Congress 2021. As of the data cutoff date of July 14, 2021, 34 patients with advanced or metastatic solid tumors with median age of 60.5 years had been treated at 8 dose levels ranging from 0.4-75mg Q2W. The median (range) duration of treatment was approximately 6 (1-74) weeks. AEs observed were consistent with the mechanism of action of MCLA-145 and were generally managed with drug interruption and/or steroids in some patients. Preliminary evidence of antitumor activity was observed at doses ≥ 25 mg. Robust T-cell activation was observed across the 10 to 75 mg biweekly dosing range, including activation of cytotoxic CD8+ cells and elevation of cytokines.

Following Incyte’s (Nasdaq: INCY) election to opt-out of its ex-U.S. development of MCLA-145, announced earlier this year, Merus holds global rights to this program. Further clinical evaluation of MCLA-145 is planned, both as monotherapy and in combination with a PD-1 blocking antibody.

MCLA-129 (EGFR x c-MET Biclonics): Solid Tumors
Dose escalation continues in the phase 1 trial: update planned for the second half of 2022

MCLA-129 is currently enrolling in a phase 1/2, open-label clinical trial consisting of dose escalation followed by a planned dose expansion. Primary objectives of phase 1 are to determine the maximum tolerated dose and/or the recommended phase 2 dose, and the objectives of phase 2 are to evaluate safety, tolerability and potential clinical activity of the recommended phase 2 dose in patients with advanced solid tumors. MCLA-129 is subject to a collaboration and license agreement with Betta Pharmaceuticals Co. Ltd. (Betta), which permits Betta to exclusively develop MCLA-129 in China, while Merus retains global rights outside of China. In October 2021, Betta announced that the first patient was dosed in a phase 1/2 trial in China sponsored by Betta, of MCLA-129 in patients with advanced solid tumors.

Collaborations Update

Incyte

In the third quarter of 2021 Merus received a milestone payment for achieving pre-clinical candidate nomination of a novel bispecific antibody (target pair program) under the global collaboration and license agreement with Incyte. Candidate nomination has triggered this program’s next phase of IND-enabling studies by Incyte.

Merus receives reimbursement for research activities related to the collaboration and is eligible to receive potential development, regulatory and commercial milestones and sales royalties for any products, if approved.

Loxo Oncology at Lilly

In January 2021 Merus and Loxo Oncology at Lilly, a research and development group of Eli Lilly and Company (Lilly) announced a research collaboration and exclusive license agreement to develop up to three CD3-engaging T-cell re-directing bispecific antibody therapies. The collaboration is progressing well with active research programs underway.

Corporate Activities

Completed two Public Offerings in 2021

In January and November 2021, Merus closed two public offerings, with the cumulative gross proceeds from the offerings of approximately $250 million, inclusive of underwriters’ 30-day option to purchase additional common shares at the public offering price. All of the shares in the offering were sold by Merus. Proceeds from these offerings are planned to be used to continue to fund Merus’ product candidates in clinical and preclinical development, as well as for general corporate purposes.

Shannon Campbell Appointed as Chief Commercial Officer

In February 2022, Merus appointed Ms. Campbell as Executive Vice President and Chief Commercial Officer to lead the commercial strategy for the most advanced clinical candidate, Zeno, as well as Merus’ robust pipeline of multispecific product candidates in development. Ms. Campbell brings over 25 years of pharmaceutical commercialization experience and joins Merus from Novartis Pharmaceuticals Corporation, where she led Novartis’s U.S. Oncology Solid Tumor Franchise and was responsible for a broad portfolio of therapies in oncology and rare diseases. Prior to Novartis, Ms. Campbell was with Bayer HealthCare Pharmaceuticals, where she was instrumental in helping to build, launch and lead Bayer’s U.S. Oncology business.

Cash Runway projected to be beyond 2024

Based on the Company’s current operating plan, Merus expects our existing cash, cash equivalents and marketable securities will fund Merus’ operations beyond 2024.

