On September 25, 2023 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that it obtained regulatory approval from the Ministry of Health, Labour and Welfare for the humanized anti-human IL-6 receptor monoclonal antibody, "Actemra Intravenous Infusion 80 mg, 200 mg, and 400 mg" [generic name: tocilizumab (genetical recombination)] for an additional indication of treatment of cytokine release syndrome induced by cancer therapy (Press release, Chugai, SEP 25, 2023, View Source;category= [SID1234635359]). Actemra was approved for the indication of cytokine release syndrome induced by tumor-specific T-cell infusion therapy in March 2019. This additional indication will make it possible to administer the drug as an anti-cytokine therapy for cytokine release syndrome (CRS) in the cancer treatment other than tumor-specific T cell infusion therapy.

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"Cytokine release syndrome is one of the adverse reactions seen with cancer treatment and can be life-threatening if severe. It is significant to be able to make Actemra widely available as the first anti-cytokine therapy for cytokine release syndrome induced by any type of cancer therapy, not only for the already approved use during tumor-specific T cell infusion therapy," said Chugai’s President and CEO, Dr. Osamu Okuda. "We will promote the proper use of Actemra, so that it may support the smooth procedure of cancer treatment."

The approval was based on results of a Japanese phase I/II clinical study of epcoritamab (genetical recombination) in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma conducted by Genmab.

As a leading company in the field of oncology, Chugai is committed to advancing the proper use of Actemra so that it can contribute to the treatment of cytokine release syndrome induced by cancer therapy.

Approval Information *Changes are underlined
Indications:
Cytokine Release Syndrome (CRS) induced by cancer therapy
Dosage and administrations (No change from approved Dosage and Administration):
The recommended dose of tocilizumab (genetical recombination) is 8 mg/kg in patients weighing ≥30 kg and 12 mg/kg in patients weighing <30 kg, as a single intravenous drip infusion

[Reference Information]
Chugai Files for Additional Indication of Actemra for Cytokine Release Syndrome Induced by Cancer Treatment in Japan (Press release issued on February 28, 2023)
View Source

Chugai’s Actemra Intravenous Infusion Receives Approval for Additional Indication and Dosing for Cytokine Release Syndrome (Press release issued on March 26, 2019)
View Source

About Actemra
Actemra is the first therapeutic antibody created in Japan by Chugai. It is designed to block the activity of IL-6, a type of inflammatory cytokine. First launched in June 2005, the intravenous injection is approved for seven indications in Japan: Castleman’s disease, rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, cytokine release syndrome induced by cancer therapy, adult Still’s disease, and SARS-CoV-2 pneumonia. In addition, Actemra subcutaneous injection is approved for three indications in Japan: rheumatoid arthritis, Takayasu arteritis, and giant cell arteritis. Actemra has obtained regulatory approval in more than 110 countries worldwide.

About Cytokine Release Syndrome
Cytokine release syndrome (CRS) is induced by the release of high levels of cytokines associated with excessive immune response and results in an extreme elevation of cytokine concentration in the blood.1 CRS is an adverse reaction common in cancer treatment, including CAR-T cell therapy and some antibody drugs, and many patients show mild to moderate influenza-like symptoms (pyrexia, nausea and chills, myalgia, etc.). However, severe hypotension, tachycardia, dyspnea, and others may be induced in some patients, and the symptoms may progress rapidly and may lead to death.

On September 25, 2023 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that it has obtained regulatory approval today from the Ministry of Health, Labour and Welfare (MHLW) for Phesgo combination for Subcutaneous Injection MA, IN [generic name: pertuzumab (genetical recombination), trastuzumab (genetical recombination) and vorhyaluronidase alfa (genetical recombination) ] (hereafter, Phesgo), antineoplastic agent / anti-HER2 humanized monoclonal antibody for the treatment of "HER2-positive breast cancer" and "Advanced or recurrent HER2-positive colorectal cancer that has progressed following cancer chemotherapy and is not amenable to curative resection (Press release, Chugai, SEP 25, 2023, View Source;category= [SID1234635358])."

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"We are pleased to have obtained approval in Japan for Phesgo, a fixed-dose combination for subcutaneous use containing the same anti-HER2 agents of Perjeta and Herceptin, the standard therapy for HER2-positive breast cancer. Reducing administration time is expected to improve convenience for patients and reduce the burden on healthcare system and professionals. We are preparing for the launch of this drug so that it can be used for treatment as soon as possible," said Dr. Osamu Okuda, Chugai’s President and CEO.

