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Patritumab Deruxtecan BLA Submission Receives Complete Response Letter from FDA Due to Inspection Findings at Third-Party Manufacturer

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The FDA issued a Complete Response Letter (CRL) for the Biologics License Application (BLA) of patritumab deruxtecan, developed by Daiichi Sankyo and Merck (MRK). This drug aims to treat adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who have been treated with at least two systemic therapies.

The CRL arose from inspection findings at a third-party manufacturing facility, not from issues with the drug's efficacy or safety data.

Patritumab deruxtecan showed promising results in the HERTHENA-Lung01 phase 2 trial with an objective response rate of 29.8% and a median duration of response of 6.4 months. The safety profile was consistent with previous trials, although there were some significant treatment-emergent adverse events (TEAEs).

Daiichi Sankyo and Merck are committed to resolving the manufacturing issues and bringing this first-in-class HER3-directed medicine to patients with treatment options.

Positive
  • Patritumab deruxtecan demonstrated an objective response rate (ORR) of 29.8% in the HERTHENA-Lung01 phase 2 trial.
  • The median duration of response (DoR) was 6.4 months.
  • No issues were identified with the efficacy or safety data submitted.
Negative
  • The FDA issued a Complete Response Letter (CRL) due to inspection findings at a third-party manufacturing facility.
  • 64.9% of patients experienced grade 3 or higher treatment-emergent adverse events (TEAEs).
  • 12 patients had confirmed treatment-related interstitial lung disease (ILD), with one grade 5 ILD event observed.

The FDA's Complete Response Letter (CRL) for patritumab deruxtecan, due to issues with a third-party manufacturer's inspection, raises significant concerns for stakeholders. While the drug's safety and efficacy data are intact, the manufacturing compliance issue might delay the drug's market entry. Such FDA letters can set back approval timelines by several months or even years, affecting potential revenue streams and patient access to new treatments.

Interestingly, patritumab deruxtecan demonstrated a notable objective response rate (ORR) of 29.8%, with cases of complete and partial responses. However, the median duration of response (DoR) of just 6.4 months shows that while the drug is effective, its benefits might be short-lived for some patients.

The occurrence of treatment-emergent adverse events (TEAEs) and serious TEAEs (Grade 3 or higher in 64.9% of cases) highlights the drug's potential side effects, including significant conditions like thrombocytopenia and neutropenia. These factors could weigh heavily on the drug's risk-benefit profile.

Such safety profiles are common in oncology and the discontinuation rate of 7.1% due to TEAEs aligns with expectations. Still, investors should watch closely for any long-term impacts of these adverse events, particularly for conditions like interstitial lung disease (ILD).

The issuance of a CRL to patritumab deruxtecan due to third-party manufacturing issues represents a potential financial setback for Daiichi Sankyo and Merck. Generally, CRLs can result in monetary losses due to the added costs for rectification and the delayed entry into the market, which in turn delays revenue generation.

From a financial perspective, the news might discourage short-term investors due to the uncertainty surrounding the resolution of manufacturing compliance. Long-term investors, however, might consider the overall potential of the drug in addressing a significant unmet medical need for previously-treated EGFR-mutated non-small cell lung cancer.

One bright spot is that the underlying efficacy and safety data were not questioned, indicating that the primary investment thesis surrounding the drug's $revenue potential remains intact. For Merck and Daiichi Sankyo, the next steps involve resolving the manufacturing issues, which could involve significant capital expenditure but potentially solidify their market position long-term.

Investors should also consider the competitive landscape and regulatory environment. Any delays could allow competitors to gain ground, impacting potential market share upon eventual approval.

The CRL for patritumab deruxtecan affects its market entry timeline, delaying its potential influence in the oncology drug market. This could have substantial ramifications, especially considering the drug's target audience—patients with EGFR-mutated non-small cell lung cancer who have already undergone multiple treatments.

This drug is aimed at a niche yet significant market segment, where treatment options are limited. Any delays here may impact the perceived reliability of Daiichi Sankyo and Merck in delivering innovative oncology solutions efficiently. It's essential for these companies to maintain strong relationships with both the FDA and their third-party manufacturers to avoid future setbacks.

Given the CRL, the competitive landscape might shift. Companies like AstraZeneca and Roche, who are also developing treatments for similar conditions, could capitalize on these delays. Timely resolution of these issues is important for maintaining competitive advantage.

  • The letter did not identify any issues with the efficacy or safety data submitted in the application

BASKING RIDGE, N.J. & RAHWAY, N.J.--(BUSINESS WIRE)-- The U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) for the Biologics License Application (BLA) seeking accelerated approval of Daiichi Sankyo (TSE: 4568) and Merck’s (known as MSD outside of the United States and Canada) (NYSE: MRK) patritumab deruxtecan (HER3-DXd) for the treatment of adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) previously treated with two or more systemic therapies.

