On May 11, 2020 AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo)’s Enhertu (trastuzumab deruxtecan) reported that it has been granted Breakthrough Therapy Designation (BTD) in the US for the treatment of patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more prior regimens including trastuzumab (Press release, AstraZeneca, MAY 11, 2020, View Source [SID1234557441]).

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Gastric cancer is the third leading cause of cancer mortality with a five-year survival rate of 5% for metastatic disease.1,2 Approximately one in five gastric cancers are considered HER2 positive.3,4

The Food and Drug Administration’s (FDA) BTD is designed to accelerate the development and regulatory review of potential new medicines that are intended to treat a serious condition and address a significant unmet medical need. The new medicine needs to have shown encouraging early clinical results that demonstrate substantial improvement on a clinically significant endpoint over available medicines.

José Baselga, Executive Vice President, R&D Oncology, said: "Current therapy options are limited for patients with HER2-positive metastatic gastric cancer and for those who relapse, there are no approved HER2-targeted medicines. We look forward to working with the FDA to further explore the potential of Enhertu to become an important new treatment and the first antibody drug conjugate for this devastating disease."

Gilles Gallant, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo, said: "DESTINY-Gastric01 represents the first randomised trial of Enhertu to demonstrate clinically meaningful and statistically significant results, including objective response and survival increases compared to physician’s choice of chemotherapy. We are thrilled that the FDA has granted Enhertu a second Breakthrough Therapy Designation."

The FDA granted BTD based on data from the registrational Phase II DESTINY-Gastric01 trial and data from the Phase I trial published in The Lancet Oncology.5,6 In DESTINY-Gastric01, patients treated with Enhertu, a HER2-directed antibody drug conjugate (ADC), demonstrated a statistically significant and clinically meaningful improvement in objective response rate (ORR), the primary endpoint, and overall survival (OS), a key secondary endpoint, versus patients treated with investigator’s choice of chemotherapy (irinotecan or paclitaxel monotherapy).

The overall safety and tolerability profile of Enhertu (6.4 mg/kg) in DESTINY-Gastric01 was consistent with that seen in the Phase I trial. The most common adverse events were haematologic and gastrointestinal including neutrophil count decrease, anaemia, nausea and decreased appetite. There were cases of drug-related interstitial lung disease (ILD) and pneumonitis, the majority of which were Grade 1 and 2, with two Grade 3 and one Grade 4. No ILD-related deaths (Grade 5) occurred in patients with gastric cancer in the Phase I trial or in the Phase II DESTINY-Gastric01 trial.

The full results of DESTINY-Gastric-01 will be presented during the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program.

Enhertu received SAKIGAKE designation in March 2018 by Japan’s Ministry of Health, Labour and Welfare (MHLW) for potential use in the same HER2-positive gastric cancer patient population and was recently submitted to the MHLW for approval. This is the second BTD granted for Enhertu in the US. Enhertu received BTD in 2017 for HER2-positive metastatic breast cancer and received approval in December 2019.

Gastric cancer

Gastric (stomach) cancer is the fifth most common cancer worldwide and the third leading cause of cancer mortality; there were approximately one million new cases reported in 2018 and 783,000 deaths.1 In the US, it is estimated that 27,600 new cases of gastric cancer will be diagnosed in 2020 and more than 11,000 people will die from the disease.7

Approximately one in five gastric cancers are HER2 positive.2,4 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including gastric, breast and lung cancers. Gastric cancer is usually diagnosed in the advanced stage, but even when diagnosed in earlier stages of the disease the survival rate remains modest.8 Recommended 1st-line treatment for HER2-positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 medicine, which has been shown to improve survival outcomes when added to chemotherapy. For gastric cancer that progresses on 1st-line treatment, there are no other approved HER2-targeting medicines.9

