On December 12, 2022 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a targeted oncology company, reported that the U.S. Food and Drug Administration (FDA) has granted accelerated approval for KRAZATI (adagrasib), a targeted treatment option for adult patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy (Press release, Mirati, DEC 12, 2022, View Source [SID1234625160]).

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Experience the full interactive Multichannel News Release here: View Source

This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).

To view the multimedia assets associated with this release, please visit: Mirati.com/approval

"The FDA approval of KRAZATI is a positive development for thousands of patients with KRASG12C mutations, including the approximately 14% of patients with NSCLC adenocarcinomas histology that harbor a KRASG12C mutation.1 Mirati is thrilled to make KRAZATI available in a tablet formulation to patients in the U.S. with advanced NSCLC who have progressed beyond a first-line treatment for the historically difficult-to-treat KRAS mutation," David Meek, chief executive officer, Mirati Therapeutics, Inc., continued, "We look forward to continuing to advance our KRAZATI development program including several monotherapy and combination studies in KRASG12C-mutated solid tumors."

KRAZATI has demonstrated a positive benefit-risk profile with accelerated approval based on the Phase 2 registration-enabling cohort of the KRYSTAL-1 study, evaluating KRAZATI 600 mg capsules administered orally twice daily in 116 patients with KRASG12C-mutated advanced NSCLC who previously received treatment with a platinum-based regimen and an immune checkpoint inhibitor. The primary efficacy endpoints were confirmed ORR and DOR as evaluated by blinded independent central review (BICR) according to response evaluation criteria in solid tumors (RECIST v1.1).

The trial demonstrated an ORR of 43% (95% CI: 34-53) with 80% (95% CI: 71-87) of patients achieving disease control. The median DOR was 8.5 months (95% CI: 6.2-13.8).

In a pooled efficacy analysis (n=132) including Phase 1/1b NSCLC and registrational Phase 2 NSCLC cohorts from the KRYSTAL-1 study evaluating adagrasib as a single agent at 600 mg capsules orally twice daily, adagrasib showed an ORR of 44% and a disease control rate of 81% based on BICR, a median DOR of 12.5 months (95% CI, 7.3-NE) and median overall survival of 14.1 months (94% CI, 9.2-19.2).

The safety profile of KRAZATI was evaluated in a pooled patient population with NSCLC and other solid tumors as a single agent at 600 mg orally twice daily in 366 patients enrolled in KRYSTAL-1 and KRYSTAL-12. The most common (≥ 25%) adverse reactions were nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea and decreased appetite. Permanent discontinuation of KRAZATI due to an adverse reaction occurred in 13% of patients.

Although KRASG12C is the most common KRAS mutation in NSCLC, patients have had limited options for the treatment of this debilitating and difficult-to-treat condition.2,3

"The approval of KRAZATI offers an effective therapy for patients with advanced NSCLC harboring the KRASG12C mutation. The positive ORR and DOR results, as observed in previously treated patients with NSCLC harboring the KRASG12C mutation, demonstrate the effectiveness of KRAZATI as an option for these difficult-to-treat patients," said Shirish M. Gadgeel, MD, chief of the Division of Hematology and Oncology, Department of Internal Medicine, Henry Ford Cancer Institute/Henry Ford Health System.

"KRASG12C in NSCLC is an area of high unmet need and new treatment options offer patients and our community new hope for survivorship," said Bonnie J. Addario, co-founder and board chair of the GO2 Foundation for Lung Cancer. "I’m pleased that patients have options, there’s more awareness of this disease and we are all focused on improving the journeys of people living with KRASG12C-mutated NSCLC."

The Company partnered with Agilent and QIAGEN to develop blood- and tissue-based companion diagnostics (CDx), respectively, for KRAZATI that are now available. With tissue and blood modalities for companion diagnostics, patients have more flexibility, and clinicians have greater options for biomarker testing. These solutions help to personalize a patient’s treatment path.

Mirati Therapeutics is launching Mirati & Me, a comprehensive program dedicated to supporting patients, caregivers and the oncology community including coverage and access, financial, educational and emotional support services. Learn more by visiting the Mirati & Me website or 1-844-647-2842.