Full Year 2021 Financial Results

Collaboration revenue for the year ended December 31, 2021 increased $19.2 million as compared to the year ended December 31, 2020, primarily as a result of $17.3 million in Lilly reimbursement revenue that did not occur in 2020, increase of $3.0M in Incyte reimbursement, partially offset by a decrease in other collaboration revenue of $1.2M. The change in exchange rates did not materially impact collaboration revenue.

Research and development expense for the year ended December 31, 2021 increased $28.1 million as compared to the year ended December 31, 2020, primarily as a result of an increase in manufacturing related costs, and higher research and development-related costs related to our programs, particularly increases in costs for zenocutuzumab and for MCLA-129.

General and administrative expense for the year ended December 31, 2021 increased $5.1 million as compared to the year ended December 31, 2020, primarily as a result increases in stock-based compensation, insurance, facilities, and personnel costs, partially offset by a decrease in consulting.

Other income, net consists of interest earned on our cash and cash equivalents held on account, accretion of investment earnings and net foreign exchange gains or losses on our foreign denominated cash, cash equivalents and marketable securities.

Merus ended 2021 with cash, cash equivalents and marketable securities of $430.7 million as compared to $207.8 million at December 31, 2020. The increase was primarily the result of closing of the collaboration and license agreement and a share purchase agreement with Eli Lilly in January 2021 for a total of $60.0 million, the aggregate net proceeds from the January 2021 follow-on offering of $129.4 million and the aggregate net proceeds from the November 2021 follow-on offering of $118.7 million.

On February 28, 2022 Semmelweis University and pharmaceutical group Sanofi reported that they have signed a cooperation agreement to increase the number of clinical trials they participate in jointly (Press release, Semmelweis University, FEB 28, 2022, View Source [SID1234609094]). Under the agreement, the university will become one of the company’s partner institutions and a member of its global network of partner sites. The agreement will enable the university to provide patients with innovative therapeutic options and its researchers and physicians to be among the first to gain experience with new treatments.

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"The strategic objectives of Semmelweis University include increasing clinical research activities and further developing strategic partnerships with the pharmaceutical industry. Participation in clinical trials and the intensification of cooperation in this area will not only enable our patients to gain access to innovative therapeutic options as soon as possible, but will also enable our researchers and doctors to be among the first to gain experience with new treatment methods," said Rector Dr. Béla Merkely on the occasion of the signing of the cooperation agreement. In 2021, around 150 new trials were launched at the university, and in the last month around 700 patients participated in trials at the university’s departments. The leading therapeutic areas are oncology, neurology, cardiology, pediatrics and dermatology, he said.

The rector noted that Sanofi is one of the world’s largest pharmaceutical groups, with a centuries-old tradition in Hungary. He pointed out that under the partnership agreement on clinical trials, Semmelweis University will become one of Sanofi’s key partner institutions and a member of its global network of partner trial sites.

Working together, we can create innovations that help people live healthier lives and improve their quality of life,"

– he said. Dr. Béla Merkely pointed out that this also plays a significant role in the research performance of the institution, which has a major impact on its position in international rankings. "Recognizing this, we have strengthened our system of support for research, development and innovation, including the establishment of the Clinical Research Coordination Center. We have developed a new set of procedures to reduce and simplify the administration of clinical research start-ups," he underlined. "The agreement is another step towards the strategic goal of making the university one of the top 100 higher education institutions in the world and one of the top 5 medical universities in Europe," said the rector.

Dr. Tamás Rónay, CEO of Sanofi Hungary, emphasized in his speech that today cooperation, joint thinking and knowledge sharing have become particularly important, which is much needed in all fields of science and society as a whole. However, the pharmaceutical industry and medicine have gone hand in hand since the very beginning. "The pharmaceutical industry is working to bring newer, more innovative, more effective and more personalized medicines to patients. Clinical trials are a key part of this process. But this clinical trial can only be successful if the patient, the doctor and the drug developer work closely together," he said. But clinical trials are not just about therapeutic benefits: trials conducted in Hungary strengthen Hungary’s role in the pharmaceutical industry, improve doctors and therapeutic protocols, and give patients access to innovative therapies not available elsewhere.

