On May 8, 2021 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and AstraZeneca reported that New data from datopotamab deruxtecan (Dato-DXd), a TROP2 directed DXd antibody drug conjugate (ADC), showed preliminary response and disease control in patients with metastatic triple negative breast cancer (TNBC) with disease progression following standard treatment (Press release, Daiichi Sankyo, MAY 8, 2021, View Source [SID1234579499]).

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These preliminary data from the TNBC cohort of the TROPION-PanTumor01 phase 1 study were presented as a late-breaking mini oral presentation (Abstract #LBA4) at the 2021 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Breast Cancer Virtual Congress (#ESMOBreast21).

TNBC accounts for approximately 10 to 15% of breast cancer cases and is associated with higher disease recurrence and worse prognosis compared to other breast cancer subtypes.1,2,3 It is estimated that only 12.2% of patients with metastatic TNBC survive five years and median overall survival is generally less than two years.2,3

The preliminary objective response rate (ORR), assessed by blinded independent central review, was 43% in 21 evaluable patients treated with datopotamab deruxtecan [6 mg/kg (n=19) or 8 mg/kg (n=2)]. Five confirmed complete or partial responses (CR/PRs) were seen, with four additional CR/PRs awaiting confirmation at the time of data cut-off of January 8, 2021. A disease control rate of 95% was observed.

"There are currently limited treatment options for patients with previously treated metastatic triple negative breast cancer, historically a very difficult-to-treat subtype of breast cancer," said Aditya Bardia, MD, MPH, Director of Breast Cancer Research, Mass General Cancer Center, Harvard Medical School. "These initial safety and efficacy results of datopotamab deruxtecan in patients with triple negative breast cancer are encouraging and warrant further development for patients with breast cancer."

The safety profile of datopotamab deruxtecan seen in the TNBC cohort is consistent with safety that has been previously reported in the non-small cell lung cancer (NSCLC) cohort of TROPION-PanTumor01. No patients discontinued treatment due to adverse events (AEs); however, dose reductions due to AEs occurred in six patients (25%) and were most commonly due to stomatitis (13%) and mucosal inflammation (8%). Grade 3 or higher treatment emergent adverse events (TEAEs) regardless of causality occurred in 33% of patients. TEAEs grade 3 or higher included stomatitis (13%), fatigue (4%) and anemia (4%) with no grade 3 or higher TEAEs of diarrhea or neutropenia. The most common TEAEs overall in ≥25% of patients were stomatitis, nausea, fatigue, vomiting, and alopecia. No cases adjudicated as drug-related interstitial lung disease (ILD) were observed.

"These preliminary results provide proof-of-concept that targeting TROP2 with datopotamab deruxtecan may be an effective treatment strategy for patients with previously treated metastatic triple negative breast cancer," said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo. "We are encouraged by the early tumor responses and disease control seen in these patients and we will continue to explore the potential of datopotamab deruxtecan in several types of breast cancer, including triple negative breast cancer."

"Triple negative breast cancer is known to be particularly aggressive and fast growing, and after treatment the risk of recurrence is faster and higher than in any other breast cancer subgroup," said Cristian Massacesi, Senior Vice President, Head of Late Stage Development Oncology R&D, AstraZeneca. "The preliminary results for datopotamab deruxtecan in this cohort of pretreated patients are encouraging for this high-potential targeted ADC."

Patients were treated with a median of four prior lines of therapy (range, 1-9, including prior lines of therapy in the [neo]adjuvant or metastatic setting) with a majority (88%) receiving more than two previous lines of treatment, including a taxane (83%), platinum-based chemotherapy (50%), immunotherapy (33%), sacituzumab govitecan (8%) and a PARP inhibitor (4%). As of data cut-off on January 8, 2021, 75% of patients remained on treatment with datopotamab deruxtecan.

