C4X Discovery Holdings and AstraZeneca Signs Exclusive USD 402 Million Global License

C4X Discovery Holdings has signed an exclusive global license with AstraZeneca worth up to USD 402 million for the development and commercialization of the NRF2 Activator program. The agreement will allow AstraZeneca to develop and market an oral therapy for the treatment of inflammatory and respiratory diseases, with a primary focus on chronic obstructive pulmonary disease (COPD).

COPD is the third leading cause of death in the world, accounting for 3.23 million deaths in 2019. However, it is a preventable and treatable chronic lung disease that affects both men and women worldwide. Abnormalities in the lungs’ small airways cause narrowing, limiting airflow in and out of the lungs, and visible destruction of parts of the lung may be observed. Smoking is a major contributor to COPD.

This is CDXD’s third significant deal with a major pharma, and it further validates its scientific expertise and strategy. The company will be eligible for USD 16 million in upfront and pre-clinical payments ahead of the first clinical trial, including USD 2 million upfront, as well as a potential USD 385.8 million in clinical development and commercial milestones, as well as tiered mid-single digit royalties upon commercialization.

Sir Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca said: “At AstraZeneca, we are committed to transforming care in respiratory and immune-mediated disease and move beyond symptom control. Our alliance with C4XD adds an important new asset to our portfolio to push the boundaries of science by targeting underlying disease drivers to potentially modify the course of these diseases.”

Dr Clive Dix, CEO of C4XD, added: “Drug Discovery is inherently scientifically complex, and it is through our unique expertise and proprietary cutting-edge technologies that C4XD is yet again proving itself as an exemplar in this field.  NRF2 is thought to be a critical but challenging anti-inflammatory target, and I am proud of the work by our team to achieve a broad stable of intellectual property for this programme, leading to our third significant deal with a truly world-renowned industry leader.  The COPD market alone is worth close to USD 20 billion and rising. But, more importantly, I know that in AstraZeneca’s hands, with their scientific, technical and commercial expertise, our NRF2 Activator programme has the potential to deliver life changing treatments for the millions of patients suffering with COPD across the world.”

FDA Rejects Spectrum’s Poziotinib for Lung Cancer

Hanmi Pharma, a South Korean company that developed the drug initially, reported that the FDA has sent Spectrum Pharma a complete response letter (CRL) for poziotinib, its pan-HER2 inhibitor for a type of lung cancer. Due to the time difference with the US and the fact that the CRL was disclosed during the US Thanksgiving holiday, Hanmi was the first to report the FDA’s rejection of the marketing application, according to a Korea Biomedical Review report. Hanmi also wanted to avoid any “unnecessary misunderstandings” regarding the timing of the disclosure.

Spectrum is expected to make an announcement later today, but the CRL has been widely anticipated, given that the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 9 to 4 against poziotinib approval in September, stating that the benefits outweigh the risks. Spectrum sought accelerated approval for poziotinib as a second-line treatment for patients with HER2 exon 20 insertion-mutated non-small cell lung cancer (NSCLC), but the FDA was unconvinced by the data presented in support of the drug in phase II.

In review documents released ahead of the ODAC meeting, the agency expressed concerns about the drug’s marginal efficacy in clinical trials, high toxicity rates, and concerns about the dose chosen for study. The objective response rate (ORR) in the phase II ZENITH20 study was 28%, with a median duration of response of around 5 months, and 12% of patients had to discontinue therapy due to side effects.

The FDA began its standard 10-month review of poziotinib in February, with the PDUFA deadline for a decision falling directly on the Thanksgiving holiday. It also expressed concern about a delay in starting a confirmatory trial of the drug, known as PINNACLE, which had yet to enroll any patients at the time.

Spectrum has since reported positive results with poziotinib as a first-line treatment for HER2 exon 20 insertion-mutated NSCLC, an aggressive form of lung cancer with no approved treatments. Spectrum acquired the global rights to poziotinib from Hanmi in 2015, excluding Korea and China.