DESTINY-Gastric01

DESTINY-Gastric01 is a registrational Phase II, open-label, multi-centre trial testing the safety and efficacy of Enhertu in a primary cohort of 188 patients from Japan and South Korea with HER2-expressing, advanced gastric cancer or gastroesophageal junction adenocarcinoma (defined as IHC3+ or IHC2+/ISH+) who have progressed on two or more prior treatment regimens including fluoropyrimidine and platinum chemotherapy and trastuzumab. Patients were randomised 2:1 to receive Enhertu or investigator’s choice of chemotherapy (paclitaxel or irinotecan monotherapy). Patients were treated with Enhertu 6.4 mg/kg once every three weeks or chemotherapy. The primary endpoint of the trial is ORR, as assessed by an independent review committee. Secondary endpoints include OS, progression-free survival, duration of response, disease control rate and time to treatment failure as well as pharmacokinetic and safety endpoints.5

Enhertu

Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the US) is a HER2-directed ADC and is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

Enhertu is approved in the US and Japan for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the DESTINY-Breast01 trial.

Enhertu clinical development

A comprehensive development programme is underway globally with six registrational trials evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-driven cancers including breast, gastric and lung cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Collaboration between AstraZeneca and Daiichi Sankyo

In March 2019, AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu worldwide, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is solely responsible for manufacturing and supply.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investment that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and ADCs – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On May 11, 2020 AstraZeneca reported that it has completed a previously communicated agreement to recover the global rights to brazikumab (formerly MEDI2070), a monoclonal antibody targeting IL23, from Allergan (Press release, AstraZeneca, MAY 11, 2020, View Source [SID1234557440]). AstraZeneca and Allergan have terminated their previous license agreement and all rights to brazikumab have therefore now returned to AstraZeneca.

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Financial considerations

Under the termination agreement, Allergan will fund up to an agreed amount, estimated to be the total costs expected to be incurred by AstraZeneca until completion of the development of brazikumab for Crohn’s disease (CD) and ulcerative colitis (UC), including the development of a companion diagnostic.

Pursuant to the 2012 collaboration between Amgen and AstraZeneca to jointly develop and commercialise a clinical-stage inflammation portfolio, including brazikumab, Amgen is entitled to receive a high single-digit to low double-digit royalty on sales of brazikumab if approved and launched. This includes the original inventor royalty. Other than this, AstraZeneca will own all rights and benefits arising from the medicine with no other payments due to Amgen or Allergan.

Brazikumab

Brazikumab is a monoclonal antibody that binds to the IL23 receptor and is in development for CD and UC with a companion biomarker. Brazikumab selectively blocks the IL23 immune signal, preventing intestinal inflammation. In Phase II trials, brazikumab demonstrated a clinical effect at week eight in tumour necrosis factor-resistant CD patients.1 The Phase IIb/III INTREPID programme is underway to assess brazikumab compared to placebo or adalimumab in CD. The Phase II EXPEDITION trial is underway to assess brazikumab compared to placebo or vedolizumab in UC. With current biologic medicines, 40% to 55% of patients have no response to therapy, and 65% to 80% of patients do not experience a full remission.2

On May 11, 2020 AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) reported that Lynparza (olaparib) in combination with bevacizumab has been approved in the US for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to 1st-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability (Press release, AstraZeneca, MAY 11, 2020, View Source [SID1234557439]). Patients will be selected for therapy based on an FDA-approved companion diagnostic test.

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The approval by the US Food and Drug Administration (FDA) was based on a biomarker subgroup analysis of the Phase III PAOLA-1 trial which showed that Lynparza in combination with bevacizumab maintenance treatment reduced the risk of disease progression or death by 67% (equal to a hazard ratio of 0.33). The addition of Lynparza improved progression-free survival (PFS) to a median of 37.2 months versus 17.7 months with bevacizumab alone in patients with HRD-positive advanced ovarian cancer.

Approximately one in two women with advanced ovarian cancer has an HRD-positive tumour. For patients with advanced ovarian cancer, the primary aim of 1st-line treatment is to delay disease progression for as long as possible with the intent to achieve long-term remission.

