Takeda Receives Positive CHMP Opinion for Fruquintinib in Previously Treated Metastatic Colorectal Cancer

Rhea-AI Summary

Takeda (NYSE:TAK) has received a positive recommendation from the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) for the approval of fruquintinib, a targeted therapy for previously treated metastatic colorectal cancer (mCRC). If approved by the European Commission, fruquintinib will be a novel treatment in the EU, highlighting its status as the first therapy to inhibit all three vascular endothelial growth factor receptors (VEGFR-1, -2, -3) for mCRC in over a decade. The therapy showed significant improvements in overall survival and progression-free survival in Phase 3 FRESCO-2 trials compared to the current standard care.

Fruquintinib's potential impacts are substantial, offering a new chemotherapy-free option that improves patient outcomes. It has already been approved in the U.S. under the brand name FRUZAQLA® as of November 2023, and launched in China in 2018 as ELUNATE®. Key safety information includes risks such as hypertension, hemorrhagic events, infections, and hepatotoxicity among others.

Positive

• Fruquintinib demonstrated significant improvements in overall survival and progression-free survival in mCRC patients compared to placebo in the multi-regional FRESCO-2 Phase 3 trial.
• The therapy offers a novel chemotherapy-free option, meeting a substantial unmet need for patients with previously treated mCRC.
• Fruquintinib features selective inhibition that allows high drug exposure and sustained target inhibition, potentially enhancing treatment efficacy in combination therapies.

Negative

• 20% of patients treated with fruquintinib discontinued treatment due to adverse reactions.
• Risk of severe side effects, including hypertension (49% incidence), hemorrhagic events, and gastrointestinal perforation, which must be closely monitored.
• Fruquintinib’s approval in the EU is still pending final decision from the European Commission, implying uncertainty in market availability and potential delays.

Insights

Medical Research Analyst

The positive opinion from the CHMP regarding Takeda's fruquintinib can be dissected from a medical research standpoint. Fruquintinib acts as an inhibitor for VEGF receptors, which are significant in tumor angiogenesis. Disruption of VEGF pathways impedes tumor growth by cutting the blood supply. This particular therapeutic stance is pivotal, given that colorectal cancer is the third most common cancer globally. The FRESCO-2 trial's significance lies in its Phase 3 status, indicating a substantial progression in clinical research, with demonstrated improvements in overall survival and progression-free survival. As safety is paramount, the manageable profile and comparable discontinuation rates with placebo highlight a favorable risk-benefit ratio. Investors should note the potential market expansion given the drug's novelty and the high incidence of metastatic colorectal cancer. The long-term outlook might include market dominance if further post-marketing studies confirm the Phase 3 results and if competitors do not introduce superior treatments.

Financial Analyst

The impending decision by the European Commission, guided by CHMP's endorsement, could open significant market opportunities for Takeda in the EU. A focus on financial implications reveals that the approval of fruquintinib could bolster Takeda's revenue streams, especially since the drug targets a broad patient demographic regardless of biomarker status. There is a notable scarcity of treatment options for mCRC, positioning fruquintinib as a potentially preferred choice among oncologists. For investors, an approval could mean an uptick in Takeda's share value driven by the drug's market exclusivity and first-mover advantage. However, one should consider the investment in post-marketing surveillance and potential competition, which could impact long-term profitability. The market's reaction will depend on the EC's final decision and the subsequent ability of Takeda to effectively commercialize fruquintinib across the European market.

Oncology Market Analyst

From an oncology market perspective, the relevance of fruquintinib lies in its potential to become a staple in mCRC treatment protocols. Its clinical profile suggests it might address a significant unmet need, which translates to high market demand. If we look at the broader picture, advancements in cancer therapies often lead to premium pricing, which in turn could affect insurance formularies and healthcare expenditures. It's important for investors to monitor how fruquintinib is positioned within the competitive landscape and how it is adopted by healthcare providers. Early adoption can be an indicator of the drug's future market capture and its solo status as a VEGF receptor inhibitor for mCRC could allow for price resilience against future competitive pressures. Additionally, the drug's oral administration offers a convenience factor that could play a role in patient preference and adherence, potentially influencing market share.

− If Approved in the European Union, Fruquintinib Will Be the First Novel Targeted Therapy for Metastatic Colorectal Cancer Regardless of Biomarker Status in Over a Decade

− Positive Opinion Based on Results from a Phase 3 Clinical Trial Which Demonstrated Significant Improvements in Overall Survival and Progression Free Survival versus Placebo Plus Best Supportive Care, with Benefit Seen Regardless of Prior Types of Therapy Received

OSAKA, Japan & CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Takeda (TSE:4502/NYSE:TAK) today announced that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of fruquintinib, a selective inhibitor of vascular endothelial growth factor receptors (VEGFR) -1, -2 and -3 for the treatment of adult patients with previously treated metastatic colorectal cancer (mCRC). The European Commission (EC) will consider the CHMP positive opinion when determining the potential marketing authorization for fruquintinib for mCRC throughout the European Union (EU), Norway, Liechtenstein and Iceland. If approved, fruquintinib will be the first and only selective inhibitor of all three VEGF receptors approved in the EU for previously treated mCRC.^1,2

“People living with metastatic colorectal cancer in the European Union currently have limited treatment options, which can lead to poor outcomes. With this positive opinion for fruquintinib, we are one step closer to potentially offering patients a new, oral, chemotherapy-free option that may provide a survival benefit,” said Awny Farajallah, M.D., chief medical officer, oncology at Takeda. “We look forward to the European Commission’s official decision in the near future as we work to redefine the treatment landscape and help address a significant unmet need for those affected by mCRC.”

