On October 1, 2024 AstraZeneca and Daiichi Sankyo reporte that its supplemental Biologics License Application (sBLA) for Enhertu (trastuzumab deruxtecan) has been accepted and granted Priority Review in the US for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer who have received at least one endocrine therapy in the metastatic setting based on the positive results from the DESTINY-Breast06 Phase III trial which compared Enhertu to chemotherapy (Press release, AstraZeneca, OCT 1, 2024, View Source [SID1234646941]).

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The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance. The Prescription Drug User Fee Act date, the FDA action date for their regulatory decision, is anticipated during the first quarter of 2025.

Enhertu was also recently granted Breakthrough Therapy Designation (BTD) by the FDA in this setting. BTD accelerates the development and regulatory review of potential new medicines intended to treat a serious condition and address a significant unmet medical need.

HR-positive, HER2-negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers.1 Despite being classified as HER2-negative, many of these tumours still carry some level of HER2 expression.2 It is estimated that up to 85-90% of tumours historically classified as HR-positive, HER2-negative, may be HER2-low or HER2-ultralow.3,4

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "While endocrine therapies are widely used in the initial treatment of HR-positive metastatic breast cancer, most patients see limited benefit with additional lines of treatment, and subsequent chemotherapy is associated with poor response rates and outcomes. The results from DESTINY-Breast06 show that Enhertu has the potential to evolve the current HR-positive treatment landscape and become the first targeted treatment for patients with HER2-low or HER2-ultralow expression following endocrine therapy."

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "This Priority Review highlights the potential to expand the existing indication of Enhertu in HER2-low metastatic breast cancer to include use in an earlier disease setting as well as in a broader patient population that includes HER2-ultralow. We look forward to working closely with the FDA with the goal of bringing Enhertu to more patients as quickly as possible."

The sBLA is based on data from the DESTINY-Breast06 Phase III trial presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and recently published in The New England Journal of Medicine.

In the trial, Enhertu reduced the risk of disease progression or death by 37% by blinded independent central review (BICR) versus chemotherapy (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.53-0.75; p<0.0001) in the overall trial population. Median PFS was 13.2 months with Enhertu compared to 8.1 months with chemotherapy.

Results were consistent between patients with HER2-low expression and HER2-ultralow expression. In the primary endpoint analysis of patients with HER2-low expression, Enhertu showed a median PFS of 13.2 months compared to 8.1 months for chemotherapy (HR 0.62; 95% CI 0.51-0.74; p<0.0001). In a prespecified exploratory analysis of patients with HER2-ultralow expression, Enhertu showed a median PFS of 13.2 months versus 8.3 months, respectively (HR 0.78; 95% CI 0.50-1.21).

The safety profile of Enhertu in DESTINY-Breast06 was consistent with previous clinical trials of Enhertu in breast cancer with no new safety concerns identified.

Enhertu is a specifically engineered HER2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

Enhertu is already approved in more than 65 countries, including the US, for patients with HER2-low metastatic breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.

Notes

Breast cancer and HER2 expression
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.5 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally.5 While survival rates are high for those diagnosed with early breast cancer, only approximately 30% of patients who are diagnosed with or who progress to metastatic disease are expected to live five years after their diagnosis.1

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including breast cancer.6 Patients with high levels of HER2 expression (IHC 3+ or 2+/ISH+) are classified as HER2-positive and treated with HER2-directed therapies, representing approximately 15-20% of all breast cancers.7 Historically, tumours that were not classified as HER2-positive were classified as HER2-negative.2

HR-positive, HER2-negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers.1 Despite being classified as HER2-negative, many of these tumours still carry some level of HER2 expression.2 It is estimated that 60-65% of HR-positive, HER2-negative breast cancers are HER2-low and potentially an additional 25% may be HER2-ultralow.3,4

Endocrine therapies are widely used in the early lines of treatment for HR-positive metastatic breast cancer; however, after two lines of treatment, further efficacy from endocrine therapy is often limited.8 The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes.8-11

Prior to the approval of Enhertu in HER2-low metastatic breast cancer post chemotherapy based on the DESTINY-Breast04 trial, there were no targeted therapies approved specifically for patients with HER2-low expression. There are no targeted therapies specifically approved for patients with HER2-low expression prior to chemotherapy or for patients with HER2-ultralow expression.12

DESTINY-Breast06
DESTINY-Breast06 is a global, randomised, open-label, Phase III trial evaluating the efficacy and safety of Enhertu (5.4mg/kg) versus investigator’s choice of chemotherapy (capecitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) advanced or metastatic breast cancer. Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. Patients were also eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting 1st-line treatment or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months.