This subcutaneous fixed-dose combination without preparation contains the same monoclonal antibodies as Perjeta and Herceptin, and also a vorhyaluronidase alfa (genetical recombination) combined in a single vial. It takes over eight minutes for a loading dose of Phesgo and over five minutes for the subsequent doses. By comparison, it takes 150 minutes for a sequential infusion of a loading dose of Perjeta and Herceptin using intravenous formulations (excluding follow-up observation), and 60-150* minutes for the subsequent maintenance dose infusions.1,2,3)

* Both drugs can be shortened to 30 minutes if the initial administration is well tolerated
This approval is based on the results of the global phase III FeDeriCa study including Japan and an overseas phase II PHranceSCa study. FeDeriCa study evaluated the pharmacokinetics, efficacy, and safety of Phesgo with patients with HER2-positive breast cancer. PHranceSCa study examined patient preference and satisfaction with subcutaneous administration of Phesgo in HER2-positive breast cancer. Chugai is responsible for the development of Phesgo in Japan and has been participating in FeDeriCa study.

The FeDeriCa study validated the non-inferiority (pharmacokinetics) of blood concentration of Perjeta between Phesgo and intravenous formulations of Perjeta and Herceptin (primary endpoint). The most common adverse events were alopecia (77% in the Phesgo group and 70% in the intravenous formulation group. The same order applies hereinafter), nausea (59%, 60%), diarrhea (58%, 55%), and anemia (34%, 41%) in the Phesgo group and the intravenous formulation group, respectively.4) In PHranceSCa study showed that 85% of patients (n=136/160) evaluated in the study preferred Phesgo, subcutaneous injection to the separate IV administration of Perjeta and Herceptin, citing less time in the clinic as the most common reason.5)

[Approval Information]

Product name: PHESGO combination for Subcutaneous Injection MA, IN

Generic name: pertuzumab (genetical recombination), trastuzumab (genetical recombination) and vorhyaluronidase alfa (genetical recombination)

Indications:

HER2-positive breast cancer
Advanced or recurrent HER2-positive colorectal cancer that has progressed following cancer chemotherapy and is not amenable to curative resection
Dosage and administration:
< HER2-positive breast cancer >
The usual adult dosage is an initial dose of 1200 mg, 600 mg, and 30000 U of pertuzumab (genetical recombination), trastuzumab (genetical recombination), and vorhyaluronidase alfa (genetical recombination), respectively, administered subcutaneously over 8 minutes, followed by 600 mg, 600 mg, and 20000 U of the second and subsequent doses over 5 minutes every 3 weeks thereafter, in combination with other antineoplastic agents. For neoadjuvant or adjuvant therapy, the duration of treatment should be up to 12 months.
< Advanced or recurrent HER2-positive colorectal cancer that has progressed following cancer chemotherapy and is not amenable to curative resection >
The usual adult dosage is an initial dose of 1200 mg, 600 mg, and 30000 U of pertuzumab (genetical recombination), trastuzumab (genetical recombination), and vorhyaluronidase alfa (genetical recombination), respectively, administered subcutaneously over 8 minutes, followed by 600 mg, 600 mg, and 20000 U of the second and subsequent doses over 5 minutes every 3 weeks thereafter.

[Reference]
Chugai Files New Drug Application in Japan for Fixed-Dose Subcutaneous Combination of Pertuzumab and Trastuzumab for HER2-Positive Breast and Colorectal Cancer (Press release issued on September 29, 2022)
View Source

About Phesgo (Pertuzumab, Trastuzumab and vorhyaluronidase alfa)
Phesgo, the fixed-dose subcutaneous combination contains the same monoclonal antibodies as Perjeta, Herceptin, and vorhyaluronidase alfa (genetical recombination) in a single vial. Hyaluronidase, an enzyme that breaks down hyaluronic acid, is considered to increase dispersion and absorption of the antibodies using Halozyme Therapeutics’ Enhanze drug delivery technology.6) The monoclonal antibodies in Phesgo are identical to those in Perjeta and Herceptin. The mechanisms of action of Perjeta and Herceptin are believed to complement each other as both bind to the HER2 receptor, but in different locations.7,8) The combination of Perjeta and Herceptin is thought to provide a more comprehensive, dual blockade of the HER signaling pathways.7,8)

About FeDeriCa study4)
FeDeriCa study is an international, multi-center, two-arm, randomized, open-label, phase III study evaluating the pharmacokinetics, efficacy and safety of subcutaneous injection of the fixed-dose combination of Perjeta and Herceptin in combination with chemotherapy, compared with standard intravenous infusions of Perjeta and Herceptin in combination with chemotherapy in 500 people with HER2-positive early breast cancer who are being treated in the neoadjuvant (before surgery) and adjuvant (after surgery) settings. The primary endpoint of the study is minimum levels of Perjeta in the blood during a given dosing interval (Ctrough). Secondary endpoints include safety; minimum levels of Herceptin in the blood during a given dosing interval (Ctrough); and pathological complete response (pCR) in the breast and axilla.