Summary of TROPION-PanTumor01 Results

Efficacy Measure

Total Evaluable in TNBC Cohort (N=21)i, ii

ORR, %iii, iv

43% (n=9)

CR/PR (confirmed)

n=5

CR/PR (pending confirmation)

n=4

DCR, %v

95% (n=20)

PD, %

5% (n=1)

CR, complete response; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PR, partial response

i Includes response evaluable patients who had ≥1 postbaseline tumor assessment or discontinued treatment. Postbaseline tumor assessments were not yet available for 3 patients at the data cutoff. One patient was not confirmed to have a target lesion per BICR and therefore had a best overall response of non-CR/non-PD.

ii Includes 2 patients that received 8 mg/kg datopotamab deruxtecan prior to selection of the 6-mg/kg dose for dose expansion.

iii Includes patients with a best overall response of CR, PR, stable disease, or non-CR/non-PD.

iv ORR is CR+PR; Responses are confirmed (CRs/PRs; n=5) plus those ongoing CRs/PRs too early to be confirmed (n=4).

v DCR is CR+PR+SD.

About TROPION-PanTumor01
TROPION-PanTumor01 is a first-in-human, open-label, two-part, multicenter phase 1 trial designed to evaluate the safety, tolerability and preliminary efficacy of datopotamab deruxtecan in patients with advanced solid tumors refractory to or relapsed from standard treatment or for whom no standard treatment is available, including NSCLC, TNBC and hormone receptor positive (HR+) breast cancer.

The dose escalation part of the study assessed the safety and tolerability of increasing doses of datopotamab deruxtecan to determine the maximum tolerated dose and/or recommended dose for expansion in patients with unresectable advanced NSCLC. The dose expansion part of the study further assessed the safety and tolerability of datopotamab deruxtecan at selected dose levels (4 mg/kg, 6 mg/kg and 8 mg/kg) in patients with NSCLC. Based on the preliminary efficacy and safety, the 6 mg/kg dose has been identified as the recommended dose for the NSCLC cohort.

The TNBC cohort was added in July 2020 and is currently evaluating patients with metastatic TNBC receiving datopotamab deruxtecan (6 mg/kg) with disease relapse or progression with standard treatment. The HR positive/HER2 negative cohort was added in March 2021 and is currently evaluating patients with metastatic HR positive/HER2 negative breast cancer receiving datopotamab deruxtecan (6 mg/kg) with disease relapse or progression with standard treatment.

Safety endpoints include dose limiting toxicities and serious adverse events. Efficacy endpoints include ORR, DCR, duration of response, time to response, progression-free survival and overall survival. Pharmacokinetic, biomarker and immunogenicity endpoints also are being evaluated.

About TROP2 in Triple Negative Breast Cancer
TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein that is overexpressed in several types of solid tumors, including breast cancer.4 Research indicates that high TROP2 expression is associated with cancer cell growth and proliferation and poor patient survival.4,5 While TROP2 is expressed across all breast cancer subtypes, it is overexpressed in approximately 80% of patients with TNBC, making it a promising molecular target for therapeutic development.5

Approximately 10 to 15% of patients with breast cancer are considered triple negative because the tumors test negative for estrogen, progesterone hormone receptors (HRs) and human epidermal growth factor 2 receptor (HER2).1,2,6 An estimated 260,000 new cases of TNBC were reported globally in 2018 with it being more common in younger women and those who are Black.1,2,7 Compared to patients with other breast cancer subtypes, prognosis for patients with metastatic TNBC is generally worse and the disease is more likely to recur following treatment with initial chemotherapy.1,3 Five-year survival of metastatic TNBC is estimated at 12.2% and median overall survival is generally less than two years.2,3

About Datopotamab Deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is a TROP2 directed antibody drug conjugate (ADC). Designed using Daiichi Sankyo’s proprietary DXd ADC technology, datopotamab deruxtecan is one of three lead ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform.

A comprehensive development program called TROPION is underway globally with trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple solid tumors, including NSCLC, TNBC and HR+ breast cancer. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

About the Daiichi Sankyo and AstraZeneca Collaboration
Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize datopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of datopotamab deruxtecan.

On May 8, 2021 Daiichi Sankyo and partner AstraZeneca reported that next-gen antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) has show glimmers of efficacy and a reasonable safety profile in its first data release in breast cancer (Press release, AstraZeneca, MAY 8, 2021, https://www.fiercebiotech.com/biotech/daiichi-sankyo-astrazeneca-s-5b-enhertu-follow-up-shows-early-signs-success-breast-cancer [SID1234579494]).