For more information, visit KRAZATI.com.

About KRAZATI (adagrasib)

Mirati has risen to meet one of the most challenging mutations in cancer research by developing KRAZATI, a highly selective and potent oral small-molecule inhibitor of KRASG12C.

Intentionally designed to meet the challenge of KRASG12C, adagrasib is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C-mutated cancers, as the KRASG12C protein regenerates every 24−48 hours.4 Adagrasib has shown clinically to be a CNS penetrant, which may be important given that CNS metastases frequently occur in NSCLC and lead to poor prognosis.5,6,7

In the U.S., KRAZATI was reviewed by the FDA for Accelerated Approval (Subpart H), which allows for the approval of drugs that treat serious conditions, and that fill an unmet medical need based on surrogate endpoints. KRAZATI was reviewed under the FDA Real-Time Oncology Review (RTOR) pilot program, which aims to explore a more efficient review process that ensures safe and effective treatments are made available to patients as early as possible. Mirati submitted a Marketing Authorization Application (MAA) in the EU in May 2022. In 2021, adagrasib achieved Breakthrough Therapy Designation in the U.S. as a potential treatment for patients with NSCLC harboring the KRASG12C mutation who have received at least one prior systemic therapy.

Adagrasib continues to be evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC, colorectal cancer, and pancreatic cancer. For more information, visit Mirati.com/science.

Mirati has an Expanded Access Program (EAP) for adagrasib for the treatment of eligible patients with KRASG12C-mutated cancers, regardless of tumor type, including patients with treated or untreated CNS metastases, in the U.S. Learn more about the EAP at Mirati.com/expanded-access-policy.

KRAZATI (adagrasib) U.S. Indication

KRAZATI is indicated for the treatment of adult patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).

KRAZATI (adagrasib) Important Safety Information

WARNINGS AND PRECAUTIONS

Gastrointestinal Adverse Reactions

In the pooled safety population, serious gastrointestinal adverse reactions observed were gastrointestinal obstruction in 1.6%, including 1.4% grade 3 or 4, gastrointestinal bleeding in 0.5% of patients, including 0.5% grade 3, and colitis in 0.3%, including 0.3% grade 3. In addition, nausea, diarrhea, or vomiting occurred in 89% of 366 patients, including 9% grade 3. Nausea, diarrhea, or vomiting led to dosage interruption or dose reduction in 29% of patients and permanent discontinuation of KRAZATI in 0.3%
Monitor and manage patients using supportive care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold, reduce the dose, or permanently discontinue KRAZATI based on severity
QTc Interval Prolongation

KRAZATI can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (eg, torsades de pointes) or sudden death
In the pooled safety population, 6% of 366 patients with at least one post-baseline electrocardiogram (ECG) assessment had an average QTc ≥501 ms, and 11% of patients had an increase from baseline of QTc >60 msec. KRAZATI causes concentration-dependent increases in the QTc interval
Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval. Avoid use of KRAZATI in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation
Monitor ECGs and electrolytes prior to starting KRAZATI, during concomitant use, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in patients who are taking medications that are known to prolong the QT interval. Withhold, reduce the dose, or permanently discontinue KRAZATI, depending on severity
Hepatotoxicity

KRAZATI can cause hepatotoxicity
In the pooled safety population, hepatotoxicity occurred in 37%, and 7% were grade 3 or 4. A total of 32% of patients who received KRAZATI had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 5% were grade 3 and 0.5% were grade 4. Increased ALT/AST leading to dose interruption or reduction occurred in 11% of patients. KRAZATI was discontinued due to increased ALT/AST in 0.5% of patients
Monitor liver laboratory tests (AST, ALT, alkaline phosphatase, and total bilirubin) prior to the start of KRAZATI, and monthly for 3 months or as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Reduce the dose, withhold, or permanently discontinue KRAZATI based on severity
Interstitial Lung Disease /Pneumonitis

KRAZATI can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal. In the pooled safety population, ILD/pneumonitis occurred in 4.1% of patients, 1.4% were grade 3 or 4, and 1 case was fatal. The median time to first onset for ILD/pneumonitis was 12 weeks (range: 5 to 31 weeks). KRAZATI was discontinued due to ILD/pneumonitis in 0.8% of patients
Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATI if no other potential causes of ILD/pneumonitis are identified
Adverse Reactions

The most common adverse reactions (≥25%) are nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, decreased appetite
Females and Males of Reproductive Potential

Infertility: Based on findings from animal studies, KRAZATI may impair fertility in females and males of reproductive potential
Please see Full Prescribing Information.