The CRL results from findings pertaining to an inspection of a third-party manufacturing facility. The CRL did not identify any issues with the efficacy or safety data submitted.

Patritumab deruxtecan is a specifically engineered potential first-in-class HER3 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed by Daiichi Sankyo and Merck.

“We will work closely with the FDA and the third-party manufacturer to address the feedback as quickly as possible in order to bring the first HER3 directed medicine to patients with previously-treated EGFR-mutated non-small cell lung cancer,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “We remain confident in the ability to develop this medicine to its full potential.”

“Patients with previously treated EGFR-mutated non-small cell lung cancer often experience recurrence and have limited treatment options,” said Marjorie Green, MD, Senior Vice President and Head of Oncology, Global Clinical Development, Merck Research Laboratories. “We are committed to working with Daiichi Sankyo and the FDA to prioritize bringing patritumab deruxtecan to these patients in need.”

The BLA is based on the primary results from the HERTHENA-Lung01 pivotal phase 2 trial that were presented at the IASLC 2023 World Conference on Lung Cancer (#WCLC23) and simultaneously published in the Journal of Clinical Oncology.

In HERTHENA-Lung01, patritumab deruxtecan was studied in 225 patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression with an EGFR TKI and platinum-based chemotherapy, which demonstrated an objective response rate (ORR) of 29.8% (95% CI: 23.9-36.2), including one complete response and 66 partial responses. The median duration of response (DoR) was 6.4 months (95% CI: 4.9-7.8).

The safety profile of patritumab deruxtecan observed in HERTHENA-Lung01 was consistent with previous phase 1 clinical trials in NSCLC with a treatment discontinuation rate of 7.1% due to treatment-emergent adverse events (TEAEs). Grade 3 or higher TEAEs occurred in 64.9% of patients. The most common (≥5%) grade 3 or higher TEAEs were thrombocytopenia (21%), neutropenia (19%), anemia (14%), leukopenia (10%), fatigue (6%), hypokalemia (5%) and asthenia (5%). Twelve patients (5.3%) had confirmed treatment-related interstitial lung disease (ILD) as determined by an independent adjudication committee. One grade 5 ILD event was observed.

About HERTHENA-Lung01
HERTHENA-Lung01 is a global, multicenter, open-label, two-arm phase 2 trial evaluating the safety and efficacy of patritumab deruxtecan in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression with an EGFR TKI and platinum-based chemotherapy. Patients were randomized 1:1 to receive 5.6 mg/kg (n=225) or an uptitration regimen (n=50). The uptitration arm was discontinued as the dose of 5.6 mg/kg of patritumab deruxtecan was selected following a risk-benefit analysis conducted from the phase 1 trial assessing the doses in a similar patient population.

The primary endpoint of HERTHENA-Lung01 was ORR as assessed by blinded independent central review (BICR). Secondary endpoints included DoR, progression-free survival, disease control rate, and time to response – all assessed by both BICR and investigator assessment – as well as investigator-assessed ORR, overall survival, safety and tolerability.

HERTHENA-Lung01 enrolled patients in Asia, Europe, North America and Oceania. For more information about the trial, visit ClinicalTrials.gov.

About EGFR-Mutated Non-Small Cell Lung Cancer
Approximately 226,000 lung cancer cases were diagnosed in the U.S. in 2022.1 Lung cancer is the third most common cancer and the leading cause of cancer-related deaths in the U.S.1 NSCLC accounts for approximately 81% of all lung cancers in the U.S., with 52% having distant spread at diagnosis.2,3 EGFR mutations occur in approximately one in five patients with NSCLC in Western populations.4

About HER3
HER3 is a member of the EGFR family of receptor tyrosine kinases.5 It is estimated that about 83% of primary NSCLC tumors and 90% of advanced EGFR-mutated tumors express HER3 after prior EGFR TKI treatment.6,7 HER3 is associated with poor treatment outcomes, including shorter relapse-free survival and significantly reduced survival.8,9 There is currently no HER3 directed therapy approved for the treatment of any cancer.

About Patritumab Deruxtecan
Patritumab deruxtecan (HER3-DXd) is an investigational HER3 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, patritumab deruxtecan is composed of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Patritumab deruxtecan was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration in December 2021 for the treatment of patients with EGFR-mutated locally advanced or metastatic NSCLC with disease progression on or after treatment with a third-generation TKI and platinum-based therapies.