Rónay pointed out that Sanofi is currently conducting more than 30 clinical trials in Hungary at nearly 100 sites, with the participation of 1,200 patients and healthy volunteers, in all key therapeutic areas of the group, and Semmelweis University is involved in all of them.

"Through our collaborations, our group is playing an increasingly important role not only in the pharmaceutical industry itself, but also in the development of health care research and the innovation ecosystem, which is of key importance to the national economy," he said. He added that the company and the university share common goals, as both are working to safeguard the health of the Hungarian people.

The cooperation agreement was signed by Rector Dr. Béla Merkely and Chancellor Dr. Lívia Pavlik on behalf of the university, and by CEO Dr. Tamás Rónay and Director of Clinical Research Dr. Mária Letanóczki on behalf of Sanofi.

In his closing remarks, Vice-Rector for Science and Innovation Dr. Péter Ferdinandy thanked the Semmelweis Citizens who helped to conclude the agreement, with special mention to Dr. János Filakovszky, director of the Clinical Research Coordination Center. He also expressed the hope that the collaboration will generate preclinical research and early phase development in addition to clinical research, which may even lead to joint intellectual properties.

On February 28, 2022 Mersana Therapeutics, Inc. (NASDAQ: MRSN), a clinical-stage biopharmaceutical company focused on discovering and developing a pipeline of antibody-drug conjugates (ADCs) targeting cancers in areas of high unmet medical need, reported financial results and provided a business update for the fourth quarter and full year ended December 31, 2021 (Press release, Mersana Therapeutics, FEB 28, 2022, View Source [SID1234609136]).

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"We are executing on a differentiated UpRi development plan with the potential for a BLA submission in 2023 based on UPLIFT data, and we are progressing further development into earlier lines of therapy with UP-NEXT and UPGRADE, all in support of our goal of building UpRi into a foundational therapy in ovarian cancer. Leveraging our three innovative platforms, the advancement of XMT-2056, XMT-1660 and XMT-1592 provides additional opportunities to have a meaningful impact on patient outcomes. Our recently announced Janssen partnership further validates our differentiated Dolasynthen platform and highlights the strategic importance placed by major oncology players on ADC innovation," said Anna Protopapas, President and Chief Executive Officer of Mersana Therapeutics. "With our enhanced capital position and meaningful clinical progress, we stand well positioned for the future, as we strive to transform Mersana into a commercial stage company with a deep pipeline of first in class molecules."

Recent Highlights and Anticipated Milestones

Upifitamab Rilsodotin (UpRi), first-in-class Dolaflexin ADC targeting NaPi2b:

Analysis from expansion cohort of UpRi Phase 1 trial accepted for oral presentation at Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer on March 19, 2022. The Company plans to present further detail of its analysis of almost 100 patients with ovarian cancer from the June 10th, 2021 data cut (previously disclosed in September 2021) which supported the decision to select 36 mg/m2 as the recommended Phase 2 dose for UPLIFT.

UPLIFT, a single-arm registration trial in platinum-resistant ovarian cancer, remains on track to complete enrollment during 3Q 2022. UPLIFT is enrolling a broader population of patients with platinum-resistant ovarian cancer than other studies in this indication through more flexible inclusion criteria with respect to lines of therapy and underlying comorbidities. UPLIFT utilizes our novel diagnostic assay to identify patients with NaPi2b high expressing tumors, which we believe to represent two thirds of ovarian cancer patients. UPLIFT’s primary endpoint will evaluate efficacy in the NaPi2b high population, and the secondary endpoint will evaluate efficacy in the overall population. The Company plans to enroll approximately 100 patients with high NaPi2b expression and up to 180 patients overall.