The Committee’s positive opinion was primarily based on results from the Phase 3 multi-regional FRESCO-2 trial. The trial investigated fruquintinib 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 fruquintinib, regardless of the prior types of therapies they received. Fruquintinib demonstrated a manageable safety profile in FRESCO-2. Adverse reactions leading to treatment discontinuation occurred in 20% of patients treated with fruquintinib plus BSC versus 21% of those treated with placebo plus BSC. Data from FRESCO-2 were published in The Lancet in June 2023.³

About Fruquintinib

Fruquintinib is a selective oral inhibitor of VEGFR -1, -2 and -3. VEGFR inhibitors play a pivotal role in blocking tumor angiogenesis. Fruquintinib 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. Fruquintinib was approved by the U.S. Food and Drug Administration (FDA) in November 2023 and is marketed under the brand name FRUZAQLA^®. 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^®.

U.S. IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

• Hypertension occurred in 49% of 911 patients with mCRC treated with FRUZAQLA, including Grade 3-4 events in 19%, and hypertensive crisis in three patients (0.3%). Do not initiate FRUZAQLA unless blood pressure is adequately controlled. Monitor blood pressure weekly for the first month and at least monthly thereafter as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue FRUZAQLA based on severity of hypertension.
• Hemorrhagic Events including serious, fatal events can occur with FRUZAQLA. In 911 patients with mCRC treated with FRUZAQLA, 6% of patients experienced gastrointestinal hemorrhage, including 1% with a Grade ≥3 event and 2 patients with fatal hemorrhages. Permanently discontinue FRUZAQLA in patients with severe or life-threatening hemorrhage. Monitor the International Normalized Ratio (INR) levels in patients receiving anticoagulants.
• Infections. FRUZAQLA can increase the risk of infections, including fatal infections. In 911 patients with mCRC treated with FRUZAQLA, the most common infections were urinary tract infections (6.8%), upper respiratory tract infections (3.2%) and pneumonia (2.5%); fatal infections included pneumonia (0.4%), sepsis (0.2%), bacterial infection (0.1%), lower respiratory tract infection (0.1%), and septic shock (0.1%). Withhold FRUZAQLA for Grade 3 or 4 infections, or worsening infection of any grade. Resume FRUZAQLA at the same dose when the infection has resolved.
• Gastrointestinal Perforation occurred in patients treated with FRUZAQLA. In 911 patients with mCRC treated with FRUZAQLA, 1.3% experienced a Grade ≥3 gastrointestinal perforation, including one fatal event. Permanently discontinue FRUZAQLA in patients who develop gastrointestinal perforation or fistula.
• Hepatotoxicity. FRUZAQLA can cause liver injury. In 911 patients with mCRC treated with FRUZAQLA, 48% experienced increased ALT or AST, including Grade ≥3 events in 5%, and fatal events in 0.2% of patients. Monitor liver function tests (ALT, AST, and bilirubin) before initiation and periodically throughout treatment with FRUZAQLA. Temporarily hold and then reduce or permanently discontinue FRUZAQLA depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests.
• Proteinuria. FRUZAQLA can cause proteinuria. In 911 patients with mCRC treated with FRUZAQLA, 36% experienced proteinuria and 2.5% of patients experienced Grade ≥3 events. Monitor for proteinuria before initiation and periodically throughout treatment with FRUZAQLA. For proteinuria ≥2g/24 hours, withhold FRUZAQLA until improvement to ≤Grade 1 proteinuria and resume FRUZAQLA at a reduced dose. Discontinue FRUZAQLA in patients who develop nephrotic syndrome.
• Palmar-Plantar Erythrodysesthesia (PPE) occurred in 35% of 911 patients treated with FRUZAQLA, including 8% with Grade 3 events. Based on severity of PPE, withhold FRUZAQLA and then resume at the same or reduced dose.
• Posterior Reversible Encephalopathy Syndrome (PRES), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one of 911 patients treated with FRUZAQLA. Perform an evaluation for PRES in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue FRUZAQLA in patients who develop PRES.
• Impaired Wound Healing. In 911 patients with mCRC treated with FRUZAQLA, 1 patient experienced a Grade 2 event of wound dehiscence. Do not administer FRUZAQLA for at least 2 weeks prior to major surgery. Do not administer FRUZAQLA for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of FRUZAQLA after resolution of wound healing complications has not been established.
• Arterial Thromboembolic Events. In 911 patients with mCRC treated with FRUZAQLA, 0.8% of patients experienced an arterial thromboembolic event. Initiation of FRUZAQLA in patients with a recent history of thromboembolic events should be carefully considered. In patients who develop arterial thromboembolism, discontinue FRUZAQLA.
• Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) and No. 6 (Sunset Yellow FCF). FRUZAQLA 1 mg capsules contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. FRUZAQLA 1 mg contains FD&C Yellow No. 6 (sunset yellow FCF), which may cause allergic reactions.
• Embryo-Fetal Toxicity. Based on findings in animal studies and its mechanism of action, FRUZAQLA can cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of childbearing potential and males with female partners of childbearing potential to use effective contraception during treatment with FRUZAQLA and for 2 weeks after the last dose.