About the KRYSTAL-1 Study

KRYSTAL-1 is an open-label Phase 1/2 multiple-expansion cohort trial evaluating adagrasib as monotherapy and in combination with other anti-cancer therapies in patients with advanced solid tumors harboring the KRASG12C mutation.

About KRASG12C in NSCLC

Lung cancer is one of the most common cancers worldwide, accounting for 2.21 million new cases and 1.8 million deaths worldwide in 2020.8 Lung cancer consists of NSCLC in approximately 85% of cases and small cell lung cancer (SCLC) in approximately 15% of cases.9 KRASG12C is the most common KRAS mutation in NSCLC, present in approximately 14% of patients with lung adenocarcinoma, and is a biomarker mutation of poor prognosis.1,3

Virtual Investor Event

Mirati Therapeutics will host a virtual Investor Event on December 13, 2022 at 8:00 a.m. EST / 5:00 a.m. PST, where Company executives will provide an overview of the recent FDA approval of KRAZATI.

Investors and the general public are invited to register and listen to a live webcast of the event through the "Investors and Media" section on Mirati.com. A replay of the event will be available shortly after the conclusion.

On December 12, 2022 The Janssen Pharmaceutical Companies of Johnson & Johnson reported new analyses from the Phase 3 MAIA study of DARZALEX (daratumumab) in combination with lenalidomide and dexamethasone (D-Rd), evaluating progression-free survival (PFS), minimal residual disease (MRD) negativity and overall response rate (ORR) at a median follow-up of 64.5 months, and overall survival (OS) at a median follow-up of 73.6 months in newly diagnosed, transplant-ineligible (TIE) patients with multiple myeloma, regardless of patients’ age and across clinically important subgroups, as well as health-related quality of life (HRQoL) among frail TIE patients (Press release, Johnson & Johnson, DEC 12, 2022, View Source [SID1234625159]). These findings were presented in oral and poster presentations at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2022 Annual Meeting, and strengthen previous data from the MAIA study across clinically relevant study endpoints and patient populations.5

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"Initial data from the MAIA study were instrumental in establishing the D-Rd regimen as a standard of care for the treatment of patients with newly diagnosed, transplant-ineligible multiple myeloma," said study author, Shaji Kumar, M.D.†, Consultant, Division of Hematology, Department of Internal Medicine, Mayo Clinic. "These updated findings continue to reinforce the overall survival benefit with the D-Rd regimen and provide important insights across key patient populations at varying ages and levels of cytogenetic risk."

An updated efficacy analysis from the MAIA study reports data after 64.5 and 73.6 months of median follow-up on the primary study endpoint, PFS, and the secondary endpoints of MRD negativity, ORR, and OS (Abstract #4559).1 Additional new post-hoc efficacy analyses report on critical subgroups, including by age (Abstract #4553) and by cytogenetic risk factors, including Gain(1q21) and Amp(1q21) (Abstract #3245).2,3

"DARZALEX-based combination regimens are foundational in the treatment of newly diagnosed multiple myeloma, and the data presented at ASH (Free ASH Whitepaper) provide further insight into the treatment of transplant-ineligible patients with the D-Rd regimen in the frontline setting," said Mark Wildgust, Ph.D., Vice President, Global Medical Affairs, Janssen Research & Development, LLC. "Building on Janssen’s deep legacy in the treatment of multiple myeloma, we remain committed to evaluating the full potential of DARZALEX in combination with lenalidomide and dexamethasone to meet the unique needs of various patient populations."