About PHranceSCa study5)
PHranceSCa study is an overseas phase II randomized clinical study to evaluate patient preference and satisfaction for the fixed-dose combination of Perjeta and Herceptin for subcutaneous injection in 160 patients with HER2-positive early breast cancer. The primary endpoint is patient’s preference for this drug based on responses to the Patient Preference Questionnaire (PPQ). Secondary endpoints include patient satisfaction with this drug and Perjeta and Herceptin intravenous formulations as measured by the Therapy Administration Satisfaction Questionnaire (TASQ), and patient’s selection of this drug during continued treatment.

On September 25, 2023 Novartis reported plans for the 100% Spin-off of the Sandoz business, with trading of new Sandoz Group AG shares and ADRs (American Depositary Receipts) to commence on October 4, 2023 (Press release, Novartis, SEP 25, 2023, View Source [SID1234635357]).

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This follows the previously announced Novartis shareholder approval for the Spin-off of Sandoz, at the EGM on September 15 2023. In addition, key regulatory approvals have been obtained, including the approval by SIX Exchange Regulation for the listing of the Sandoz shares on the SIX Swiss Exchange (subject to technical deliveries only).

The shares of Sandoz are expected to be listed and traded from October 4, 2023 on the SIX Swiss Exchange with the symbol "SDZ". Sandoz will be included in the Swiss Performance Index (SPI), Swiss Leader Index (SLI) and other relevant Swiss indices following completion of the Spin-off, as announced by the SIX Swiss Exchange. Sandoz ADRs are envisaged to be traded on the OTCQX, with the symbol to be available shortly before the Spin-off date.

Key ratings agencies have confirmed Sandoz’ credit rating will be investment grade following the Spin-off, placing the company in a strong position among its peers. Moody’s Investors Service and S&P Global Ratings have rated Sandoz Baa2 and BBB, respectively.

Sandoz has secured debt financing of USD 3.75 billion (in various currencies) through a group of banks which will also support Sandoz with a revolving credit facility of USD 1.25 billion to serve as an undrawn backstop facility.

The Spin-off will be completed via distribution of a dividend-in-kind by Novartis, which is expected to occur on October 4, 2023. Each Novartis shareholder will receive one Sandoz share for every five Novartis shares and each Novartis ADR holder will receive one Sandoz ADR for every five Novartis ADRs. Novartis shareholders and ADR holders will receive a cash amount for any fractional interest. The Spin-off is expected to be tax neutral for Swiss tax and US federal income tax purposes.

The listing prospectus of Sandoz and any supplements thereto can be accessed through the following links:

Click here (www.sandoz.com/prospectus) to access the Listing Prospectus,
Click here (www.sandoz.com/sandoz-spin) to access the supplements to the Listing Prospectus and other related documents.
Additional Transaction Details

Completion of the proposed Spin-off is subject to satisfaction of certain conditions, including no event outside of the control of Novartis preventing the Spin-off and no material adverse change. There can be no assurance regarding the ultimate timing of the proposed transaction or that the transaction will be completed.

On September 25, 2023 4SC AG (4SC, FSE Prime Standard: VSC), a biotech company improving the lives of patients suffering with advanced-stage CTCL, reported that renowned dermato-oncology expert and study investigator, Professor Dr. Rudolf Stadler, University Hospital Johannes Wesling, Minden, Germany, presented positive new data from the pivotal RESMAN study of resminostat (Kinselby) at the EORTC Cutaneous Lymphoma Tumour Group Annual Meeting, at the Leiden University Medical Center Amsterdam, The Netherlands, 21-23 September (Press release, 4SC, SEP 25, 2023, View Source [SID1234635356]).

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The presented findings show that maintenance therapy is now clinically proven to postpone disease progression in advanced CTCL which could significantly change clinical practice. In RESMAIN, one of the largest randomized, controlled clinical trials in advanced CTCL, resminostat (Kinselby) treatment has shown a statistically significant improvement in progression free survival of 97.6% compared to placebo, with a risk reduction of 38% in recently announced headline trial results (median PFS: 8.3 months versus 4.2 months; p=0.015; HR: 0.623 (95%CI: 0.424, 0.916).

Furthermore, resminostat (Kinselby)’s median time to next treatment (median TTNT) versus placebo showed a significant improvement of 8.8 months compared to 4.2 months; p= 0.002; HR: 0.594 (95% CI: 0.424, 0.916).

The side effects of resminostat were mainly mild to moderate, manageable and reversible and the known safety profile of resminostat (Kinselby) was confirmed in the RESMAIN study.

