European Commission Approve First China Domestic anti-PD-L1 mAb sugemalimab as First-Line Treatment for Non-Small Cell Lung Cancer

Sugemalimab becomes the world's first anti-PD-L1 monoclonal antibody (mAb) approved in Europe for first-line treatment of both squamous and non-squamous non-small cell lung cancer (NSCLC), also marking the first successful international approval of a China domestic anti-PD-L1 mAb.

• The European Commission (EC) approval is based on the results of GEMSTONE-302 Phase 3 trial, which demonstrated that sugemalimab in combination with chemotherapy significantly prolonged progression-free survival and overall survival in treatment-naive patients with metastatic NSCLC.

• CStone has entered into a strategic commercialization partnership with Ewopharma for sugemalimab in Central & Eastern Europe and Switzerland.

• Discussions for commercial partnerships in Western Europe, Latin America, the Middle East, Southeast Asia, etc., are progressing well and are expected to conclude soon.

• CStone is actively preparing to submit additional Marketing Authorization Applications (MAAs) to the European Medicines Agency (EMA) for new indications, including Stage III NSCLC, first-line Gastric Cancer, first-line Esophageal Cancer, and relapsed/refractory extranodal natural killer/T-cell lymphoma (r/r ENKTL).

SUZHOU, China, July 26, 2024 /PRNewswire/ -- CStone Pharmaceuticals ("CStone", HKEX: 2616), an innovation-driven biopharmaceutical company focused on the research and development of anti-cancer therapies, today announced that the European Commission (EC) has approved sugemalimab (Brand name: Cejemly®) in combination with platinum-based chemotherapy is indicated for the first-line treatment of adults with metastatic non-small-cell lung cancer (NSCLC) with no sensitizing EGFR mutations, or ALK, ROS1 or RET genomic tumor aberrations. Sugemalimab has become the first anti-PD-L1 monoclonal antibody (mAb) approved in Europe in combination with chemotherapy as first-line treatment for both squamous and non-squamous NSCLC, making CStone the first innovative biopharmaceutical company to successfully bring a China domestic anti-PD-L1 mAb to the international market.

The EC approval is primarily based on the results of the GEMSTONE-302, a multicenter, randomized, double-blind phase 3 study. The study demonstrated that sugemalimab in combination with chemotherapy significantly prolonged progression-free survival and overall survival compared to placebo combined with chemotherapy in treatment-naïve patients with metastatic NSCLC. The study results have been published in The Lancet Oncology and Nature Cancer and have been presented at multiple international academic conferences. Additionally, long-term treatment and survival data from the GEMSTONE-302 study will be presented in a poster session (#1318P) at the 2024 ESMO Annual Meeting.

Dr. Jason Yang, CEO, President of R&D and Executive Director of the Board at CStone, said, "We are extremely excited by today's announcement, which represents a major milestone in CStone's journey towards becoming a leading global company dedicated to eradicating cancer. Sugemalimab has not only become CStone's first independently developed product to receive overseas marketing authorization but it is also the world's first anti-PD-L1 mAb to receive regulatory approval in Europe in combination with chemotherapy as first-line treatment for both squamous and non-squamous NSCLC. This achievement reflects the international regulatory authorities' recognition of our high-quality R&D and manufacturing standards, and it infuses new momentum into our globalization initiatives. We are encouraged by level of interest in sugemalimab commercial partnership from companies around the world which signifies the large unmet need in this class for newer and better drugs. We are actively engaging with potential partners in Western Europe, Latin America, the Middle East and Africa, Southeast Asia, and Canada and we expect to announce the completion of these deals soon."

Dr. Yang recalled, " In early May 2023, CStone regained the development and commercialization rights for sugemalimab outside Greater China. Since then, the entire company acted swiftly, with all departments working in coordination to thoroughly review regulatory and submission documents, assess their completeness, perform gap analyses, screened and replaced numerous suppliers, and completed the applicant transfer and submission dossier updates. Within just over a month of fully taking over the MAA, the EMA issued a critical Day 120 List containing 194 outstanding questions. After analyzing a vast amount of data, our team submitted a detailed response to the EMA within the required timeframe. By Day 180, nearly 90% of the responses had been accepted by EMA’s Reviewers, and the remaining ones were further clarified and eventually agreed by the EMA Reviewers.. During the review period, we also successfully passed the EMA's routine GMP inspection of the manufacturing plant, and GCP inspections of two study centers and a CRO, which lasted a total of three weeks. Subsequently, at the end of May this year, we received a positive opinion from the EMA's Committee for Medicinal Products for Human Use (CHMP) recommending approval of sugemalimab. I truly believe that this journey, marked by numerous challenges, reflects the CStone team's resilience and innovative spirit."

Dr. Jason Yang emphasized, "The international approval and commercialization of sugemalimab mark a significant milestone in CStone's Pipeline 1.0 strategy, demonstrating our success in developing best-in-class immuno-oncology drugs for monotherapy and as a foundation for combination therapies. In Pipeline 2.0, we have global rights for a range of highly promising candidates, either in international multicenter clinical trials or approaching the clinical stage, with the potential to be first-in-class or best-in-class. Additionally, we are actively exploring the combination of sugemalimab with other treatment modalities, such as antibody-drug conjugates (ADCs) and bi-/tri-specific antibodies, to enhance its clinical value as a backbone of cancer immunotherapy."

Dr. Yang added, "The seven-year journey of sugemalimab to becoming a first-line treatment for NSCLC in Europe and other cancers in China is a testament to the extensive expertise of numerous Chinese oncology specialists. It also reflects the dedication of patients who participated in sugemalimab clinical trials and the relentless efforts of our R&D team over the years. The remarkable results of the GEMSTONE-302 study provide definitive scientific evidence supporting the use of sugemalimab in combination with chemotherapy as a first-line standard therapy for Stage IV NSCLC. We are honored and humbled that this 'Chinese innovative solution' may significantly improve outcomes for lung cancer patients worldwide, offering both longer survival and a better quality of life."

Meanwhile, CStone is actively preparing to submit multiple Marketing Authorization Applications (MAAs) for additional indications, including Stage III NSCLC, first-line Gastric Cancer, first-line Esophageal Cancer, and relapsed/refractory extranodal natural killer/T-cell lymphoma (r/r ENKTL).

About Lung Cancer

In 2020, lung cancer was the third most diagnosed cancer in Europe and the leading cause of cancer-related mortality, accounting for one fifth of cancer deaths.[1] Approximately fifty to seventy percent of lung cancer cases in Europe are diagnosed in Stage IV. [2] Globally, it is estimated that NSCLC accounts for approximately 85% of all lung cancers.[3]

About Sugemalimab

The anti-PD-L1 monoclonal antibody sugemalimab was developed by CStone using OmniRat® transgenic animal platform, which allows creation of fully human antibodies in one step. Sugemalimab is a fully human, full-length anti-PD-L1 immunoglobulin G4 (IgG4) monoclonal antibody, which may reduce the risk of immunogenicity and toxicity for patients, a unique advantage over similar drugs. Sugemalimab's unique molecular design enables a dual mechanism of action that not only blocks PD-1/PD-L1 interaction, but also induces antibody dependent cellular phagocytosis (ADCP) by cross-linking PD-L1 expressing tumor cells with tumor associated macrophages (TAMs) without harming Effector T-cells. This differentiation has resulted in potentially best-in-class efficacy/safety across a variety of tumor types.