The median age of the 737 patients enrolled in the MAIA trial was 73 (range: 45 to 90) years, with 44 percent of participants over the age of 75 years. Findings from the post-hoc subgroup analysis were consistent with previously reported data from the MAIA study on age and showed D-Rd improved OS, PFS, MRD-negativity, and ORR compared to Rd alone in all three age groups examined, including patients under 70 years of age, between 70 and 75 years of age, and under the age of 75.2

In patients under 75 years (D-Rd, n=208; Rd, n=208) who were treated with D-Rd, median PFS was not reached vs. 37.5 months in the Rd arm [hazard ratio (HR): 0.52, 95 percent confidence interval (CI), 0.39-0.68]. MRD-negativity was 36.1 percent vs. 12.0 percent [odds ratio (OR), 4.13; 95 percent CI, 2.49-6.84]. The ORR was 95.2 percent vs. 81.7 percent.2
In patients under 70 years of age (D-Rd, n=78; Rd, n=77) who were treated with D-Rd, median PFS was not reached vs. 39.2 months in the Rd arm (HR, 0.35; 95 percent CI, 0.21-0.56). MRD-negativity was 35.9 percent vs. 11.7 percent (OR, 4.23; 95 percent CI, 1.84-9.75). The ORR was 93.6 percent vs. 80.5 percent.2
Lastly, in patients ages 70 through 75 (D-Rd, n=130; Rd, n=131), who were treated with D-Rd, median PFS was reached at 61.9 months vs. 37.5 months in the Rd arm (HR, 0.64; 95 percent CI, 0.45-0.89; P = 0.0079). MRD-negativity was 36.2 percent vs. 12.2 percent (OR, 4.07; 95 percent CI, 2.16-7.67). The ORR was 96.2 percent vs. 82.4 percent.2
A second analysis in key clinical subgroups (Abstract #3245) reported increased PFS, MRD-negativity and ORR following treatment with D-Rd in patients 75 or older, with International Staging System (ISS) stage III disease, with high cytogenetic risk, with renal insufficiency, and with extramedullary plasmacytomas.3 Key highlights include:

Patients with high cytogenetic risk, defined as having one or more of the abnormalities t[4;14], t[14;16] or del17p, had a median PFS of 45.3 months following treatment with D-Rd vs. 29.6 months with Rd alone (HR, 0.57; 95 percent CI, 0.34-0.96) (D-Rd, n=48; Rd, n=44). MRD-negativity was 25.0 percent compared to 2.3 percent (OR, 14.33, 95 percent CI, 1.78-115.59) and the ORR was 91.7 percent vs. 75 percent (OR, 3.67, 95 percent CI, 1.07-12.55).3
Patients with Gain(1q21) or Amp(1q21) had a median PFS of 53.2 months following treatment with D-Rd vs. 32.3 months with Rd alone (HR, 0.63; 95 percent CI, 0.46-0.88) (D-Rd, n=127; Rd, n=120). MRD-negativity was 33.1 percent compared to 11.7 percent (OR, 3.74, 95 percent CI, 1.92-7.30) and the ORR was 95.3 percent vs. 85 percent (OR, 3.56, 95 percent CI,1.36-9.30).3
The rates of Grade 3/4 and serious treatment-emergent adverse events (TEAEs) were similar in both treatment groups for patients 75 years of age or older, with a lower rate of discontinuation due to TEAEs for patients treated with D-Rd compared to Rd alone.3
In a fourth analysis presented from the MAIA study, patient-reported outcomes (PRO) data were highlighted in an oral presentation, and showed sustained improvements in HRQoL and physical functioning among a subgroup of frail patients treated with D-Rd compared to Rd, with a notable reduction in pain throughout the duration of treatment (Abstract #472).4 A higher percentage of patients continued treatment with D-Rd, compared to those receiving Rd alone.4

About the MAIA Trial
The randomized, open-label, multicenter Phase 3 study included 737 newly diagnosed patients with multiple myeloma ineligible for high-dose chemotherapy and autologous stem cell transplant (ASCT), aged 45-90 years (median age of 73).6 Patients were randomized to receive either D-Rd or Rd alone in 28-day cycles. In the D-Rd arm, patients received DARZALEX 16 milligrams per kilogram (mg/kg) IV weekly for cycles 1 – 2, every two weeks for cycles 3 – 6 and every four weeks for cycle 7 and thereafter.6 Patients in the D-Rd and Rd treatment arms received 25 mg of lenalidomide on days 1 – 21 of each 28-day cycle, and dexamethasone at 40 mg once a week for each cycle. Patients in both treatment arms continued until disease progression or unacceptable toxicity.6