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥20%) following treatment with FRUZAQLA included hypertension, palmar-plantar erythrodysesthesia (hand-foot skin reactions), proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia.

DRUG INTERACTIONS: Avoid concomitant administration of FRUZAQLA with strong or moderate CYP3A inducers.

USE IN SPECIFIC POPULATIONS

• Lactation: Advise women not to breastfeed during treatment with FRUZAQLA and for 2 weeks after the last dose.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-662-8532 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see FRUZAQLA (fruquintinib) full Prescribing Information

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, associated with more than 935,000 deaths in 2020. In Europe, CRC was the second most common cancer in 2020, with approximately 520,000 new cases and 245,000 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, with an estimated 148,000 new cases and 60,000 deaths, in 2020.⁴ 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 fruquintinib plus BSC vs placebo plus BSC in patients with previously treated mCRC (NCT04322539). The study met all its primary and key secondary endpoints, demonstrating that treatment with fruquintinib resulted in statistically significant and clinically meaningful improvement in OS and PFS. The safety profile of fruquintinib in FRESCO-2 was consistent with previously reported fruquintinib studies. Results from the study were presented at ESMO in September 2022 and subsequently published in The Lancet in June 2023.^11,3

The Phase 3 FRESCO-2 trial supported the marketing authorization application (MAA) from the EMA for fruquintinib, which was validated and accepted for review in June 2023.

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.

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Medical Information

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References:

1. Xu X, et al. Efficacy and safety of regorafenib and fruquintinib as third-line treatment for colorectal cancer: a narrative review. Transl Cancer Res 2022;11(1):276-287. doi: 10.21037/tcr-20-3539.
2. Sun Q, et al. (2014) Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy, Cancer Biol Ther. 2014 15:12, 1635-1645. Doi: 10.4161/15384047.2014.964087.
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. Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660.
5. American Cancer Society. Cancer Facts & Figures 2024. Atlanta, American Cancer Society; 2024.
6. Bando H, et al. Therapeutic landscape and future direction of metastatic colorectal cancer. Nat Rev Gastroenterol Hepatol 2023; 20(5)306-322. doi:10.1038/s41575-022-00736-1.
7. D'Haene N, et al. Clinical application of targeted next-generation sequencing for colorectal cancer patients: a multicentric Belgian experience. Oncotarget. 2018;9(29):20761-20768. Published 2018 Apr 17. doi:10.18632/oncotarget.25099.
8. Venderbosch, et al. Mismatch repair status and braf mutation status in metastatic colorectal cancer patients: A pooled analysis of the Cairo, Cairo2, coin, and Focus Studies. Clinical Cancer Res.,2014; 20(20):5322–5330. doi:10.1158/1078-0432.ccr-14-0332.
9. Koopman, M., et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer. 209;100(2), 266–273. doi:10.1038/sj.bjc.6604867.
10. Ahcene Djaballah S, et al. HER2 in Colorectal Cancer: The Long and Winding Road From Negative Predictive Factor to Positive Actionable Target. Am Soc Clin Oncol Educ Book. 2022;42:1-14. doi:10.1200/EDBK_351354.
11. Dasari NA, et al. LBA25 – FRESCO-2: A global phase 3 multiregional clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Ann Oncol. 2022 Sep;33(suppl_7): S808-S869. Doi:10.1016/annonc/annonc1089.

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Media:

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Jun Saito

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U.S. and International Media

Emma Nash

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Source: Takeda Pharmaceutical Company Limited

FAQ

What is the potential impact of fruquintinib approval for TAK in the EU?

The approval of fruquintinib would mark it as the first novel targeted therapy for previously treated metastatic colorectal cancer in the EU in over a decade, potentially fulfilling a significant unmet medical need and extending Takeda's oncology portfolio in the region.

What were the trial results for TAK's fruquintinib in treating mCRC?

The FRESCO-2 Phase 3 trial results showed that fruquintinib significantly improved overall survival and progression-free survival in patients with previously treated metastatic colorectal cancer compared to placebo plus best supportive care.

What are the major safety concerns associated with TAK's fruquintinib?

Major safety concerns for fruquintinib include a high risk of hypertension, serious hemorrhagic events, infections, gastrointestinal perforation, and hepatotoxicity. Regular monitoring and appropriate management are recommended for patients on this therapy.