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Having already seen some positives in its non-small cell lung cancer test, which is further along, Daiichi and AstraZeneca published the first look at Dato-DXd in triple-negative breast cancer (TNBC) at a late-breaking mini oral presentation at the 2021 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Breast Cancer Virtual Congress conference Saturday.

Nearly one year ago, AZ agreed to pay $1 billion upfront over two years for ex-Japan rights to the drug, which works as an ADC that targets tumor-associated protein TROP2, plus another $5 billion in milestones.

The drug combines an antibody targeting TROP2 that’s conjugated using a stable linker with a potent topoisomerase I inhibitor payload. It has a lower drug-to-antibody ratio that Daiichi suggests should both boost cell-killing activity and limit side effects.

The deal for the drug was after the success of AZ’s $6.9 billion deal for Enhertu (trastuzumab deruxtecan) from Daiichi, penned back in 2019. Within a few months of AZ coming on board, that drug was approved for patients with previously treated HER2-positive breast and gastric cancer. Dato-DXd will not be matching that record, but its TNBC data out over the weekend have the Japanese pharma optimistic about its future.

The data are still early, just a phase 1 and in only 21 patients, and Daiichi was keen to stress that there is a far way to go show just how well its drug workscu and how safe it will be in a larger patient population.

But in an early peek, the TNBC cohort of the TROPION-PanTumor01 phase 1 trial saw an objective response rate, assessed by blinded independent central review, hit 43% in 21 evaluable patients treated with Dato-DXd.

Five confirmed complete or partial responses were also seen, with four additional CR/PRs awaiting confirmation at the time of data cutoff on Jan. 8, 2021. A disease control rate of 95% was also observed.

RELATED: Gilead splashes out $21B for Immmunomedics, keeping the pedal on new target weeks after AZ-Daiichi deal

No p-values have yet been assigned, but this favors well (with the many cross-trial comparison caveats abound) with what will likely be its main rival, Gilead/Immunomedics’ Trodelvy (sacituzumab govitecan-hziy), an antibody and topoisomerase inhibitor conjugate directed to the TROP-2 receptor, which has, among others, FDA approval in TNBC that has spread.

At ESMO (Free ESMO Whitepaper) 2020, Trodelvy showed an ORR of 35%, though this was a phase 3 with more patients, and it also saw overall survival with a median of 12.1 months versus 6.7 months for chemo. Future trials for Daiichi’s drug will look to assess its survival potential, a key weapon it will need for any approval, but the company saw reasons to be cheerful about its prospects from these data.

On the safety side there had been concerns about drug-related interstitial lung disease, which had been noted by analysts as being seen in earlier trials. Daiichi said no such ILD cases were seen in this test, though Gilles Gallant, Ph.D., senior vice president and global head, oncology development, oncology R&D at Daiichi, told Fierce Biotech that they could not say for sure that this was not an issue, and future trials are needed to find that answer.

It did see less instances of severe diarrhea than are usual with the tech it uses, though six patients did have to have dose reductions because of adverse events. Daiichi said that these were most commonly due to stomatitis (13%) and mucosal inflammation (8%). Grade 3 or higher treatment emergent adverse events, regardless of cause, occurred in 33% of patients. The most common adverse events overall were stomatitis, nausea, fatigue, vomiting, and alopecia. No-one left the test due to adverse events, however.

Gallant, who was cautious about the trial simply because of how early it is and the small number of patients, does believe the drug is best-in-class in terms of its construct which differs from the likes of Trodelvy.

On May 7, 2021 OCI reported thet the company has decided to invest in Panolos Bioscience, a domestic bio venture company with anticancer drug candidates and multifunctional recombinant protein technology (Press release, Panolos Bioscience, MAY 7, 2021, View Source [SID1234633686]).

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On the same day, OCI announced on the 26th that it had signed an investment contract worth 5 billion won with Panolos Bioscience. "Through this strategic partnership, we will be able to secure expertise in the field of anticancer drugs," said OCI President Kim Taek-joong.

Panolos Bioscience is developing new biological therapeutics by utilizing αARTTM (Anti-angiogenesis-based Artifact Re-targeting Tri-specifics platform), a multi-specific drug generation platform. OCI explained that it is a platform that can reduce the side effects of single-target protein therapeutics and has excellent potential for expanding new drug pipelines through multiple targeting.