Earlier results from the MAIA study supported the U.S. Food and Drug Administration (FDA) approval of DARZALEX in combination with Rd. These data were also published in The New England Journal of Medicine in 2019. An updated OS analysis was published in The Lancet Oncology in 2021.

About DARZALEX
DARZALEX (daratumumab) received U.S. FDA approval in November 2015 and is approved in eight indications in multiple myeloma, three of which are in the frontline setting, including newly diagnosed patients who are transplant eligible and ineligible.7

DARZALEX is the first CD38-directed antibody approved to treat multiple myeloma.7 DARZALEX is approved in more than 100 countries and DARZALEX-based regimens have been used in the treatment of more than 300,000 patients worldwide and more than 68,000 patients in the U.S. alone.7 There are more than 37 company-sponsored clinical trials, including 14 Phase 3 studies, evaluating the efficacy and safety of DARZALEX.7

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement which granted Janssen an exclusive license to develop, manufacture and commercialize daratumumab.

Since 2020, the National Comprehensive Cancer Network (NCCN) has recommended DARZALEX-based combination regimens for the treatment of newly diagnosed multiple myeloma and relapsed and refractory multiple myeloma. For newly diagnosed multiple myeloma, the NCCN guidelines recommend DARZALEX in combination with lenalidomide and dexamethasone as a preferred regimen in Category 1; DARZALEX in combination with bortezomib, melphalan, and prednisone as a recommended regimen for non-transplant candidates in Category 1; and DARZALEX in combination with bortezomib, thalidomide and dexamethasone as useful in certain circumstances for transplant candidates in Category 2A. In relapsed/refractory myeloma, four DARZALEX regimens are listed as preferred regimens for early relapses (1-3 prior therapies) in Category 1: DARZALEX in combination with lenalidomide and dexamethasone; DARZALEX in combination with bortezomib and dexamethasone; DARZALEX in combination with carfilzomib and dexamethasone; and DARZALEX in combination with pomalidomide and dexamethasone [after two prior therapies, including lenalidomide and a proteasome inhibitor (PI)]. The NCCN recommends DARZALEX in Category 2A after at least three prior therapies, including a PI and an immunomodulatory agent, or for patients who are double refractory to a PI and an immunomodulatory agent.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.8,9 In multiple myeloma, these plasma cells change, spread rapidly and replace normal cells in the bone marrow with tumors. In 2022, it is estimated that more than 34,000 people will be diagnosed with multiple myeloma, and more than 12,000 will die from the disease in the U.S.9 While some people diagnosed with multiple myeloma have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.10

INDICATIONS
DARZALEX (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:

In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
DARZALEX is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS
Infusion-Related Reactions
DARZALEX can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life–threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision.

When DARZALEX dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, i.e., 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX .

Interference With Serological Testing
Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.

Neutropenia and Thrombocytopenia
DARZALEX may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX until recovery of neutrophils or for recovery of platelets.

Interference With Determination of Complete Response
Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Embryo-Fetal Toxicity
Based on the mechanism of action, DARZALEX can cause fetal harm when administered to a pregnant woman. DARZALEX may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX and for 3 months after the last dose.

The combination of DARZALEX with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

ADVERSE REACTIONS
The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion–related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

Please click here to see the full Prescribing Information.

On December 12, 2022 Nektar Therapeutics (Nasdaq: NKTR) reported two presentations of NKTR-255 at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Nektar Therapeutics, DEC 12, 2022, View Source [SID1234625158]).

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NKTR-255 is an investigational IL-15 receptor agonist designed to boost antitumor immunity by increasing the proliferation and survival of natural killer (NK) and memory CD8+ T cells, thereby enhancing the formation of long-term immunological memory, which may lead to sustained antitumor immune response.