Isabelle Ray-Coquard, principal investigator of the PAOLA-1 trial and medical oncologist, Centre Léon Bérard and President of the GINECO group, said: "Ovarian cancer is a devastating disease. The magnitude of benefit in HRD-positive patients in the PAOLA-1 trial is impactful. The combination of Lynparza and bevacizumab now provides women with HRD-positive advanced ovarian cancer with a new standard of care and I look forward to seeing this translate into clinical practice."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: "This approval represents another milestone for Lynparza in patients with ovarian cancer. The median progression-free survival of more than three years offers new hope for more women to delay relapse in this difficult-to-treat disease. These results further establish that HRD-positive is a distinct subset of ovarian cancer, and HRD testing is now a critical component for the diagnosis and tailoring of treatment for women with advanced ovarian cancer."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "Advances in understanding the role of biomarkers and PARP inhibition have fundamentally changed how physicians treat this aggressive type of cancer. Today’s approval based on the PAOLA-1 trial highlights the importance of HRD testing at diagnosis to identify those who may benefit from Lynparza in combination with bevacizumab as a 1st-line maintenance treatment."

The full results from the Phase III PAOLA-1 trial were published in The New England Journal of Medicine.

Regulatory reviews are currently underway in the EU, Japan and other countries for Lynparza based on results from the PAOLA-1 trial. As part of a broad development programme, Lynparza is being tested as a monotherapy and in combination across multiple tumour types including as a potential adjuvant treatment of patients with germline BRCA-mutated high-risk HER2-negative primary breast cancer in the Phase III OlympiA trial.

Financial considerations

Following this approval for Lynparza in the US, AstraZeneca will receive from MSD $100m in Collaboration Revenue, anticipated to be booked by the Company during the second quarter of 2020.

Ovarian cancer

Ovarian cancer is the eighth most common cause of death from cancer in women worldwide.1 In 2018, there were nearly 300,000 new cases diagnosed and around 185,000 deaths.2 Most women are diagnosed with advanced (Stage III or IV) ovarian cancer and have a five-year survival rate of approximately 30%.3 Approximately 50% of ovarian cancers are HRD-positive including BRCA1/2 mutation. 4,5 Some 22% of ovarian cancers have a BRCA1/2 mutation.5

For patients with advanced ovarian cancer, the primary aim of 1st-line treatment is to delay progression of the disease for as long as possible and maintain the patient’s quality of life with the intent of achieving complete remission.6,7,8,9

In the US, bevacizumab was approved for use in combination with chemotherapy for the 1st-line treatment of advanced ovarian cancer in 2018. Within two years nearly half of all patients with advanced ovarian cancer are receiving this combination treatment.10

PAOLA-1

PAOLA-1 is a double-blind Phase III trial testing the efficacy and safety of Lynparza in combination with bevacizumab vs. bevacizumab alone, as a 1st-line maintenance treatment for newly diagnosed advanced FIGO Stage III-IV high-grade serous or endometroid ovarian, fallopian tube, or peritoneal cancer patients who had a complete or partial response to 1st-line treatment with platinum-based chemotherapy and bevacizumab. AstraZeneca and MSD announced in August 2019 that the trial met its primary endpoint of PFS.

Simultaneously, the Myriad Genetics myChoice CDx test has been approved in the US as a companion diagnostic for Lynparza in this new indication.

Homologous recombination deficiency

HRD, which defines a sub-group of ovarian cancer, encompasses a wide range of genetic abnormalities, including BRCA mutations and beyond. As with BRCA gene mutations, HRD interferes with normal cell DNA repair mechanisms and confers sensitivity to PARP inhibitors including Lynparza.5

Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair, such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in a number of countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer. It is approved in the US, the EU, Japan, China, and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in the US, Japan, and a number of other countries for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer. Lynparza is approved in the US and several other countries for the treatment of germline BRCA-mutated metastatic pancreatic cancer. Regulatory reviews are underway in several jurisdictions for ovarian, breast, pancreatic and prostate cancers.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 30,000 patients worldwide. Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells

The AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and Koselugo (selumetinib), a MEK inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investment that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On May 10, 2020 Ascentage Pharma (6855.HK), a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that latest clinical data of the company’s drug candidates, including the MDM2-p53 inhibitor APG-115, novel Bcl-2/Bcl-xL dual inhibitor APG-1252, and IAP inhibitor APG-1387, will be presented in three poster discussions and a poster at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Ascentage Pharma, MAY 10, 2020, View Source [SID1234557437]). Because of concerns about the current coronavirus (COVID-19) pandemic, this year’s annual meeting will be held in a virtual format from May 29 through May 31, 2020.