FDA Issues Complete Response Letter to Poziotinib for Metastatic NSCLC Harboring HER2 Exon 20 Mutations

FDA’s Oncologic Drugs Advisory Committee (ODAC) has issued a complete response letter to poziotinib which couldn’t secure approval for the treatment of metastatic non-small cell lung cancer (NSCLC) harboring HER2 exon 20 mutations, which was licensed out to the U.S. partner Spectrum Pharmaceuticals. Hanmi Pharmaceutical confirmed its disapproval after ODAC voted 9-4, stating that the current benefits of the drug did not outweigh its risks. 

HER2 exon 20 insertion mutations have shown to be oncogenic trigger gene mutations in metastatic NSCLC. ODAC is an individual department of experts that review and evaluate the safety and efficacy data of oncological drugs existing in clinical trial stages. The committee further reports to FDA; however, the finalized decisions are made by FDA. Further, FDA will take charge of the final decisions by 24th November, as per the Prescription Drug User Fee Act (PDUFA).

“We are disappointed by the outcome of the ODAC meeting, as patients with NSCLC HER2 exon 20 insertion mutations are in need of additional effective and safe therapies. We plan to carefully evaluate our options for this program as we approach the PDUFA date,” said Tom Riga, president, and CEO of Spectrum Pharmaceuticals, in a statement. The recommendations of ODAC were followed by an unfavourable statement from the FDA scientist session where most of the reviews about the drug poziotinib were negative and followed by comments such as the drug wasn’t able to deliver meaningful advantage over available therapies and requires an additional analysis. Also, the safety profile of the drug was very weak providing only 28 percent of overall response rate (ORR). 

Japan Approves Trastuzumab Deruxtecan for Previously Treated HER2+ Metastatic Breast Cancer

Japan’s Ministry of Health, Labor, and Welfare (MHLW) approved fam-trastuzumab deruxtecan (Enhertu) for previously treated HER2 harbouring metastatic breast cancer. The approval came after the data from phase 3  DESTINY-Breast03 trial where trastuzumab deruxtecan showed reduction in the risk of disease progression and death rate by 72% as compared to the data obtained by ado-trastuzumab emtansine. The median progression-free survival (PFS) for patients treated with trastuzumab deruxtecan was unachieved, whereas PFS for T-DM1 was 6.8 months. 

“We are proud of the quality and speed in which we were able to deliver a confirmatory phase 3 trial that demonstrated the superiority of [trastuzumab deruxtecan] in prolonging PFS compared to T-DM1 in patients with previously treated HER2 positive metastatic breast cancer,” Wataru Takasaki, PhD, executive officer, head of R&D Division in Japan, Daiichi Sankyo, stated in a press release. “This approval by the MHLW highlights the importance of the conditional approval system in Japan that allows for early approval of medicines to treat serious conditions such as breast cancer.”

Japan approved trastuzumab deruxtecan back in March 2020 for the treatment of HER2-positive unresectable or recurrent breast cancer after prior chemotherapy. However, it limited its use to  patients who are refractory or intolerant to standard treatments. The previous approval was based on findings from the phase 2 DESTINY-Breast01 trial.

Previously, AstraZeneca and Daiichi Sankyo Company, Limited confirmed that their drug Trastuzumab was approved for reviewing the Biologics License Application (BLA) by US FDA and was granted Priority Review. Trastuzumab deruxtecan is a HER2-targeting antibody drug conjugate (ADC) and a potent drug candidate or treating HER2-positive metastatic breast cancer. The date for Prescription Drug User Fee Act (PDUFA) for trastuzumab deruxtecan. The Prescription Drug User Fee Act (PDUFA) date for trastuzumab deruxtecan, a HER2-targeting antibody drug conjugate (ADC) and potential new medicine for the treatment of HER2-positive metastatic breast cancer, was set for the second quarter of 2020.

EC Approves Regeneron’s Libtayo for Advanced Cervical Cancer

On November 22, 2022, Regeneron Pharmaceuticals, Inc. announced that the European Commission (EC) had approved Libtayo® (cemiplimab) as monotherapy for the treatment of adult patients with recurrent or metastatic cervical cancer and disease progression on or after platinum-based chemotherapy. The European Commission (EC) approval of Libtayo was based on global EMPOWER-Cervical 1 trial results demonstrating 12 months overall median survival (OS) for the overall patient population.