The National Medical Products Administration (NMPA) of China has approved sugemalimab for five indications:

• In combination with chemotherapy as first-line treatment of patients with metastatic squamous and non-squamous NSCLC;

• For the treatment of patients with unresectable Stage III NSCLC whose disease has not progressed following concurrent or sequential platinum-based chemoradiotherapy;

• For the treatment of patients with relapsed or refractory extranodal NK/T-cell lymphoma;

• In combination with fluorouracil and platinum-based chemotherapy as first-line treatment of patients with unresectable locally advanced, recurrent or metastatic ESCC; and

• In combination with fluoropyrimidine- and platinum-containing chemotherapy as first-line treatment for unresectable locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma with a PD-L1 expression (Combined Positive Score [CPS] ≥5).

The European Commission (EC) has approved sugemalimab (brand name: Cejemly®) in combination with chemotherapy for the first-line treatment of patients with metastatic NSCLC.

The Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom has accepted the marketing authorization application for sugemalimab in combination with chemotherapy for first-line treatment of metastatic NSCLC. The application is currently under review.

About CStone

CStone (HKEX: 2616), established in late 2015, is an innovation-driven biopharmaceutical company focused on the research and development of anti-cancer therapies. Dedicated to addressing patient's unmet medical needs in China and globally, the company has made significant strides since its inception. To date, the company has successfully launched four innovative drugs and secured approvals for 15 new drug applications (NDAs) covering 9 indications. The company's pipeline is balanced by 12 promising candidates, featuring potentially first-in-class or best-in-class antibody-drug conjugates (ADCs), multispecific antibodies, immunotherapies and precision medicines. CStone also prides itself on a management team with comprehensive experiences and capabilities that span the entire drug development spectrum, from preclinical and translational research to clinical development, drug manufacturing, business development, and commercialization.

For more information about CStone, please visit www.cstonepharma.com.

IR contact: ir@cstonepharma.com

PR contact: pr@cstonepharma.com

Forward-looking statements

The forward-looking statements made in this article only relate to events or information as of the date when the statements are made in this article. Except as required by law, we undertake no obligation to update or publicly revise any forward-looking statements, whether as a result of new information, future events or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. All statements in this article are made on the date of publication of this article and may change due to future developments.

Disclaimer: only for communication and scientific use by medical and health professionals.

[1] Dyba T, et al. The European cancer burden in 2020: Incidence and mortality estimates for 40 countries and 25 major cancers. Eur J Cancer. 2021;157:308-347.
[2] van Meerbeeck, J. et al. Lung cancer screening in Europe: where are we in 2021? Transl Lung Cancer Res,2021;10(5) 2407-2417.
[3] Zhang, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7:78985-78993.

Citius Pharmaceuticals Receives FDA Approval for LYMPHIR™ (denileukin diftitox-cxdl) Immunotherapy for r/r CTCL

Citius Pharmaceuticals Receives FDA Approval for LYMPHIR™ (denileukin diftitox-cxdl) Immunotherapy for the Treatment of Adults with Relapsed or Refractory Cutaneous T-Cell Lymphoma

• Only systemic treatment for relapsed or refractory (r/r) CTCL to target the IL-2 receptor on malignant T-cells and Tregs

• LYMPHIR is expected to launch within the next five months

• LYMPHIR's approval marks the first novel targeted systemic therapy approved by the FDA r/r CTCL since 2018

• Approval based on Phase 3 Pivotal Study 302 results that demonstrated 36% ORR, reduction in skin disease in 84% of patients, clinically significant pruritis improvement, and no cumulative toxicity

CRANFORD, N.J., Aug. 8, 2024 /PRNewswire/ -- Citius Pharmaceuticals, Inc. (NASDAQ: CTXR) ("Citius", "Citius Pharma"), announced today that the U.S. Food and Drug Administration (FDA) has approved LYMPHIR™ (denileukin diftitox-cxdl), a novel immunotherapy for the treatment of r/r cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy. LYMPHIR is the only CTCL therapy that targets the interleukin-2 (IL-2) receptor found on malignant T-cells and Tregs. This is the first indication for LYMPHIR and the first FDA-approved product for Citius Pharma.

"LYMPHIR offers new hope for patients suffering from cutaneous T-cell lymphoma, a rare and chronic cancer characterized by debilitating skin lesions and severe itching. This approval is a significant milestone for CTCL patients. The introduction of LYMPHIR, with its potential to rapidly reduce skin disease and control symptomatic itching without cumulative toxicity, is expected to expand the CTCL treatment landscape and grow the overall market, currently estimated to be $300-$400 million," stated Leonard Mazur, Chief Executive Officer of Citius Pharmaceuticals.

"LYMPHIR, with an initial indication in the treatment of CTCL, is the first of our pipeline candidates to receive FDA approval. Citius is dedicated to working closely with healthcare providers to ensure that all r/r CTCL patients have timely access to this important new therapy. We are preparing to launch LYMPHIR in the U.S. market within the next five months," added Mazur.

"We are grateful to the clinicians, patients, and researchers who contributed to the development of LYMPHIR. We believe LYMPHIR's unique IL-2 receptor-targeted treatment, which kills tumor cells directly, and concurrently depletes host Tregs in order to boost the body's immune response, is an important differentiator and offers clinically meaningful benefits to a significant percentage of r/r patients. As the only IL-2 receptor-targeted immunotherapy for CTCL, LYMPHIR provides a novel and non-cross-resistant treatment option without cumulative toxicity for Stage I-III r/r patients for whom symptomatic skin involvement interferes with their daily quality of life. LYMPHIR's median time-to-response of only 1.4 months (min, max: 0.7, 5.6) offers many patients rapid skin relief," added Dr. Myron Czuczman, Chief Medical Officer of Citius Pharmaceuticals.

CTCL is a rare and often debilitating chronic non-Hodgkin lymphoma that primarily affects the skin. Approximately 2,500-3,000 patients are diagnosed each year with an estimated 40,000 living with the disease. Patients with r/r CTCL have limited treatment options. No universally defined single treatment is used to treat these patients with incurable cancer. Patients typically cycle through several skin-directed therapies before the cancer becomes resistant and/or progressive at which point systemic agents are needed to achieve effective disease control. Reducing and controlling skin plaques and itching without cumulative toxicity is a primary goal of CTCL treatment. Systemic medicines are prescribed until the disease progresses again or when dose-limiting toxicity occurs, after which HCPs prescribe a different systemic medicine. LYMPHIR provides another viable option in the treatment landscape with unique benefits to patients. It offers a novel mechanism of action designed to target and eradicate malignant T-cells while preserving healthy tissue. It is the only treatment option that targets the IL-2 receptors found in T-cell lymphomas and Tregs.