”PB101”, a next-generation anti-cancer drug candidate based on the αART platform, is a candidate for all types of Vascular Endothelial Growth Factor (VEGF)2, which is excessively produced around cancer cells (VEGF-A, VEGF-B, Placental Growth Factor). factor) to inhibit the growth of cancer cells.

Unlike conventional VEGF-inhibiting drugs that target only a portion of VEGF, it blocks all delivery pathways to reduce drug resistance and increase efficacy. PB101 is currently in the state of development of a process capable of mass production. Panolos Biosciences aims to start preclinical 3 in May and enter phase 1 clinical trial in 2022.

On May 7, 2021 Defence Therapeutics Inc. ("Defence" or the "Company"), a Canadian biotech Company focused on the development of novel and highly specific vaccines and antibody-drug conjugates targeting cancer and infectious diseases reported that it begin its trading on the CSE as of today

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The primary objective and business of Defence is the research, development and advancement of three main products using its proprietary Accum technology:
– Dendritic Cell (DC) cancer vaccines using Accum (AccuvacTM).
– A new protein-based vaccine formulation against COVID and infectious disease.
– ADCs (Antibody Drug Conjugates) targeting various cancer.

AccuvacTM: for Dendritic Cell cancer vaccines
Defence has optimized the chemical manufacturing of its experimental antigens to efficiently link the Accum moiety. When used to pulse DCs, these modified antigens were shown to breakdown endosomal membranes leading to efficient processing, presentation and activation of responding T cells. The prophylactic vaccination led to 100% protection against cancer growth. This process was rechallenged three times and led to a continue 100% protection against cancerous tumor growth.

Therapeutic vaccination of animals with pre-established tumors triggered a substantial delay in tumor growth as a stand-alone therapy. Combination of AccuvacTM to the immune-checkpoint inhibitor anti-PD1 cured 70% of treated animals.

To build upon this success, Defence is developing second and third generation Accum moieties to further enhance the potency and the efficacy of the AccuvacTM.
Defence has engineered two Accum variants with direct anti-tumoral effects. The results of the Accum variants displayed efficiency at killing melanoma, lymphoma, colon and breast cancer cells in vitro. In vivo studies are currently ongoing to test the intratumoral delivery of these variants as a means to induce regression of established tumors.

A COVID Vaccine
Defence is using the Accum technology to develop a distinct COVID-19 protein-based vaccine. So far, the vaccine is highly immunogenic in tests with rodent animals with antibody titers lasting for more than 16 weeks. In addition, the generated antibodies "neutralized" the ability of pseudotyped viruses (an artificial virus with COVID-19 S proteins) from infecting cells. Defence is currently preparing the initiation of IND-enabling studies while preparing to begin the Phase I trial.

Antibody Drug Conjugates
Defence has demonstrated that the Accum technology enhances the ability of the ADC Kadcyla (T-DM1) to specifically target and kill breast cancer cells. Defence completed the synthesis of 18 different Accum-variants conjugated to T-DM1 at 10X ratio. A toxicity screening will be performed in the near future on the selected breast cancer cell line to identify additional leads. A Phase 1 clinical trial for breast cancer is currently being prepared.

On May 7, 2021 Luye Pharma Group announced that its biopharmaceutical drug 博优诺 (Bevacizumab Injection), developed by the Group’s holding subsidiary Boan Biotech, has received marketing authorization from China’s National Medical Products Administration (NMPA), for the treatment of advanced, metastatic or recurrent non-small-cell lung cancer (NSCLC), and metastatic colorectal cancer (Press release, Luye Pharma, MAY 7, 2021, View Source [SID1234597708]). 博优诺 is the third biosimilar of Avastin to enter the market in China, as well as the first product from Boan Biotech’s pipeline to receive marketing authorization.