Patritumab deruxtecan is currently being evaluated as both a monotherapy and in combination with other therapies in a global development program, which includes HERTHENA-Lung02, a phase 3 trial evaluating the efficacy and safety of patritumab deruxtecan versus platinum-based chemotherapy in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression on or after treatment with a third-generation EGFR TKI; HERTHENA-Lung01, a phase 2 trial in metastatic or locally advanced NSCLC with an activating EGFR mutation previously treated with at least one EGFR TKI and one platinum-based chemotherapy-containing regimen; HERTHENA-PanTumor01, a phase 2 trial in locally advanced or metastatic solid tumors, including melanoma, gastric and head and neck cancer, among other types of cancer, previously treated with at least one prior systemic therapy; a phase 1 trial in combination with osimertinib in EGFR-mutated locally advanced or metastatic NSCLC; and a phase 1 trial in previously treated patients with advanced NSCLC. A phase 1/2 trial in HER3 expressing metastatic breast cancer also has been completed.

About the Daiichi Sankyo and Merck Collaboration
Daiichi Sankyo and Merck entered into a global collaboration in October 2023 to jointly develop and commercialize patritumab deruxtecan (HER3-DXd), ifinatamab deruxtecan (I-DXd) and raludotatug deruxtecan (R-DXd), except in Japan where Daiichi Sankyo will maintain exclusive rights. Daiichi Sankyo will be solely responsible for manufacturing and supply.

About the DXd ADC Portfolio of Daiichi Sankyo
The DXd ADC portfolio of Daiichi Sankyo currently consists of six ADCs in clinical development across multiple types of cancer. ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.

Designed using Daiichi Sankyo’s proprietary DXd ADC Technology to target and deliver a cytotoxic payload inside cancer cells that express a specific cell surface antigen, each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan and DS-3939 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo
Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical needs. For more information, please visit www.daiichisankyo.com.

Merck’s Focus on Cancer
Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www.merck.com/research/oncology/.

About Merck
At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA
This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

_______________________________
References:
1 World Health Organization. International Agency for Research on Cancer. U.S. Cancer Fact Sheet. Accessed June 2024.
2 American Society of Clinical Oncology. Lung Cancer – Non-Small Cell: Statistics. Accessed June 2024.
3 SEER. Adenocarcinoma of the Lung and Bronchus Stage Distribution of SEER Incidence Cases. 2012-2021. Accessed June 2024.
4 Tan AC, et al. J Clin Oncol. 2022;40(6):611-625.
5 Mishra R, et al. Onco Rev. 2018; 12(355):45-62.
6 Scharpenseel H, et al. Scientific Reports. 2019; 9:7406.
7 Yonesaka K, et al. Clin Cancer Res. 2022; 15:28(2):390-403.
8 Gandullo-Sánchez L et al. J Exp Clin Cancer Res. 2022; 41:310.
9 Yu H.A., et al. Annals of Oncology. 2024; 35(5): P437-447.

Daiichi Sankyo

Global/US Media:

Jennifer Brennan

Daiichi Sankyo, Inc.

jennifer.brennan@daiichisankyo.com

+1 908 900 3183 (mobile)

Japan Media:

DS-PR@daiichisankyo.co.jp



Investor Relations Contact:

DaiichiSankyoIR@daiichisankyo.co.jp

Merck

Media:

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julie.cunningham@merck.com



Nikki Lupinacci

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Investors:

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Damini Chokshi

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Source: Daiichi Sankyo

FAQ

Why did the FDA issue a Complete Response Letter for patritumab deruxtecan?

The FDA issued a Complete Response Letter due to inspection findings at a third-party manufacturing facility, not because of issues with the drug's efficacy or safety data.

What is patritumab deruxtecan designed to treat?

Patritumab deruxtecan is designed to treat adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who have been previously treated with at least two systemic therapies.

What were the results of the HERTHENA-Lung01 trial for patritumab deruxtecan?

The HERTHENA-Lung01 trial showed an objective response rate of 29.8% and a median duration of response of 6.4 months for patritumab deruxtecan.

What are the next steps for Merck and Daiichi Sankyo regarding patritumab deruxtecan?

Merck and Daiichi Sankyo plan to work closely with the FDA and the third-party manufacturer to address the inspection findings and aim to bring patritumab deruxtecan to patients as soon as possible.

What are the significant adverse events observed in the HERTHENA-Lung01 trial?

Significant adverse events included grade 3 or higher thrombocytopenia (21%), neutropenia (19%), anemia (14%), and interstitial lung disease (ILD), with one grade 5 ILD event observed.

Merck & Co., Inc.

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