"As a treating oncologist, I have seen the profound negative effect on the quality of life in patients with r/r CTCL. Given the long-term nature of the disease, pruritus, ulceration of the tumors, and secondary pyogenic skin infection, it is vital to get this skin involvement under control. LYMPHIR is the first therapeutic option in many years to offer hope of reducing skin disease, bringing us one step closer to filling the need for CTCL patients, particularly those that are not able to complete or continue prior therapies," stated Dr. Francine Foss, Professor of Hematology and Director of the Multidisciplinary T-cell Lymphoma Program at Yale Cancer Center, New Haven, CT.

The approval of LYMPHIR is based on results from the Phase 3 Pivotal Study 302 (NCT01871727) of CTCL patients who had previously received at least one systemic treatment. Actual study patients received a median of 4 (min, max: 1, 18) prior anticancer therapies. The primary efficacy population includes 69 patients with stage I-III CTCL who were treated with denileukin diftitox-cxdl (9 μg /kg/day). The primary efficacy outcome measure was Objective Response Rate (ORR), as assessed by an Independent Review Committee (IRC). The ORR was 36.2%, (95% CI: 25.0-48.7), with 8.7% achieving a Complete Response (CR).

The median time to response was rapid at 1.41 months, with the majority of responders (~70%) seeing results after 1–2 cycles of treatment. Duration of response was at least 6 months for 52.0% of the patients. 84.4% (54/64) of skin evaluable subjects had a decrease in skin tumor burden and 12.5% (8/64) saw complete clearing of skin disease. Pruritis was evaluated as an exploratory endpoint with 31.7% of patients demonstrating clinically significant pruritus improvement. Importantly, no cumulative toxicity was observed in patients receiving LYMPHIR.

LYMPHIR's safety profile is consistent with the known safety profile for denileukin diftitox. Across three studies of 119 CTCL patients receiving 9 μg dose of denileukin diftitox, the most common (≥20%) adverse reactions, including laboratory abnormalities, were increased transaminases, albumin decreased, nausea, edema, hemoglobin decreased, fatigue, musculoskeletal pain, rash, chills, constipation, pyrexia, and capillary leak syndrome (CLS).

The U.S. Prescribing Information for LYMPHIR contains a boxed warning that CLS, including life-threatening or fatal reactions, can occur in patients receiving LYMPHIR. Monitor patients for signs and symptoms of CLS during treatment. Withhold LYMPHIR until CLS resolves, or permanently discontinue based on severity. Additional "Important Safety Information" is available below and LYMPHIR's full prescribing information may be accessed here in the next few days.

This approval includes a postmarketing requirement from the FDA to characterize the risk of visual impairment in CTCL patients treated with LYMPHIR.  Citius is committed to the safety of patients and will continue to monitor all safety data as it emerges.

About Study 302

The efficacy of LYMPHIR was evaluated in Study 302, an open-label, single-arm, multicenter trial in patients with r/r Stage I to IV CTCL. Eligible patients were required to have expression of CD25 on ≥ 20% of biopsied malignant cells by immunohistochemistry. The study excluded patients with significant cardiac disease or uncontrolled infections. Patients received LYMPHIR at 9 mcg/kg as an intravenous infusion daily from Day 1 through Day 5 of each 21-day cycle. Patients continued to receive LYMPHIR until disease progression or unacceptable toxicity. 

The efficacy population includes 69 patients with r/r Stage I to III CTCL. Of the 69 patients, the median age was 64 years (range: 28 to 87 years), 65% were male, 73% were White, 19% Black or African American, 1% Asian, and 14% Hispanic or Latino. The CTCL disease stage was IA in 7%, IB in 23%, IIA in 13%, IIB in 35%, IIIA in 12%, and IIIB in 10%. The median number of prior therapies was 4 (range: 1 to 18), including both skin-directed and systemic therapies. Prior therapies included photodynamic therapy (56%), total skin electron beam therapy (42%), systemic retinoids (49%), methotrexate/pralatrexate (49%), histone deacetylase inhibitor (35%), brentuximab vedotin (26%) and mogamulizumab (12%). 

Efficacy was established based on ORR, according to ISCL/EORTC Global Response Score (GRS) per Independent Review Committee (Olsen 2011). Efficacy results are shown in the table below.

About LYMPHIR™ (denileukin diftitox-cxdl)

LYMPHIR is a targeted immune therapy for r/r (R/R) CTCL indicated for use in Stage I-III disease after at least one prior systemic therapy. It is a recombinant fusion protein that combines the IL-2 receptor binding domain with diphtheria toxin fragments. The agent specifically binds to IL-2 receptors on the cell surface, causing diphtheria toxin fragments that have entered cells to inhibit protein synthesis. After uptake into the cell, the DT fragment is cleaved and the free DT fragments inhibit protein synthesis, resulting in cell death. Denileukin diftitox-cxdl demonstrated the ability to deplete immunosuppressive regulatory T lymphocytes (Tregs) and antitumor activity through a direct cytocidal action on IL-2R-expressing tumors.

In 2021, denileukin diftitox received regulatory approval in Japan for the treatment of CTCL and PTCL. Subsequently, in 2021, Citius acquired an exclusive license with rights to develop and commercialize LYMPHIR in all markets except for Japan and certain parts of Asia.

About Cutaneous T-cell Lymphoma

Cutaneous T-cell lymphoma is a type of cutaneous non-Hodgkin lymphoma (NHL) that comes in a variety of forms and is the most common type of cutaneous lymphoma. In CTCL, T-cells, a type of lymphocyte that plays a role in the immune system, become cancerous and develop into skin lesions, leading to a decrease in the quality of life of patients with this disease due to severe pain and pruritus. Mycosis Fungoides (MF) and Sézary Syndrome (SS) comprise the majority of CTCL cases.  Depending on the type of CTCL, the disease may progress slowly and can take anywhere from several years to upwards of ten to potentially reach tumor stage. However, once the disease reaches this stage, the cancer is highly malignant and can spread to the lymph nodes and internal organs, resulting in a poor prognosis. Given the duration of the disease, patients typically cycle through multiple agents to control disease progression. CTCL affects men twice as often as women and is typically first diagnosed in patients between the ages of 50 and 60 years of age. Other than allogeneic stem cell transplantation, for which only a small fraction of patients qualify, there is currently no curative therapy for advanced CTCL.