HER2 status in the trial was confirmed by central laboratory and was performed on an archival tumour sample obtained at the time of initial metastatic diagnosis or later. If archival tissue was not available, a fresh tissue sample was required.

The primary endpoint is PFS in the HR-positive, HER2-low patient population as measured by BICR. Key secondary endpoints include PFS by BICR in the overall trial population (HER2-low and HER2-ultralow), OS in the HER2-low patient population and OS in the overall trial population. Other secondary endpoints include ORR, DOR, time to first subsequent treatment or death, time to second subsequent treatment or death and safety.

DESTINY-Breast06 enrolled 866 patients (n=713 for HER2-low and n=153 for HER2-ultralow) randomised at multiple sites in Asia, Europe, Australia, North America and South America. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Enhertu (5.4mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+ or in-situ hybridisation [ISH]+) breast cancer who have received a prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial.

Enhertu (5.4mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.

Enhertu (5.4mg/kg) is approved in more than 45 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/kg) is approved in more than 45 countries worldwide for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Full approval in China for this indication will depend on whether a randomised controlled confirmatory clinical trial can demonstrate clinical benefit in this population.

Enhertu (5.4mg/kg) is approved in the US for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumours who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication in the US may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu development programme
A comprehensive global clinical development programme is underway evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers. Trials in combination with other anti-cancer treatments, such as immunotherapy, also are underway.

On October 1, 2024 Heidelberg Pharma AG (FSE: HPHA), a clinical stage company developing innovative Antibody Drug Conjugates (ADCs), reported that new clinical data from its lead Amanitin-based ADC candidate, HDP-101, were presented at the International Myeloma Society (IMS) Annual Meeting, held in Rio de Janeiro, Brazil on 27 September 2024 (Press release, Heidelberg Pharma, OCT 1, 2024, View Source [SID1234646977]).

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HDP-101 is being evaluated in an ongoing Phase I/IIa clinical trial in the indication of relapsed or refractory multiple myeloma, a bone marrow cancer with a high unmet medical need. Clinical data from the fifth cohort demonstrated complete remission in one patient who had been heavily pre-treated. This patient showed an objective improvement ("partial response") in the 2nd cycle of treatment and complete remission was confirmed after the 11th cycle.

In addition, several patients showed promising biological activity and an objective improvement demonstrating the potential of HDP-101 as a treatment option for patients with the disease.

Following the presentation at IMS, Heidelberg Pharma will host an R&D webinar on 15 October 2024 at 17:00 CEST/ 11:00 EDT, for investors, analysts, and media.

The R&D webinar will feature presentations by the Heidelberg Pharma management team, alongside Key Opinion Leaders (KOLs) in the myeloma field: Shambavi Richard, MD, Associate Professor Icahn School of Medicine at Mount Sinai Hospital, New York, USA and Robert Z. Orlowski, MD, PhD, (Ad Interim) Director of Myeloma, and Professor of Medicine in the Departments of Lymphoma/Myeloma and Experimental Therapeutics, University of Texas, Houston, Texas, and principal investigator at MD Anderson Cancer Center, Houston, Texas, USA.

Webinar participants will have the opportunity to submit questions in advance of the webinar or ask questions live during the event.

On September 30, 2024 Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, reported the publication of its KOMET-001 Phase 1 study manuscript in The Lancet Oncology journal (Press release, Kura Oncology, SEP 30, 2024, View Source [SID1234646927]). The paper, entitled "Ziftomenib in relapsed/refractory acute myeloid leukaemia (KOMET-001): results from an open-label, multi-cohort, phase 1a/1b trial," is now available on The Lancet Oncology website and in the Scientific Manuscripts section on Kura’s website.