The study design of an upcoming Phase 2/3, randomized, double-blind, placebo-controlled, multicenter clinical trial of NKTR-255 following CD19-directed chimeric antigen receptor T (CAR-T) cell therapy in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) was presented by Miguel-Angel Perales, M.D., Chief, Adult Bone Marrow Transplant Service, at Memorial Sloan Kettering Cancer Center on Sunday, December 11th. Pre-clinical studies demonstrate that NKTR-255 can potentiate the effects of CAR-T therapies and a number of early clinical studies are currently underway to evaluate the role of NKTR-255 following CAR-T cell treatment for different hematologic malignancies.

Additionally, results from the ongoing Phase 1 study of NKTR-255 as a monotherapy and in combination with daratumumab in patients with R/R multiple myeloma (MM) or non-Hodgkin’s lymphoma (NHL) were presented by Krina Patel, M.D., Associate Professor, Department of Lymphoma-Myeloma, at the University of Texas MD Anderson Cancer Center on Monday, December 12th. The data showed that NKTR-255 resulted in an expansion and proliferation of NK cells following daratumumab’s on-target depletion of CD38-expressing NK cells.

"NKTR-255 administration one-day following dara resulted in a 4-fold expansion of the NK cells, returning NK cells to the same baseline level seen before dara administration. This exciting result shows that NKTR-255 can restore dara-induced NK cell depletion and may potentiate its ADCC mechanism. Moreover, NKTR-255 treatment resulted in NK cell expansion and induction of NK-cell activation markers across multiple cycles further validating NKTR-255’s effect," said Jonathan Zalevsky, Ph.D., Head of Research and Development at Nektar. "Additional work presented at ASH (Free ASH Whitepaper) highlights our new trial evaluating NKTR-255 as a unique potentiator of cellular therapy in a Phase 2/3 study in relapsed or refractory lymphoma patients who are seeking long-term efficacy from currently available CAR-T cell therapy."

2022 ASH (Free ASH Whitepaper) presentations are available for download at www.nektar.com/science/scientific-posters-and-presentations.

Key details and takeaways from the presentation are as follows:

Abstract 3335 (Trial in Progress): "A Phase 2/3, Randomized, Double Blind, Placebo-Controlled, Multicenter Study of NKTR-255 Vs Placebo Following CD-19 Directed CAR-T Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphoma", Perales M., et al.

Based on preclinical and clinical evidence, NKTR-255 has the potential to improve efficacy of currently approved cellular therapy by enhancing antitumor effect and durability of responses.
The upcoming Phase 2/3 study will enroll eligible patients with R/R LBCL who have received an FDA-approved CAR-T cell product. Patients will receive NKTR-255 intravenously, starting approximately 14 days following CAR-T therapy, with continued dosing every 21 days.
The primary objective of the Phase 2 portion of the study is to identify the dose of NKTR-255 for the Phase 3 portion of the study based on safety, tolerability, and complete response rate (CRR) at month 6, the primary efficacy endpoint.
Abstract 4652: "Safety, Tolerability, PK/PD and Preliminary Efficacy of NKTR-255, a Novel IL-15 Receptor Agonist, in Patients with Relapsed/Refractory Hematologic Malignancies", Patel K., et al.

NKTR-255 was well tolerated in heavily pre-treated patients with hematologic malignancies (NHL and MM) in doses up to 12 μg/kg and in combination with daratumumab in doses up to 9 μg/kg (in MM). The majority of treatment-related adverse events (TRAE) were low-grade, transient, and easily managed. The maximum tolerated dose (MTD) was not reached.
No new safety signals or overlapping toxicities were observed with the doublet and dose escalation is ongoing.
Early evidence of clinical activity was observed in this heavily pre-treated and highly refractory patient population with the doublet (NKTR-255 + daratumumab).
Peak fold-changes of ~17-fold NK cell and ~2-fold in CD8+ T cell expansion were observed in the first 2 cycles with NKTR-255 monotherapy doses up to 12 μg/kg. Sustained proliferative ability of NK and CD8+ T cells across multiple cycles indicated no evidence of tachyphylaxis.
Preliminary data from patients previously treated with off-the-shelf allogenic CAR-T cells indicate that allo-CAR-T cells persisted with NKTR-255 monotherapy, suggesting no alloreactivity to off-the-shelf allo-CAR-T cells.
With combination therapy, NK cell rescue was observed with sustained increases in NK and CD8+ T cells despite daratumumab’s on-target depletion of CD38 expressing NK cells.
About NKTR-255