INDICATION

LYMPHIR is an IL2-receptor-directed cytotoxin indicated for the treatment of adult patients with r/r Stage I-III cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: CAPILLARY LEAK SYNDROME

Capillary leak syndrome (CLS), including life-threatening or fatal reactions, can occur in patients receiving LYMPHIR. Monitor patients for signs and symptoms of CLS during treatment. Withhold LYMPHIR until CLS resolves, or permanently discontinue based on severity.

WARNINGS AND PRECAUTIONS

Capillary Leak Syndrome

LYMPHIR can cause capillary leak syndrome (CLS), including life-threatening or fatal reactions. CLS was defined in the clinical trials as the occurrence of at least 2 of the following symptoms at any time during LYMPHIR therapy: hypotension, edema, and serum albumin <3 g/dL. These symptoms were not required to occur simultaneously to be characterized as capillary leak syndrome.

As defined, CLS occurred in 27% of patients in the pooled population across 3 clinical trials, including 8% with Grade 3. There was one (0.8%) fatal occurrence of CLS. Of the patients with CLS, 22% had recurrence. The majority of CLS events (81%) occurred within the first 2 cycles of treatment. The median time to onset from Cycle 1, Day 1 was 6.5 days (range: 1 to 77), the median duration of CLS was 14 days (range: 2 to 40), and 75% of patients had resolution. The most common symptoms included edema, hypoalbuminemia, and hypotension. Pleural effusion, pericardial effusion, and dehydration also occurred.

Regularly assess patients for weight gain, new onset or worsening of edema, dyspnea, and hypotension (including orthostatic changes). Monitor serum albumin levels prior to the initiation of each cycle of therapy and more often as clinically indicated.

Withhold, reduce dose, or permanently discontinue based on severity. If LYMPHIR is withheld, resume LYMPHIR following resolution of CLS and when serum albumin is greater than or equal to 3 g/dL.

Visual Impairment

LYMPHIR can cause serious visual impairment, including changes in visual acuity and color vision. In the pooled population across 3 clinical trials, visual impairment occurred in 9%, with Grade 1 in 8% and Grade 2 in 1%. The most commonly reported symptom was blurred vision. Of the patients with visual impairment, 67% had resolution of their visual impairment.

Perform baseline ophthalmic examination and monitor as clinically indicated. If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, or blurred vision, refer for ophthalmologic evaluation.

Withhold LYMPHIR until visual impairment resolves or permanently discontinue based on severity.

Infusion-Related Reactions

LYMPHIR can cause serious infusion-related reactions. Infusion-related reactions were reported in 69% of patients in the pooled population across 3 clinical trials of patients who received LYMPHIR, with Grade 3 infusion-related reactions in 3.4% [see Adverse Reactions (6.1)]. Eighty-three percent of infusion-related reactions occurred in Cycles 1 and 2. The most common symptoms included nausea, fatigue, chills, musculoskeletal pain, vomiting, fever, and arthralgia.

Premedicate patients for the first three cycles prior to starting a LYMPHIR infusion [see Dosage and Administration (2.3)]. Monitor patients frequently during infusion. For Grade 2 or higher infusion reactions, premedicate at least 30 minutes prior to each subsequent infusion with a systemic steroid for at least 3 cycles.

Interrupt or discontinue LYMPHIR based on severity [see Dosage and Administration (2.4)]. Institute appropriate medical management.

Hepatotoxicity

LYMPHIR can cause hepatotoxicity. In the pooled safety population, elevated ALT occurred in 70% of patients, with Grade 3 ALT occurring in 22%; elevated AST occurred in 64% of patients, with Grade 3 AST elevation occurring in 9%. For Grade 3 events, median time to onset was 8 days (range: 1 to 15 days); median time to resolution was 15 days (range: 7 to 50 days); all cases of Grade 3 ALT or AST elevations resolved [see Adverse Reactions (6.1)]. Elevated total bilirubin occurred in 5% of patients, with Grade 3 occurring in 0.9%.

Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold, reduce dose, or permanently discontinue LYMPHIR based on severity.

Embryo-Fetal Toxicity

Based on its mechanism of action, LYMPHIR can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to the initiation of LYMPHIR. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment and for 7 days following the last dose of LYMPHIR.

ADVERSE REACTIONS

The most common adverse reactions (≥20%), including laboratory abnormalities, are increased transaminases, albumin decreased, nausea, edema, hemoglobin decreased, fatigue, musculoskeletal pain, rash, chills, constipation, pyrexia, and capillary leak syndrome

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary
Based on its mechanism of action, LYMPHIR can cause fetal harm when administered to a pregnant woman. There are no available data on the use of LYMPHIR in pregnant women to evaluate for a drug-associated risk. No animal reproductive and developmental toxicity studies have been conducted with denileukin diftitox.

Denileukin diftitox-cxdl causes depletion of regulatory T lymphocytes (Treg), immune activation, and capillary leak syndrome, compromising pregnancy maintenance. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

Lactation

Risk Summary
No data are available regarding the presence of denileukin diftitox-cxdl in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LYMPHIR and for 7 days after the last dose.

Females and Males of Reproductive Potential

Based on its mechanism of action, LYMPHIR can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating LYMPHIR.

Contraception

Females 
Advise females of reproductive potential to use effective contraception during treatment with LYMPHIR and for 7 days after the last dose.

Infertility

Males
Based on findings in rats, male fertility may be compromised by treatment with. The reversibility of the effect on fertility is unknown.

Pediatric Use
Safety and effectiveness of LYMPHIR in pediatric patients have not been established.

Geriatric Use
Of the 69 patients with Stage I-III r/r CTCL who received LYMPHIR, 34 patients (49%) were 65 years of age and older and 10 patients (14%) were 75 years of age and older. Clinical studies of LYMPHIR did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. 

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Citius Pharmaceuticals at 1-844-459-6744.

Please read Important Safety Information and full Prescribing Information, including Boxed WARNING, for LYMPHIR™ which will be available in the next few days

About Citius Pharmaceuticals, Inc.

Citius Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to the development and commercialization of first-in-class critical care products. In August 2024, the FDA approved LYMPHIR, a targeted immunotherapy for an initial indication in the treatment of cutaneous T-cell lymphoma. Citius Pharma's late-stage pipeline also includes Mino-Lok®, an antibiotic lock solution to salvage catheters in patients with catheter-related bloodstream infections, and CITI-002 (Halo-Lido), a topical formulation for the relief of hemorrhoids. A Pivotal Phase 3 Trial for Mino-Lok and a Phase 2b trial for Halo-Lido were completed in 2023. Mino-Lok met primary and secondary endpoints of its Phase 3 Trial. Citius is actively engaged with the FDA to outline next steps for both programs. For more information, please visit www.citiuspharma.com.

First FDA approval for a systemic therapy for patients with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation

On August 6, 2024, the Food and Drug Administration approved vorasidenib (Voranigo, Servier Pharmaceuticals LLC), an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor, for adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, following surgery including biopsy, sub-total resection, or gross total resection.