Additional analyses established that those treated showed a clinically meaningful improvement in median "total" PFS (defined from start of last prior therapy to disease progression) of 24.3 months, compared to 14.9 months for those in the placebo group. It was also noted that there was a significant delay in the development of new, or worsening of existing, skin tumours.

Jason Loveridge, Ph.D., CEO of 4SC, commented: "Positive data from the RESMAIN study demonstrate that resminostat (Kinselby) is effective in significantly slowing disease progression in CTCL patients. This unique treatment, which is the only proven maintenance therapy for CTCL, means that it is well placed to offer significant benefits for patients who would otherwise have no other similar treatment options available to them.

Our focus in the near term is on the registration, approval and commercialization of Kinselby in the European Union, Switzerland and the UK and we are on track to file for European Marketing Approval of Kinselby in Q1 2024, to rapidly bring this therapy into clinical use. 4SC is well positioned for realization of resminostat (Kinselby)’s considerable value through either a sale, licensing, or partnership agreement."

The Company will host a live webinar on Wednesday 4th October to discuss the findings presented at EORTC. Dr. Susanne Danhauser-Riedl, 4SC’s Chief Medical Officer, will be joined by medical experts, Professor Dr. Rudolf Stadler and Professor Julia Scarisbrick, who will provide further detail on these data, with the presentation being followed by the opportunity to ask questions during a Q&A session moderated by Dr. Jason Loveridge, 4SC’s Chief Executive Officer.

Title: Presentation by Professor Rudolf Stadler and Professor Julia Scarisbrick on recent new positive data from the RESMAIN study

Date and Time: Wednesday 4th October, 3.00pm CET

Register and submit questions: View Source

On September 25, 2023 Novartis reported that the Phase III NETTER-2 trial with Lutathera (INN: lutetium (177Lu) oxodotreotide / USAN: lutetium Lu 177 dotatate) met its primary endpoint (Press release, Novartis, SEP 25, 2023, View Source [SID1234635353]). First line treatment with Lutathera in combination with long-acting octreotide demonstrated a significant improvement in progression-free survival (PFS) in patients with newly diagnosed somatostatin receptor (SSTR)-positive, Grade 2 and 3, advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) versus high-dose long-acting octreotide alone1,2. No new or unexpected safety findings were observed in the study and data are consistent with the already well-established safety profile of Lutathera1-4.

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NETs are a type of cancer that originate in neuroendocrine cells throughout the body and are commonly considered slow-growing malignancies. However, some NETs are associated with rapid progression and poor prognosis and in many cases, diagnosis is delayed until patients have advanced disease5-7. Even though NETs are a rare (orphan) disease, their incidence has grown over 500% in the last three decades5-8 and there is an urgent need for additional treatment options for patients newly diagnosed with inoperable or advanced disease.

With these results, NETTER-2 is Lutathera’s second Phase III trial showing clinically meaningful results for patients2,4. The approval of Lutathera was originally based on the pivotal NETTER-1 trial, which demonstrated highly significant and clinically meaningful PFS prolongation for patients treated with Lutathera in combination with long-acting octreotide versus high-dose (60 mg) long-acting octreotide for SSTR-positive, inoperable midgut neuroendocrine tumors (NETs) who were progressing despite standard treatment3-4,9.

"These positive results for Lutathera are quite remarkable and they represent the potential for radioligand therapy to make a meaningful impact for newly diagnosed patients living with advanced GEP-NETs," said Jeff Legos, Executive Vice President, Global Head of Oncology Development at Novartis. "Exploring the use of radioligand therapies in earlier lines of treatment for patients with cancer is part of our larger, collaborative effort to precisely deliver novel treatment modalities directly to the cancer cells to improve patient outcomes."

The findings from NETTER-2 will be presented at an upcoming medical meeting and discussed with regulatory authorities.

About NETTER-2
NETTER-2 (NCT03972488) is an open-label, multi-center, randomized, comparator-controlled Phase III trial assessing whether Lutathera plus long-acting octreotide when taken as a first line treatment can prolong PFS in patients with high-proliferation rate tumors (G2 and G3), compared to treatment with high-dose (60 mg) long-acting octreotide2. Eligible patients were diagnosed with SSTR-positive advanced GEP-NETs within 6 months before enrollment2.

About Lutathera
Lutathera (INN: lutetium (177Lu) oxodotreotide / USAN: lutetium Lu 177 dotatate) is an Advanced Accelerator Applications RLT approved in the United States for the treatment of SSTR-positive GEP-NETs, including foregut, midgut and hindgut neuroendocrine tumors in adults and in Europe for unresectable or metastatic, progressive, well-differentiated (G1 and G2), SSTR-positive GEP-NETs in adults.