NKTR-255 is a biologic that targets the IL-15 pathway in order to activate the body’s innate and adaptive immunity. Through optimal engagement of the IL-15 receptor complex, NKTR-255 is designed to enhance functional NK cell populations and formation of long-term immunological memory, which may lead to sustained and durable anti-tumor immune response.

Preclinical and clinical findings suggest NKTR-255 has the potential to synergistically combine with antibody-dependent cellular cytotoxicity molecules as well as to enhance CAR-T therapies.

Nektar has initiated a Phase 1 dose escalation and expansion clinical study of NKTR-255 in adults with relapsed or refractory non-Hodgkin lymphoma or multiple myeloma (NCT04136756), as well as a Phase 1/2 clinical study of NKTR-255 in patients with relapsed or refractory head and neck squamous cell carcinoma or colorectal cancer (NCT04616196).

There are two ongoing investigator sponsored trials evaluating NKTR-255 following treatment with a CAR-T cell therapy. Fred Hutchinson Cancer Center is conducting a Phase 1 study evaluating NKTR-255 in combination with CD19 CAR-T cell therapy in patients with relapsed or refractory large B-cell lymphoma (NCT05359211), and Stanford University is conducting a Phase 1 study evaluating NKTR-255 in combination with CD19/22 CAR-T cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (NCT03233854).

On December 12, 2022 TC BioPharm (Holdings) PLC ("TC Biopharm" or the "Company") (NASDAQ: TCBP) (NASDAQ: TCBPW), a clinical stage biotechnology company developing platform allogeneic gamma-delta T cell therapies for cancer treatment, reported its financial results for the first half ended June 30, 2022 and provided a shareholder update (Press release, TC Biopharm, DEC 12, 2022, View Source [SID1234625157]).

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"The current year has been an eventful time for TC BioPharm as we launched our Phase 2b in AML," said Bryan Kobel, Chief Executive Officer. "Since completing our IPO in early 2022, we have advanced testing of our lead drug, OmnImmune, are actively forging strategic relationships with key industry leaders and established a strong foundation capable of supporting long-term growth. I am pleased with the current trajectory of the Company and eager to leverage the many opportunities that lay before us, as we execute on our clinical strategy and business development efforts from the second half of 2022. I look forward to providing additional operational announcements in 2023 as we continue to focus on our primary goal of enhancing overall shareholder value through clinical inflection points and strategic efforts."

First Half 2022 Highlights

On February 15, 2022, the Company announced closing of its $17.5 million Initial Public Offering and began trading on the NASDAQ stock exchange under the ticker "TCBP"
Earlier this year, TC BioPharm formally announced positive interim data its Phase 1a/2b human study evaluating safety and tolerability of TCB-002, OmnImmune, the Company’s allogeneic unmodified gamma delta t-cell product, a novel therapeutic targeting the potential treatment of relapse/refractory Acute Myeloid Leukemia ("AML")
In March 2022, TC BioPharm received MHRA and Research Ethics Committee approvals to initiate phase 2B/3 Clinical Trials for the treatment of Acute Myeloid Leukemia
During the First Quarter 2022, the Company announced that orphan drug status had been granted for lead product OmnImmune
In June 2022, the Company announced the closing of a further offering raising $4.6 million before expenses
Financial results

Basic and diluted income/(loss) per share was £0.93 (or $1.13) and £0.76 (or $0.92) for the six months ended June 30, 2022, respectively, compared to (£6.79) and (£6.79) for the six months ended June 30, 2021, respectively. Total net income for the six months ended June 30, 2022 was £0.5 million (or $0.6 million), respectively, compared to a net loss of £2.6 million, for the same period in 2021.