Full prescribing information for Voranigo will be posted on Drugs@FDA. 

This is the first approval by the FDA of a systemic therapy for patients with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation.

Efficacy and Safety

Efficacy was evaluated in 331 patients with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery enrolled in INDIGO (NCT04164901), a randomized, multicenter, double-blind, placebo-controlled trial. Patients were randomized 1:1 to receive vorasidenib 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity. IDH1 or IDH2 mutation status was prospectively determined by the Life Technologies Corporation Oncomine Dx Target Test. Patients randomized to placebo were allowed to cross over to vorasidenib after documented radiographic disease progression. Patients who received prior anti-cancer treatment, including chemotherapy or radiation therapy, were excluded.

The major efficacy outcome measure was progression-free survival (PFS) using a blinded independent review committee per modified Response Assessment in Neuro-Oncology for Low Grade Glioma (RANO-LGG) criteria. An additional efficacy outcome measure was time to next intervention. The hazard ratio for PFS was 0.39 (95% CI: 0.27, 0.56), p-value <0.0001. The median time to next intervention was not reached for the vorasidenib arm and was 17.8 months for the placebo arm (HR=0.26; 95% CI: [0.15, 0.43], p <0.0001).

The most common (≥15%) adverse reactions were fatigue, headache, COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizure. The most common Grade 3 or 4 laboratory abnormalities (>2%) were increased alanine aminotransferase, increased aspartate aminotransferase, GGT increased, and decreased neutrophils.

The recommended vorasidenib dose in adult patients is 40 mg orally once daily until disease progression or unacceptable toxicity. The recommended vorasidenib dose in pediatric patients 12 years and older is based on body weight:

• Patients weighing ≥ 40 kg: 40 mg orally once daily.

• Patients weighing < 40 kg: 20 mg orally once daily.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), Health Canada, Switzerland’s Swissmedic, and Israel’s Ministry of Health (IMoH). The application reviews are ongoing at the other regulatory agencies.

Expedited Programs

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.  

This application was granted priority review, fast track designation, breakthrough designation and orphan drug designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

FDA Approves First Gene Therapy to Treat Adults with Metastatic Synovial Sarcoma

The U.S. Food and Drug Administration approved Tecelra (afamitresgene autoleucel), a gene therapy indicated for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA antigen(s) A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive, and whose tumor expresses the MAGE-A4 antigen as determined by FDA authorized companion diagnostic devices.

Synovial sarcoma is a rare form of cancer in which malignant cells develop and form a tumor in soft tissues of the body. This type of cancer can occur in many parts of the body, most commonly developing in the extremities. The cancerous cells may also spread to other parts of the body. Each year, synovial sarcoma impacts about 1,000 people in the U.S. and most often occurs in adult males in their 30s or younger. Treatment typically involves surgery to remove the tumor and may also include radiotherapy and/or chemotherapy if the tumor is larger, returns after being removed or has spread beyond its original location. 

“Potentially life-threatening cancers such as synovial sarcoma continue to have a devastating impact on individuals, especially those for whom standard treatments have limited efficacy due to tumor growth and progression,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER). “The approval of this state-of-the-art immunotherapy technology provides a critical new option for a patient population in need and demonstrates the FDA’s dedication to the advancement of beneficial cancer treatments.”

Tecelra is also the first FDA-approved T cell receptor (TCR) gene therapy. The product is an autologous T cell immunotherapy composed of a patient’s own T cells. T cells in Tecelra are modified to express a TCR that targets MAGE-A4, an antigen (substance that normally triggers your immune system) expressed by cancer cells in synovial sarcoma. The product is administered as a single intravenous dose. 

Tecelra was approved using the Accelerated Approval pathway, under which the FDA may approve drugs for serious or life-threatening diseases or conditions where there is an unmet medical need and the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients (improving how patients feel or function, or whether they survive longer). This pathway can allow earlier approval while the company conducts further trials to verify the predicted clinical benefit. A confirmatory trial is ongoing to verify Tecelra’s clinical benefit.

“Adults with metastatic synovial sarcoma, a life-threatening form of cancer, often face limited treatment options in addition to the risk of cancer spread or recurrence,” said Nicole Verdun, M.D., director of the Office of Therapeutic Products in CBER. “Today’s approval represents a significant milestone in the development of an innovative, safe and effective therapy for patients with this rare but potentially fatal disease.”

The safety and effectiveness of Tecelra was evaluated in a multicenter, open-label clinical trial including patients with inoperable and metastatic synovial sarcoma who had received prior systemic therapy and whose tumor expressed the MAGE-A4 tumor antigen. Effectiveness was evaluated based on overall response rate and the duration of response to treatment with Tecelra. Among the 44 patients in the trial who received Tecelra, the overall response rate was 43.2% and the median duration of response was six months.

The most common adverse reactions associated with Tecelra included nausea, vomiting, fatigue, infections, fever, constipation, dyspnea (shortness of breath), abdominal pain, non-cardiac chest pain, decreased appetite, tachycardia (abnormally fast heart rate), back pain, hypotension, diarrhea and edema (swelling due to buildup of fluid in body tissues).

Patients treated with Tecelra may experience cytokine release syndrome (CRS), which is a dangerous type of aggressive immune system response, including potentially life-threatening reactions. CRS was observed following administration of Tecelra during clinical trials. A Boxed Warning is included in the label containing information about this risk.

Patients may also exhibit Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS), an immune system-related syndrome that can occur following some immunotherapies, infections, secondary malignancies, or hypersensitivity reactions, and severe cytopenia (an abnormally low level of blood cells) for several weeks following lymphodepleting chemotherapy and Tecelra infusion. Patients receiving this product should be monitored for signs and symptoms of infection and are advised not to drive or engage in hazardous occupations or activities for at least four weeks after receiving Tecelra.

The FDA granted Tecelra Orphan Drug, Regenerative Medicine Advanced Therapy and Priority Review designations for this indication.

This application was reviewed using a coordinated, cross-agency approach, including CBER, the FDA’s Oncology Center of Excellence and the Center for Devices and Radiological Health.

The FDA granted the approval of Tecelra to Adaptimmune, LLC.

FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy

On August 1, 2024, the Food and Drug Administration approved dostarlimab-gxly (Jemperli, GSK) with carboplatin and paclitaxel, followed by single-agent dostarlimab-gxly, for adult patients with primary advanced or recurrent endometrial cancer (EC). Dostarlimab-gxly previously was approved with carboplatin and paclitaxel, followed by single-agent dostarlimab-gxly, for primary advanced or recurrent EC that is mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H).

Full prescribing information for Jemperli will be posted on Drugs@FDA.