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博优诺 and Avastin are Equivalent in Efficacy – Bevacizumab is a Standard Therapy for the Treatment of Multiple Cancers

The marketing approval for 博优诺 is based on the Guidelines on Similarity Evaluation and Indication Extrapolation of Biosimilars issued by the NMPA’s China Center for Drug Evaluation in February 2021. 博优诺 and Avastin were compared head-to-head in two pivotal clinical studies – the first was a pharmacokinetic(PK) study among healthy subjects, and the second was a comparative study of efficacy and safety in metastatic or recurrent non-squamous NSCLC patients. Both studies met primary endpoints, demonstrating that 博优诺 and Avastin are equivalent in efficacy and highly similar in terms of PK characteristics, safety, and immunogenicity.

As a classic anti-angiogenic oncology drug, Bevacizumab is considered standard therapy and is recommended by a number of guidelines worldwide for treating multiple malignant tumors. The drug is indicated for the treatment of NSCLC, metastatic colorectal cancer, glioblastoma, renal cell carcinoma, cervical cancer, ovarian cancer, and other solid tumors worldwide, with its efficacy and safety widely recognized by physicians and patients through its long-term clinical use. According to the Guidelines on Similarity Evaluation and Indication Extrapolation of Biosimilars, all indications for Avastin approved in China can also be gradually applied to 博优诺.

In addition, the combination of Bevacizumab and paclitaxel provides unique advantages in treatment. 博优诺 can be used with Luye Pharma’s core product paclitaxel liposome injection (Lipusu) to achieve a good synergy effect.

Preparing to Market 博优诺 – Meeting Patient Needs

According to data from the World Health Organization’s International Agency for Research on Cancer, the number of new cancer cases reported in 2020 in China was 4.57 million, the highest in the year and accounting for 23.7% of the total in the world. Lung cancer and colorectal cancer are the two cancers with the highest incidence rate in China, with 820 thousand and 560 thousand new cases each, respectively. Based on the high and ever-increasing number of patients in these two disease areas, the approval of 博优诺 is expected to help patients gain access to high-quality medication and address unmet needs.

Meanwhile, Bevacizumab Injection has been included in China’s National Reimbursement Drug List, further increasing accessibility. As the third biosimilar of Avastin to enter Chinese market, 博优诺 is expected to have optimistic prospects. According to the data from IQVIA, global sales of Bevacizumab Injection totaled USD 6.09 billion, with sales in China accounting for RMB 3.63 billion in 2020.

Through comprehensive leverage of its expertise along the whole industry value chain, Boan Biotech has been active in the preparation for 博优诺 entering the market, in manufacturing, sales team building, market access channels, and other areas. In addition, Luye Pharma Group’s long-term accumulated resources and expansive networks in the field of oncology are also expected to bring synergetic effects to enable the success of 博优诺.

Boan Biotech’s Rapid R&D Pipeline Development – Efficiency in Innovation

Boan Biotech’s antibody discovery research is based on three technology platforms: Human Antibody Transgenic Mouse and Phage Display Technology, Bispecific T-cell Engager Technology, and ADC Technology. By leveraging its efficient and innovative capabilities, the company has developed more than 10 innovative antibody product candidates with international intellectual property protection, and 8 biosimilar products including 博优诺 .

"We are delighted to see 博优诺 become the first product from Boan Biotech’s pipeline approved for marketing, and hope it will bring benefit to patients in need of high-quality and affordable anti-angiogenic treatment." said Jiang Hua, Chief Executive Officer of Boan Biotech, "The approval of 博优诺 is an important milestone for us and validates our efforts in the field with a tangible and substantial payoff. Focusing on the development of biopharmaceuticals, we hope to further accelerate R&D progress with more innovative products, serving more patients in China and around the globe."

In addition to 博优诺, Boan Biotech has a series of biopharmaceutical products in various stages of clinical development, including LY-CovMab, an innovative antibody for the treatment of COVID-19, which has completed phase I clinical trial in China and is soon to start the phase II clinical trials in China, the U.S. and Europe. Other Boan Biotech biosimilar products are expected to bear fruit in the near future. Phase III clinical trials in China for LY06006 (a biosimilar of Prolia) are nearing completion, with final administration of the drug completed for all the subjects, and the drug already receiving approval for clinical trials in Europe and the U.S. LY01011 (A biosimilar of Xgeva) is undergoing phase III clinical trials in China and phase I clinical trials in Europe and the U.S., and LY09004, a biosimilar of Eylea is also undergoing phase III clinical trials in China.