The trial was conducted in association with GOG Foundation, Inc. (GOG), the European Network for Gynaecological Oncological Trial groups (ENGOT), and NRG Oncology-Japan. EMPOWER-Cervical 1 was an open-label, multi-center Phase 3 trial evaluating Libtayo monotherapy versus an investigator’s choice of commonly used chemotherapy in patients with recurrent or metastatic cervical cancer who had progressed on platinum-based chemotherapy. The trial evaluated Libtayo compared to an investigator’s choice of chemotherapy and enrolled 608 patients across 14 countries, irrespective of PD-L1 expression status or histology. 

Earlier, in March 2021, the trial was stopped early based on the highly significant effect of Libtayo on overall survival (OS) among squamous cell carcinoma (SCC) patients following a unanimous recommendation by the Independent Data Monitoring Committee.

Dr. Israel Lowy, Senior Vice President, Translational and Clinical Sciences of Oncology at Regeneron, stated that “Libtayo® was the first programmed cell death protein (PD)-1 inhibitor to demonstrate significant improvements in survival compared to chemotherapy in a Phase III trial. With this fourth approval from the EC, Libtayo® can now be extended to appropriate patients in the European Union (EU) with advanced cervical cancer, irrespective of their PD-L1 status or histology”.

Cervical cancer is one of the prominent causes of cancer death in women worldwide. As per the estimate, about 600,000 new Cervical cancer cases are registered yearly, and nearly 350,000 lost their lives due to it.  “Despite recent advancements in the prevention and treatment of cervical cancer, there remain limited options for people with recurrent or metastatic cases,” said Israel Lowy. However, with the approval of Libtayo, the advanced cervical cancer treatment scenario is expected to evolve immensely in the coming years. 

FDA Starts Speedy Review of Takeda’s Dengue Vaccine

On November 22, 2022, Takeda announced that the US FDA had accepted and granted priority review of the Biologics License Application (BLA) for TAK-003. Takeda’s tetravalent dengue vaccine candidate (TAK-003) is an investigational dengue vaccine candidate. TAK-003 is based on a live-attenuated dengue serotype 2 virus, which provides the genetic “backbone” for all four vaccine viruses. In the phase 2 clinical trial, TAK-003 induced immune responses against all four dengue serotypes, in both seropositive and seronegative participants in children and adolescents. 

The TAK-003 BLA is supported by safety and efficacy data from the pivotal Phase 3 Tetravalent Immunization against Dengue Efficacy Study (TIDES) trial, where the dengue vaccine candidate met its primary endpoint by preventing 80.2% of symptomatic dengue cases at 12 months. TAK-003 is being evaluated in the US for the prevention of dengue disease caused by any dengue virus serotype in individuals 4 years through 60 years of age. Currently, TAK-003 has not been approved by the FDA or any other health authority outside of Indonesia. Gary Dubin, M.D., president of the Global Vaccine Business Unit at Takeda, stated that “If approved, we believe TAK-003 has the potential to become an important dengue prevention option for healthcare providers, and we continue to be encouraged by our discussions with the FDA,”. 

Earlier in October 2022, the CHMP of the European Medicines Agency (EMA) recommended the approval of Takeda’s dengue vaccine candidate, TAK-003, for the prevention of dengue disease caused by any serotype in individuals four years of age and older in Europe.  Dengue fever, also known as breakbone fever, is a mosquito-borne virus endemic in more than 125 countries. It is caused by four dengue viruses spread by the Aedes aegypti mosquito. As per the CDC, nearly 400 million cases of dengue fever occur across the globe every year. Dengue can lead to the severity of muscle spasms and joint pain, dandy fever, or seven-day fever because of the usual duration of symptoms. It is observed that the incidence of dengue has increased globally over the past two decades and is a leading cause of fever among travelers returning from Latin America, the Caribbean, and Southeast Asia.