Efficacy and Safety

Efficacy was evaluated in RUBY (NCT03981796), a randomized, multicenter, double-blind, placebo-controlled trial conducted in 494 patients with primary advanced or recurrent EC. Patients were randomized (1:1) to either dostarlimab-gxly with carboplatin and paclitaxel, followed by dostarlimab-gxly, or placebo with carboplatin and paclitaxel, followed by placebo. Chemotherapy regimens are described in the above link for full prescribing information. Randomization was stratified by mismatch repair (MMR)/microsatellite instability (MSI) status, prior external pelvic radiotherapy, and disease status (recurrent, primary Stage III, or primary Stage IV).

The major efficacy outcome measures were progression-free survival (PFS) (investigator-assessed using RECIST v1.1) in the dMMR/MSI-H and overall populations, and overall survival (OS) in the overall population. In the overall population, a statistically significant OS improvement was observed with a median OS of 44.6 months (95% CI: 32.6, not reached) and 28.2 months (95% CI: 22.1, 35.6) in the dostarlimab-gxly and placebo arms, respectively (Hazard Ratio=0.69 [95% CI: 0.54, 0.89]; 1-sided p-value=0.002). Median PFS in the overall population was 11.8 months (95% CI: 9.6, 17.1) and 7.9 months (95% CI: 7.6, 9.5) in the dostarlimab-gxly and placebo arms, respectively (Hazard Ratio=0.64 [95% CI: 0.51, 0.80]; 1-sided p-value <0.0001).

The most common adverse reactions (≥20%) with dostarlimab-gxly with carboplatin and paclitaxel were anemia, increased creatinine, peripheral neuropathy, decreased white blood cell count, fatigue, nausea, alopecia, low platelets, increased glucose, lymphopenia, neutropenia, liver function test abnormalities, arthralgia, rash, constipation, diarrhea, decreased albumin, abdominal pain, dyspnea, decreased appetite, increased amylase, urinary tract infection and vomiting. Immune-mediated adverse reactions with dostarlimab-gxly were similar to those previously reported for dostarlimab-gxly. See dostarlimab-gxly full prescribing information for complete adverse reactions.

The recommended dostarlimab-gxly dose is 500 mg every 3 weeks for 6 cycles with carboplatin and paclitaxel, followed by 1,000 mg monotherapy every 6 weeks until disease progression or unacceptable toxicity, or up to 3 years. Dostarlimab-gxly should be administered before chemotherapy when administered on the same day.

Expedited Programs

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 3 weeks ahead of the FDA goal date.

This application was granted priority review. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

FDA approves Darzalex Faspro with bortezomib, lenalidomide, and dexamethasone for 1st line multiple myeloma

On July 30, 2024, the Food and Drug Administration approved daratumumab and hyaluronidase-fihj (Darzalex Faspro, Janssen Research & Development, LLC) in combination with bortezomib, lenalidomide, and dexamethasone for induction and consolidation in patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT).

Full prescribing information for Darzalex Faspro will be posted on Drugs@FDA.

Efficacy and Safety

Efficacy was evaluated in PERSEUS (NCT03710603), an open-label, randomized, active-controlled trial in patients with newly diagnosed multiple myeloma eligible for ASCT. Enrollment was limited to patients 70 years of age and younger. A total of 709 patients were randomized: 355 to the Darzalex Faspro with bortezomib, lenalidomide, and dexamethasone (Darzalex Faspro-VRd) arm and 354 to the bortezomib, lenalidomide, and dexamethasone (VRd) arm.

The major efficacy outcome measure was progression-free survival (PFS) as assessed by an independent review committee based on International Myeloma Working Group (IMWG) response criteria. PERSEUS demonstrated an improvement in PFS in the Darzalex Faspro-VRd arm as compared to the VRd arm; the median PFS had not been reached in either arm. Treatment with Darzalex Faspro-VRd resulted in a reduction in the risk of disease progression or death by 60% compared to VRd alone (HR [95% CI]: 0.40 [0.29, 0.57]; p-value < 0.0001).

The most common adverse reactions (≥20%) were peripheral neuropathy, fatigue, edema, pyrexia, upper respiratory infection, constipation, diarrhea, musculoskeletal pain, insomnia, and rash.

The recommended Darzalex Faspro dose is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase). See the prescribing information for the dosage recommendations for the other drugs.

Expedited Programs

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

FDA accelerated approval for Genmab’s bi-specific epcoritamab for 3L r/r follicular lymphoma

On June 26, 2024, the Food and Drug Administration granted accelerated approval to epcoritamab-bysp (Epkinly, Genmab US, Inc.), a bispecific CD20-directed CD3 T-cell engager, for adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

Full prescribing information for Epkinly will be posted on Drugs@FDA.

Efficacy and safety were evaluated in EPCORE NHL-1 (Study GCT3013-01; NCT03625037), an open-label, multi-cohort, multicenter, single-arm trial that included 127 patients with relapsed or refractory FL after at least 2 lines of systemic therapy. The primary efficacy and safety were based on 127 patients who received a 2 step-up dosing regimen. A separate dose optimization cohort of 86 patients evaluated the recommended 3-step up dosage schedule for cytokine release syndrome (CRS) mitigation.

The main efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), determined by an Independent Review Committee using the Lugano 2014 criteria. In the 127 patients in the primary efficacy population, the ORR was 82% (95% CI: 74.1, 88.2) with 60% achieving complete responses. With an estimated median follow-up of 14.8 months among responders, the estimated median DOR was not reached (NR) (95% CI: 13.7, NR). The 12-month Kaplan-Meier estimate for DOR was 68.4% (95% CI: 57.6%, 77.0%). Efficacy was similar in the 86 patients who received the 3 step-up dosage schedule.

The prescribing information includes a Boxed Warning for serious or fatal cytokine release syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity (ICANS). Warnings and Precautions include serious infections and cytopenias. ICANS occurred in 6.0%, and serious infections in 40%. Among 86 patients with relapsed or refractory follicular lymphoma who received the recommended 3-step dosage regimen, CRS occurred in 49%, all events were grades 1 (45%) or 2 (9%).

The most common adverse reactions (≥20%) were injection site reactions, cytokine release syndrome, COVID-19 infection, fatigue, upper respiratory tract infection, musculoskeletal pain, rash, diarrhea, pyrexia, cough, and headache. The most common Grade 3 to 4 laboratory abnormalities (≥10%) were decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, and decreased hemoglobin.

The recommended regimen consists of epcoritamab-bysp administered subcutaneously in 28-day cycles until disease progression or unacceptable toxicity. The recommended dose is a 3 step-up dosage schedule in Cycle 1 (0.16 mg on Day 1, 0.8 mg on Day 8, 3 mg on Day 15, and 48 mg on Day 22), Cycle 2 and 3 (48 mg on Days 1, 8, 15, and 22), Cycles 4 to 9 (48 mg on Days 1 and 15), and Cycle 10 and beyond (48 mg on Day 1).