UP-NEXT, a Phase 3 trial of UpRi monotherapy maintenance, informed by FDA and CHMP feedback, expected to initiate enrollment in 2Q 2022. UP-NEXT has the potential to serve as a confirmatory trial, and support global registrations, positioning UpRi as the potential next novel targeted agent, and the first ADC, to launch into the platinum sensitive space. UP-NEXT will evaluate UpRi as a maintenance agent following treatment with platinum doublets in recurrent platinum-sensitive ovarian cancer. Watch-and-wait remains the standard of care for patients who have previously received or are poorly served by existing maintenance agents, as well as patients who achieve only stable disease after receiving platinum doublet therapies. UP-NEXT is designed to provide data to address these unmet needs.

UPGRADE, the Company’s Phase 1/2 combination umbrella trial, is currently in dose escalation and remains on track to disclose interim data during 2H 2022. The dose escalation portion of this trial is intended to determine the recommended Phase 2 dose of UpRi in combination with carboplatin. The expansion portion of the trial is intended to provide proof of concept for a potential new standard of care for platinum-sensitive ovarian cancer, earlier in the disease by demonstrating that the combination of UpRi with platinum followed by UpRi monotherapy continuation could result in improved efficacy and tolerability with the ultimate goal of improving clinical benefit for patients. UPGRADE will inform further development of UpRi in this broader and earlier line patient population.
XMT-1592, first Dolasynthen ADC targeting NaPi2b:

XMT-1592, a Dolasynthen ADC targeting NaPi2b, continues in dose exploration. The Company plans to provide an update on next steps for XMT-1592, which is currently in Phase 1 dose exploration, in the second half of 2022. XMT-1592 was designed to provide Mersana with a second shot on goal in non-small cell lung cancer adenocarcinoma based on the differentiated preclinical data in this indication.
XMT-1660, Dolasynthen ADC targeting B7-H4:

Investigational New Drug (IND)-enabling studies of XMT-1660 progressing with Phase 1 trial expected to start in mid-2022. B7-H4 is expressed in high unmet need tumors such as breast, endometrial and ovarian cancers and is expressed on both tumor cells and immunosuppressive tumor-associated macrophages (TAMs). Targeting this antigen provides the potential for both a direct, cytotoxic antitumor effect as well as delivering additional payload directly to the tumor microenvironment. The Company conducted preclinical drug-to-antibody-ratio (DAR) ranging studies and compared XMT-1660 to other B7-H4 ADCs with different DARs and found that XMT-1660 DAR-6 consistently outperformed these other ADCs in in vivo models and demonstrated a favorable pharmacokinetic and tolerability profile in mice and non-human primates.
XMT-2056, the Company’s first Immunosynthen STING-agonist ADC targeting HER2:

IND-enabling studies of XMT-2056 progressing with Phase 1 trial expected to start in mid-2022. In vitro and in vivo studies demonstrate that Immunosynthen STING-agonist ADCs activate the STING pathway in both tumor-resident immune cells and tumor cells, offering the potential for an increased therapeutic index and an advantage over other innate immune activating pathways. The Company developed XMT-2056 based on its differentiated anti-HER2 antibody that binds to a novel epitope, providing the opportunity for both monotherapy and combinations with well-established anti-HER2 therapies. In both high and low HER2 models, XMT-2056 monotherapy demonstrated increased efficacy in comparison to benchmark agents such as a trastuzumab-TLR7/8 agonist ADC as well as a small molecule systemically-administered STING agonist. XMT-2056 was generally well-tolerated in non-human primate studies with no clinical signs and no adverse findings in clinical pathology or histopathology after single and repeat IV doses.
Strategic Partnerships:

Collaboration with Janssen leverages Mersana’s ADC expertise and innovative Dolasynthen platform and further enhances financial position. In February, the Company announced a research collaboration and license agreement with Janssen Biotech, Inc. to discover novel ADCs for up to three targets by leveraging Mersana’s ADC expertise and the Dolasynthen platform with Janssen’s antibodies. As part of the agreement, Mersana received $40 million in an upfront payment with the potential for more than $1 billion in total milestone payments and mid-single-digit to low double-digit percentage royalties on future net sales.
Strengthened Financial Position:

Entered into a new line of credit for increased financial flexibility. In October 2021, the Company entered into a new credit facility for up to $100 million with Oxford Finance LLC (Oxford) and Silicon Valley Bank (SVB), drawing $25 million at signing. An additional $35 million is available at the Company’s option, with the remaining balance available primarily upon achievement of certain pipeline and UpRi development milestones. In connection with this new facility, the Company retired the prior debt financing agreement with Silicon Valley Bank.
Raised $45.6 million from At-The-Market (ATM) facility in Q1 2022 with significant participation from existing long-term investors.
The Company believes its current cash and cash equivalents plus available borrowing under its line of credit will be sufficient to fund its current operating plan commitments into the second half of 2023. As of December 31, 2021, the Company had cash and cash equivalents of $177.9 million and subsequently received a $40 million upfront payment under the Janssen collaboration agreement and $45.6 million of net proceeds from sales of the Company’s common stock under its ATM. In addition, the Company currently has the option to borrow $35 million under the new line of credit with Oxford & SVB.
Upcoming Events

Mersana plans to participate in a corporate panel discussion on ovarian cancer at the Cowen 42nd Annual Health Care Conference scheduled for March 9, 2022.
Mersana plans to present at the SGO Annual Meeting on Women’s Cancer (Society of Gynecologic Oncology) on March 19, 2022.
Fourth Quarter 2021 Financial Results

Net cash used in operating activities in the fourth quarter of 2021 was $42.4 million.

Research and development expenses for the fourth quarter of 2021 were $37.4 million, compared to $22.9 million for the same period in 2020. The difference was primarily due to an increase in manufacturing and clinical costs on the UpRi program, an increase in headcount and an increase in research and manufacturing costs on preclinical programs. Non-cash stock-based compensation expense included in these research and development expenses was $2.6 million.

General and administrative expenses for the fourth quarter of 2021 were $10.7 million, compared to $5.9 million during the same period in 2020 primarily due to an increase in headcount and consulting and professional fees. Non-cash stock-based compensation expense included in these general and administrative expenses was $2.3 million.

Net loss for the fourth quarter of 2021 was $49.0 million, or $0.68 per share, compared to net loss of $28.8 million, or $0.42 per share, for the same period in 2020. Weighted average common shares outstanding for the quarter ended December 31, 2021, and December 31, 2020, were 71,921,322 and 68,630,078, respectively.
Full Year 2021 Financial Results

Research and development expenses for the full year 2021 were $132.0 million, compared to $67.0 million for the full year 2020. The difference was primarily due to an increase in manufacturing and clinical development activities, an increase related to preclinical and discovery stage programs, and an increase in headcount. Non-cash stock-based compensation expense included in these research and development expenses was $10.0 million.

General and administrative expenses for the full year 2021 were $36.9 million, compared to $21.9 million during the full year 2020. The difference was primarily due to an increase in headcount and consulting and professional fees. Non-cash stock-based compensation expense included in these general and administrative expenses was $8.4 million.

Net loss for the full year 2021 was $170.1 million, or $2.41 per share, compared to net loss of $88.0 million, or $1.43 per share, for the full year 2020. Weighted average common shares outstanding for the periods ended December 31, 2021, and December 31, 2020, were 70,580,949 and 61,485,205, respectively.
Cash and cash equivalents as of December 31, 2021, were $177.9 million, compared to $255.1 million in cash and cash equivalents as of December 31, 2020.
Conference Call Details

Mersana Therapeutics will host a conference call today at 8:00 a.m. ET to report financial results for the fourth quarter and full year 2021 and provide certain business updates. To access the call, please dial 877-303-9226 (domestic) or 409-981-0870 (international) and provide the Conference ID 7999454. A live webcast of the presentation will be available on the Investors & Media section of the Mersana website at www.mersana.com.