For the six months ended June 30, 2022, our research and development expenses were £3.7 million (or $4.5 million), as compared to £2.9 million for the six months ended June 30, 2021. For the six months ended June 30, 2022, our administrative expenses were £4.1 million (or $5.3 million), compared to £0.9 million for the six months ended June 30, 2021. For the six months ended June 30, 2022, our administrative expenses related to preparing for a listing were £1.1 million (or $1.4 million), compared to £Nil for the six months ended June 30, 2021.

Cash and cash equivalents were £6.0 million or $7.3 million as of June 30, 2022 compared to £1.6 million as of December 31, 2021. We subsequently raised a further £6.0 million (or $7.3 million) in the November 2022 PIPE before deductions for estimated attributable expense of £0.7 million (or $0.9 million).

We maintain our books and records in pounds sterling. For the convenience of the reader, we have translated pound sterling amounts as of and for the period ended June 30, 2022 into U.S. dollars at a rate of £1.00 to $1.2162.

On December 12, 2022 PharmAbcine Inc. (KOSDAQ: 208340ks), a clinical-stage biotech company focusing on the development of next-generation antibody therapeutics, reported that the Company has entered into a clinical collaboration agreement with MSD (Merck & Co., Inc., Rahway, NJ., USA), to initiate a Phase I combination trial of PMC-309, a novel anti-VISTA (V-domain Ig suppressor of T cell activation) antibody, in combination with KEYTRUDA (pembrolizumab), MSD’s anti-PD-1 therapy (Press release, PharmAbcine, DEC 12, 2022, View Source [SID1234625156]).

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Under the terms of the agreement, PharmAbcine will sponsor a Phase I study in Australia to evaluate the safety and clinical efficacy of the combination therapy for the treatment of multiple advanced solid tumors, and MSD will supply KEYTRUDA.

"We are excited to announce another pipeline combination project in collaboration with MSD besides olinvacimab, our lead anti-VEGFR2 antibody, undergoing a Phase II study in combination with KEYTRUDA in mTNBC (metastatic Triple Negative Breast Cancer) patients," said Dr. Jin-San Yoo, CEO of PharmAbcine. "In preclinical studies, PMC-309 demonstrated significantly enhanced tumor growth reduction when used with an anti-PD-1 drug in in vivo mouse model compared to both monotherapies of PMC-309 and an anti-PD-1 drug. We look forward to the opportunity to investigate this approach in a clinical setting."

Dr. Yoo also added, "In comparison to the existing immuno-oncology drugs that directly activate T cells, PMC-309’s distinct mechanism of indirectly activating T cells by inhibiting immunosuppressive cells may represent a novel strategy for patients who do not respond well or have become resistant to the existing treatments and are in need of new therapies. "We are optimistic about PMC-309’s best-in-class potential, and we are particularly excited to continue to evaluate it in combination with KEYTRUDA, one of the key leading molecules in cancer immunotherapy."

Further details of agreement and clinical protocols were not disclosed.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

About PMC-309

PMC-309 is a novel IgG1 anti-VISTA (V-domain Ig Suppressor of T cell Activation) antagonizing antibody that can be used for the treatment of various tumor types. By inhibiting VISTA, an immune checkpoint receptor mainly expressed on MDSC (Myeloid-Derived Suppressor Cells) and Tregs (regulatory T cells), it can play a pivotal role in maintaining the immunosuppressive environment around the tumor cells.

In the nonclinical studies, it has been discovered that PMC-309 can promote both innate immunity (monocyte activation, M1 macrophage proliferation) and adaptive immunity (T cell activation) unlike the existing drugs which show significant changes only in adaptive immunity. In addition, the in vivo data showed that PMC-309 demonstrated significantly improved tumor growth inhibition when used in combination with an anti-PD-1 drug compared to both monotherapies of PMC-309 and an anti-PD-1 drug. These findings suggest that PMC-309 can offer a new treatment strategy in immuno-oncology area as it can be used in combination with other drugs to improve their low-response rates.

The GLP-Toxicology studies were already completed, and no serious safety issues were observed. The Company plans to submit Clinical Trial Application in early 2023.