This application is approved under the accelerated approval pathway. To verify the clinical benefit of epcoritamab-bysp, a Phase 3 randomized trial (NCT05409066) is ongoing and close to fully enrolled (95%), which is evaluating rituximab and lenalidomide alone or in combination with epcoritamab-bysp in patients with relapsed or refractory FL.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review and breakthrough designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

European Approval for Takeda's FRUZAQLA in Previously Treated Metastatic Colorectal Cancer

Approval Based on Results from Positive, Global, Phase 3 FRESCO-2 Trial

• FRUZAQLA (fruquintinib) is the First Novel Targeted Therapy in the EU for Metastatic Colorectal Cancer (mCRC) Regardless of Biomarker Status in Over a Decade

OSAKA, Japan and CAMBRIDGE, Massachusetts, June 21, 2024 – Takeda (TSE:4502/NYSE:TAK) today announced that the European Commission (EC) approved FRUZAQLA (fruquintinib) as a monotherapy indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with available standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents, and who have progressed on or are intolerant to treatment with either trifluridine-tipiracil or regorafenib. The decision follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) on April 25, 2024, and approval by the U.S. Food and Drug Administration (FDA) for adults with mCRC who have been previously treated with oxaliplatin- and irinotecan-based regimens on November 8, 2023.1,2

"People living with metastatic colorectal cancer face numerous difficulties, stemming both from their illness and the adverse effects of therapies. Given the complex nature of the disease, introducing innovative treatments such as fruquintinib – an oral, chemotherapy-free targeted agent – is essential. I am looking forward to having a new choice for appropriate patients," said Josep Tabernero, MD, PhD, director of Vall d´Hebron Institute of Oncology (VHIO).

The approval is based on results from the Phase 3 multi-regional FRESCO-2 trial. The trial investigated FRUZAQLA plus best supportive care (BSC) versus placebo plus BSC in patients with previously treated mCRC. FRESCO-2 met all its primary and key secondary efficacy endpoints and showed consistent benefit among patients treated with FRUZAQLA, regardless of the prior types of therapies they received. FRUZAQLA demonstrated a manageable safety profile in FRESCO-2. Adverse reactions leading to treatment discontinuation occurred in 20% of patients treated with FRUZAQLA plus BSC versus 21% of those treated with placebo plus BSC. Data from FRESCO-2 were published in The Lancet in June 2023.3

"Today's approval marks an important moment for the colorectal cancer community in the EU. For the first time in over a decade, patients with previously treated metastatic colorectal cancer have a new targeted treatment option that can be used irrespective of whether their tumors harbor actionable mutations," said Teresa Bitetti, president of the Global Oncology Business Unit at Takeda. “We look forward to offering patients a novel treatment option that has a manageable safety profile and can be effective regardless of the prior types of therapies they have received.”

About FRUZAQLA (fruquintinib)

FRUZAQLA is a selective oral inhibitor of all three VEGF receptors (-1, -2 and -3). VEGFR inhibitors play a pivotal role in blocking tumor angiogenesis. FRUZAQLA was designed to have enhanced selectivity that limits off-target kinase activity, allowing for high drug exposure, sustained target inhibition, and flexibility for potential use as part of combination therapy.

Takeda has the exclusive worldwide license to further develop, commercialize, and manufacture fruquintinib outside of mainland China, Hong Kong and Macau. FRUZAQLA was approved by the U.S. Food and Drug Administration (FDA) in November 2023. A submission to the Japan Pharmaceuticals and Medical Devices Agency (PMDA) took place in September 2023. Fruquintinib is developed and marketed in China by HUTCHMED. Fruquintinib was approved for marketing by the China National Medical Products Administration (NMPA) in September 2018 and commercially launched in China in November 2018 under the brand name ELUNATE®.

EUROPEAN UNION IMPORTANT SAFETY INFORMATION

Please consult the FRUZAQLA (fruquintinib) Summary of Product Characteristics (SmPC) before prescribing.

Guidance for use: FRUZAQLA should be initiated by a physician experienced in the administration of anticancer therapy. Patients should be given the package leaflet.

CONTRAINDICATIONS: Hypersensitivity to the active substance or to any of the excipients.

SPECIAL POPULATIONS: Renal impairment: No dose adjustment is required for patients with mild, moderate, or severe renal impairment; Hepatic impairment: No dose adjustment is required for patients with mild or moderate hepatic impairment. FRUZAQLA is not recommended for use in patients with severe hepatic impairment as FRUZAQLA has not been studied in this population; Elderly: No dose adjustment is required in patients aged 65 years or above; Paediatric population: There is no relevant use of FRUZAQLA in the paediatric population for the indication of metastatic colorectal cancer; Women of childbearing potential/Contraception in females: Women of childbearing potential should be advised to use highly effective contraception during treatment and for at least 2 weeks following the last dose of FRUZAQLA; Pregnancy: There are no clinical data available on the use of FRUZAQLA in pregnant women. Based on its mechanism of action, FRUZAQLA has the potential to cause foetal harm. Animal studies have shown reproductive toxicity, including foetal malformations. FRUZAQLA should not be used during pregnancy unless the clinical condition of the woman requires treatment with FRUZAQLA. If FRUZAQLA is used during pregnancy or if the patient becomes pregnant while on treatment, the patient must be informed of the potential hazard to the foetus; Breast-feeding: The safe use of FRUZAQLA during breast-feeding has not been established. It is not known whether FRUZAQLA or its metabolites are excreted in human milk. There are no animal data on the excretion of FRUZAQLA in animal milk. A risk to the breastfeeding newborns/infants cannot be excluded. Breastfeeding should be discontinued during treatment and for 2 weeks after the last dose; Fertility: There are no data on the effects of FRUZAQLA on human fertility. Results from animal studies indicate that FRUZAQLA may impair male and female fertility.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Hypertension: Hypertension, including hypertensive crisis, has been reported in patients treated with FRUZAQLA. Pre-existing hypertension should be monitored and adequately controlled in accordance with standard medical practices before starting FRUZAQLA treatment.

Hypertension should be medically managed with antihypertensive medicinal products and adjustment of the FRUZAQLA dose, if necessary. FRUZAQLA should be permanently discontinued for hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis.

Haemorrhagic events: Haemorrhagic events have been reported in patients treated with FRUZAQLA, including gastrointestinal (GI) tract events. Serious and sometimes fatal bleeding events have been reported in patients after treatment with FRUZAQLA.

Haematologic and coagulation profiles should be monitored in accordance with standard medical practices in patients at risk for bleeding, including those treated with anticoagulants or other concomitant medicinal products that increase the risk of bleeding. In the event of severe bleeding requiring immediate medical intervention, FRUZAQLA should be permanently discontinued.

Gastrointestinal perforation: GI perforation events, including fatal events, have been reported in patients treated with FRUZAQLA.

Symptoms of GI perforation should be periodically monitored during treatment with FRUZAQLA.