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The ASCO (Free ASCO Whitepaper) Annual Meeting is the most authoritative meeting in the oncology space. The purpose of this meeting is to disseminate premier scientific research and cutting-edge treatment approaches in oncology to the world.

"We are excited to present the clinical advances of three of our drug candidates," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Through these results, Ascentage Pharma is demonstrating its capabilities of global clinical development in apoptosis. We are striving to offer more treatment options for patients with unmet medical needs."

Four posters will be presented at ASCO (Free ASCO Whitepaper)20, including:

Poster Discussion Sessions

Phase Ib study of a novel, small-molecule MDM2 inhibitor APG-115 combined with pembrolizumab in U.S. patients with metastatic solid tumors
Time: May 29th, 8:00–11:00am, EST

Abstract: #3512

Session: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology

First-in-human study of palcitoclax (APG-1252), a novel dual Bcl-2/Bcl-xL inhibitor, demonstrated advantages in platelet safety while maintaining anticancer effect in U.S. patients with metastatic solid tumors
Time: May 29th, 8:00–11:00am, EST

Abstract: #3509

Session: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology

Phase Ib study of a novel bivalent IAP antagonist APG-1387 in combination of pembrolizumab for patients with advanced solid tumors
Time: May 29th, 8:00–11:00am, EST

Abstract: #3508

Session: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology

Poster Session

Phase I study results of APG-115, a MDM2-p53 antagonist, in Chinese patients with advanced liposarcoma and other solid tumors
Time: May 29th, 8:00–11:00am, EST

Abstract: #11542

Session: Sarcoma

On May 10, 2020 Hummingbird Bioscience, an innovative biotherapeutics company focused on the discovery and development of new breakthrough therapies, reported that it has closed an extended Series B funding round of US$25 million (Press release, Hummingbird Bioscience, MAY 10, 2020, View Source [SID1234557436]). This brings the total capital raised through financing activities and strategic partnerships to more than US$65 million to date.

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Leading the Series B extension is new investor SK Holdings, with participation from existing shareholders including Heritas Capital and SEEDS Capital, the investment arm of Enterprise Singapore.

The Series B round was extended to US$25 million due to significant over-subscription, with the addition of select quality and value-add investors. Hummingbird will use the new funds to accelerate development of new candidates into clinical trials and strengthen its scientific and research and development capabilities.

"We are delighted to have SK Holdings join our investor base. Hummingbird is building a strong portfolio of promising new therapies that we believe can deliver very meaningful benefit for patients across a broad spectrum of disease. These new funds give us further resources to develop our early stage pipeline, and support the clinical development of our lead programs," said Dr Piers Ingram, Chief Executive Officer and co-founder, Hummingbird Bioscience.

"Heritas Capital is pleased to continue our backing of the Hummingbird team since leading its Series A extended round," commented Chik Wai Chiew, Executive Director and Chief Executive Officer, Heritas Capital Management. "Even as the COVID-19 pandemic has resulted in a slow-down in investing, we are mindful that backing leading innovative biotech companies, especially players such as Hummingbird, to develop cures for addressing patients’ needs remains our priority."

Earlier this year Hummingbird announced publication of positive data on its lead candidate, HMBD-001, a first-in-class HER3 antibody; and manufacturing of HMBD-002, a first-in-class VISTA antibody. Regulatory submissions to initiate Phase I studies for these two candidates are expected in the second half of 2020.