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"The results from the KOMET-001 Phase 1 study are encouraging as they demonstrate meaningful benefit of ziftomenib in NPM1-mutant acute myeloid leukemia (AML), and publication of these data expands the growing evidence supporting the efficacy and safety of ziftomenib in a disease indication of unmet need," said Ghayas C. Issa, M.D., assistant professor of Leukemia at The University of Texas MD Anderson Cancer Center. "We are thankful for the patients and their families for their participation in the KOMET-001 trial and for the scientific community who have contributed to this research to advance more tolerable and effective treatment options for AML patients."

The KOMET-001 study is a Phase 1/2 global, open-label, multi-cohort clinical trial evaluating the safety, tolerability and clinical activity of ziftomenib in relapsed/refractory (R/R) AML. In the Phase 1a dose escalation portion, patients received ziftomenib once daily in 28-day cycles and in the Phase 1b dose validation/expansion portion, patients were randomized to two parallel cohorts at 200 mg and 600 mg. As of the data cutoff on August 30, 2023, 83 patients received one or more doses of ziftomenib and the primary objective of this study was to determine the recommended phase 2 dose (RP2D) based on safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary activity. The results demonstrated promising clinical activity with manageable toxicity in heavily pretreated patients including marrow blast reduction, neutrophil and platelet recovery, transfusion independence, and clearance of measurable residual disease.

"Our Phase 1 study provided the critical safety and clinical activity data in order to determine the RP2D and support our pivotal Phase 2 registration-directed trial in patients with NPM1-mutant AML," said Stephen Dale, M.D., Chief Medical Officer of Kura Oncology. "These data reinforce our commitment to developing novel investigational therapies, including menin inhibitors, to realize the transformative value for patients with acute leukemias. The clinical data generated to date, including the insights gained from this study, demonstrate the potential for ziftomenib to become a cornerstone of AML therapy through monotherapy and combination approaches."

In May 2024, Kura Oncology announced completion of enrollment in the Phase 2 portion of KOMET-001, a registration-directed trial of ziftomenib in patients with R/R NPM1-mutant AML. Enrollment of the 85 patients in Phase 2 was completed in fewer than 16 months and the Company expects to report topline data from the trial in early 2025.

About NPM1-mutant AML

AML is the most common acute leukemia in adults and begins when the bone marrow makes abnormal myeloblasts (white blood cells), red blood cells or platelets. Despite the many available treatments for AML, prognosis for patients remains poor and a high unmet need remains. The menin pathway is considered a driver for multiple genetic alterations of the disease, of which NPM1 mutations are among the most common, representing approximately 30% of AML cases. While patients with NPM1-m AML have high response rates to frontline therapy, relapse rates are high and survival outcomes are poor, with only 30% overall survival at 12 months in the R/R setting. Additionally, NPM1 mutations frequently occur with co-mutations in other disease-associated genes, including FLT3, DNMT3A and IDH1/2, with prognosis heavily influenced by the presence of co-occurring mutations. Adult patients with NPM1-m AML and select co-mutations and/or R/R disease have a poor prognosis, with median overall survival of only approximately 7.8 months in 2nd line, 5.3 months in 3rd line, and 3.5 months following the 4th line1. There are currently no FDA-approved therapies targeting NPM1-m AML.

About Ziftomenib

Ziftomenib is a novel, once-daily, oral investigational drug candidate targeting the menin-KMT2A/MLL protein-protein interaction for treatment of genetically defined AML patients with high unmet need. In the KOMET-001 Phase 1 study, ziftomenib demonstrated encouraging safety and tolerability with reported events consistent with features and manifestations of underlying disease. Clinical activity of ziftomenib as a monotherapy was optimal at the 600 mg daily dose and a 35% complete remission rate was observed in 20 patients with NPM1-mutant AML treated at the recommended Phase 2 dose (600 mg). Ziftomenib has received Breakthrough Therapy Designation (BTD) from the U.S. Food and Drug Administration for the treatment of R/R NPM1-mutant AML. Additional information about clinical trials for ziftomenib can be found at kuraoncology.com/clinical-trials/#ziftomenib.