FRUZAQLA should be permanently discontinued in patients developing GI perforation.

Proteinuria: Proteinuria events have occurred in patients treated with FRUZAQLA.

Proteinuria should be monitored before initiation and during treatment with FRUZAQLA in accordance with standard medical practices. If urine dipstick proteinuria ≥ 2 g / 24 hours is detected, dose interruptions, adjustments, or discontinuation may be necessary. FRUZAQLA should be permanently discontinued in patients developing nephrotic syndrome.

Palmar-plantar erythrodysaesthesia syndrome (PPES): PPES is the most frequently reported dermatological adverse reaction.

If Grade ≥ 2 skin reactions are detected, dose interruptions, adjustments, or discontinuation may be necessary.

Posterior reversible encephalopathy syndrome (PRES): PRES has been reported in 1 patient (0.1%) treated with FRUZAQLA in clinical studies. PRES is a rare neurologic disorder that can present with headache, seizure, lethargy, confusion, altered mental function, blindness, and other visual or neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). In patients developing PRES, discontinuation of FRUZAQLA, along with control of hypertension and supportive medical management of other symptoms, are recommended.

Impaired wound healing: Impaired wound healing has been reported in 1 patient (0.1%) treated with FRUZAQLA in clinical studies

Patients are recommended to withhold FRUZAQLA for at least 2 weeks prior to surgery. FRUZAQLA should not be resumed for at least 2 weeks after surgery, as clinically indicated when there is evidence of adequate wound healing.

Arterial and venous thromboembolic events: It is recommended to avoid starting treatment with FRUZAQLA in patients with a history of thromboembolic events (including deep vein thrombosis and pulmonary embolism) within the past 6 months or if they have a history of stroke and/or transient ischemic attack within the last 12 months. If arterial thrombosis is suspected, FRUZAQLA should be discontinued immediately.

INTERACTIONS

Effects of other medicinal products on the pharmacokinetics of FRUZAQLA

CYP3A inducers

Co-administration of FRUZAQLA with rifampicin (a strong CYP3A inducer) 600 mg once daily decreased FRUZAQLA AUCinf by 65% and decreased Cmax by 12%. The concomitant use of FRUZAQLA with strong and moderate CYP3A inducers should be avoided.

CYP3A inhibitors

Co-administration of FRUZAQLA with itraconazole (a strong CYP3A inhibitor) 200 mg twice daily did not result in clinically meaningful changes in the area under the concentration-time curve (AUC) and Cmax of FRUZAQLA. No dose adjustment of FRUZAQLA is needed during concomitant use with CYP3A inhibitors.

Gastric acid lowering agents

Co-administration of FRUZAQLA with rabeprazole (a proton pump inhibitor) 40 mg once daily did not result in clinically meaningful changes in the AUC of FRUZAQLA. No dose adjustment of FRUZAQLA is needed during concomitant use with gastric acid lowering agents.

Effect of FRUZAQLA on the pharmacokinetics of other medicinal products

Medicinal products that are substrates of P-glycoprotein (P-gp)

Co-administration of a single dose of dabigatran etexilate 150 mg (a P-gp substrate) with a single dose of FRUZAQLA 5 mg decreased AUC of dabigatran by 9%. No dose adjustment is recommended for P-gp substrates during concomitant use with FRUZAQLA.

Medicinal products that are substrates of breast cancer resistance protein (BCRP)

Co-administration of a single 10 mg dose of rosuvastatin (a BCRP substrate) with a single 5 mg dose of FRUZAQLA decreased AUC of rosuvastatin by 19%. No dose adjustment is recommended for BCRP substrates during concomitant use with FRUZAQLA.

UNDESIRABLE EFFECTS: The most commonly reported adverse reactions with FRUZAQLA are:

• Very common (frequency ≥1/10): Thrombocytopenia, hypothyroidism, anorexia, hypertension, dysphonia, diarrhoea, stomatitis, aspartate aminotransferase increased, total bilirubin increased, alanine aminotransferase increased, palmar-plantar erythrodysaesthesia syndrome, musculoskeletal discomfort, arthralgia, proteinuria, asthenia, and fatigue

• Common (≥1/100 to <1/10): Pneumonia, upper respiratory tract infection, bacterial infections, leukopenia, neutropenia, hypokalemia, epistaxis, throat pain, gastrointestinal haemorrhage, gastrointestinal perforation, pancreatic enzymes increased, oral pain, rash, and mucosal inflammation

About CRC

CRC is a cancer that starts in either the colon or rectum. According to the International Agency for Research on Cancer, CRC is the third most prevalent cancer worldwide and was associated with more than 1.9 million new cases and 900,000 deaths in 2022. In Europe, CRC was the second most common cancer in 2022, with approximately 538,000 new cases and 248,000 deaths.4 In the U.S., it is estimated that 153,000 patients will be diagnosed with CRC and 53,000 deaths from the disease will occur in 2024.5 In Japan, CRC was the most common cancer in 2022, with more than 145,000 new cases and 60,000 deaths.4 Although early-stage CRC can be surgically resected, metastatic CRC remains an area of high unmet need with poor outcomes and limited treatment options. Some patients with metastatic CRC may benefit from personalized therapeutic strategies based on molecular characteristics; however, most patients have tumors that do not harbor actionable mutations.6,7,8,9,10

About the Phase 3 FRESCO-2 Trial

The FRESCO-2 study is a multi-regional clinical trial conducted in the U.S., Europe, Japan and Australia investigating FRUZAQLA plus BSC vs placebo plus BSC in patients with previously treated mCRC (NCT04322539). The study met all of its primary and key secondary endpoints, demonstrating that treatment with FRUZAQLA resulted in statistically significant and clinically meaningful improvement in OS and PFS. The safety profile of FRUZAQLA in FRESCO-2 was consistent with previously reported fruquintinib monotherapy studies. Results from the study were presented at ESMO in September 2022 and subsequently published in The Lancet in June 2023.11,3

About Takeda

Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit www.takeda.com.

Media Contacts:

Japanese Media

Jun Saito

jun.saito@takeda.com

U.S. and International Media

Emma Nash

emma.nash@takeda.com

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Medical Information

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References:

1. Takeda Pharmaceuticals. (2024 April 26). Takeda Receives Positive CHMP Opinion for Fruquintinib in Previously Treated Metastatic Colorectal Cancer [Press Release]. Available here.

2. Takeda Pharmaceuticals. (2023 November 8). Takeda Receives U.S. FDA Approval of FRUZAQLA™ (fruquintinib) for Previously Treated Metastatic Colorectal Cancer [Press Release]. Available here.

3. Dasari NA, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;402(10395):41-53. doi:10.1016/S0140-6736(23)00772-9.

4. Bray F, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 [online ahead of print]. doi: 10.3322/caac.21834

5. American Cancer Society. Cancer Facts & Figures 2024. Atlanta, American Cancer Society; 2024.

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