On September 30, 2024 Aktis Oncology, a clinical-stage biotechnology company pioneering the discovery and development of novel targeted alpha radiopharmaceuticals to treat a broad range of solid tumors, reported the successful closing of an oversubscribed and upsized $175 million Series B financing (Press release, Aktis Oncology, SEP 30, 2024, View Source [SID1234646945]). The financing was led by RA Capital Management, and co-led by RTW Investments and Janus Henderson Investors. A select syndicate of additional new investors joined the financing, including funds and accounts advised by T. Rowe Price Associates, Inc., Avidity Partners, and an undisclosed life sciences-focused investment fund. All existing institutional investors participated, as well as existing strategic investors Bristol Myers Squibb, Eli Lilly and Company, and MRL Ventures Fund, the therapeutics-focused corporate venture fund of Merck & Co., Inc.

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Aktis Oncology also announced that three abstracts, including one oral presentation, have been accepted for presentation at the upcoming EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, October 23-25, 2024.

"The overwhelming support from high caliber investors underscores the progress we have made on our pipeline, platform, and supply chain capabilities, exemplified by the significant opportunity for AKY-1189, our first-in-class miniprotein alpha radioconjugate targeting Nectin-4 in development for several tumor types," said Matthew Roden, PhD, President and Chief Executive Officer of Aktis Oncology. "With over $300 million in cash, we are well-positioned to prosecute several opportunities to expand the benefit of this exciting modality into new patient populations."

In conjunction with the financing, Andrew Levin, MD, PhD, Partner and Managing Director at RA Capital Management, will join the Aktis Oncology Board of Directors. Lauren Lee, PhD, from RTW Investments, and Vish Sridharan, MD, from Janus Henderson Investors, will join as Observers to the Board of Directors.

"Aktis has leveraged its unique technology platform, experienced team, robust supply chain and radiopharmaceutical development capabilities to generate a promising and differentiated pipeline of next-generation radiopharmaceuticals," said Andrew Levin, MD, PhD, Partner and Managing Director at RA Capital Management. "We are pleased to support Aktis through the next stage of its growth as it seeks to bring new options to patients with cancer."

On September 30, 2024 Celaid Therapeutics reported that it has been awarded up to approx. 2.7 billion yen ($19M USD) in non-dilutive grant funding as "Strengthening Program for Pharmaceutical Startup Ecosystem" program by the Japanese Agency for Medical Research and Development (AMED) (Press release, Celaid Therapeutics, SEP 30, 2024, View Source [SID1234649809]). The grant will be used to support the development of Celaid’s lead program "CLD-001", an ex vivo expanded Hematopoietic Stem Cell (HSC) Therapy for pediatric non-malignant diseases.

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"The Japanese government has announced that it will provide funding support for pharmaceutical startups over the next five years through 300 billion yen ($2.1 Billion USD) grant as Strengthening Program for Pharmaceutical Startup Ecosystem program. Being selected for this program is a vote of

Through this grant program, Celaid will reinforce non-clinical and clinical development of CLD-001 in the US. and accelerate development to deliver CLD-001 to patients suffering from pediatric nonmalignant diseases worldwide as soon as possible.

About CLD-001, an ex vivo expanded Hematopoietic Stem Cell (HSC) Therapy
CLD-001 is being developed as a hematopoietic stem cell therapy product for severe pediatric nonmalignant disease. Rare blood diseases such as aplastic anemia, primary immunodeficiency, inherited metabolic disorder, and sickle cell disease, which start in childhood and are associated with various physical and neurological complications, have a very poor prognosis. Currently, the only curative therapy is allogeneic hematopoietic stem cell transplantation (HSCT). On the other hand, there are still significant unmet needs for allogeneic HSCT due to donor problems such as bone marrow donor shortage and HLA type mismatch, as well as side effects such as transplant-related mortality and graft-versus-host disease (GvHD). CLD-001 is a hematopoietic stem cell product that solves the donor problem, side effects, and disadvantages described above

In addition to solving the donor problem by using frozen cord blood stored in a cord blood bank as the cell source, CLD-001 also solves the bottleneck of low HSC counts in cord blood with our proprietary HSC expansion technology, enabling us to provide HSCs with the best HLA type for the patient. CLD-001, the HLA best-match and bone marrow-constructible HSCs, is expected to significantly improve overall survival after HSC therapy.