On September 15, 2023 GSK plc (LSE/NYSE: GSK) reported that the US Food and Drug Administration (FDA) has approved Ojjaara (momelotinib) for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post-polycythaemia vera and post-essential thrombocythaemia), in adults with anaemia (Press release, GlaxoSmithKline, SEP 15, 2023, View Source [SID1234635181]). Ojjaara is a once-a-day, oral JAK1/JAK2 and activin A receptor type 1 (ACVR1) inhibitor. To date, it is the only approved medicine for both newly diagnosed and previously treated myelofibrosis patients with anaemia that addresses the key manifestations of the disease, namely anaemia, constitutional symptoms, and splenomegaly (enlarged spleen).[4]

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Nina Mojas, Senior Vice President, Oncology Global Product Strategy, GSK, said: "The vast majority of myelofibrosis patients eventually develop anaemia, causing them to discontinue treatments and require transfusions. Given this high unmet need, we are proud to add Ojjaara to our oncology portfolio and address a significant medical need in the community. We look forward to helping improve outcomes in this difficult-to-treat blood cancer."

Myelofibrosis is a blood cancer affecting approximately 25,000 patients in the US.[4],[5],[6] Myelofibrosis can lead to severely low blood counts, including anaemia and thrombocytopaenia; constitutional symptoms such as fatigue, night sweats, and bone pain; and splenomegaly. About 40% of patients have moderate to severe anaemia at the time of diagnosis, and nearly all patients are estimated to develop anaemia over the course of the disease.[7],[8],[9],[10] Physicians have had limited treatment options to treat myelofibrosis patients with anaemia. These patients often require transfusions and more than 30% will discontinue treatment due to anaemia.​ Patients who are transfusion dependent have a poor prognosis and shortened survival.[1],[11],[12],[13],[14],[15],[16],[17],[18]

Ruben A. Mesa, MD, FACP, President and Executive Director, Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, said: "With momelotinib we have the potential to establish a new standard of care for myelofibrosis patients with anaemia. Addressing key manifestations of myelofibrosis, including anaemia, constitutional symptoms and splenomegaly, makes a significant difference in the treatment regimen for these patients who have limited options to address these aspects of the disease."

The FDA approval of momelotinib is supported by data from the pivotal MOMENTUM study and a subpopulation of adult patients with anaemia from the SIMPLIFY-1 phase III trial. MOMENTUM was designed to evaluate the safety and efficacy of momelotinib versus danazol for the treatment and reduction of key manifestations of myelofibrosis in an anaemic, symptomatic, JAK inhibitor-experienced population. The MOMENTUM trial met all its primary and key secondary endpoints, demonstrating statistically significant response with respect to constitutional symptoms, splenic response and transfusion independence, in patients treated with momelotinib versus danazol.[2] SIMPLIFY-1 was designed to evaluate the efficacy and safety of momelotinib versus ruxolitinib in myelofibrosis patients who had not received a prior JAK-inhibitor therapy.[1] Safety and efficacy results for SIMPLIFY-1 were based upon a subset of patients with anaemia.

In these clinical trials, the most common adverse reactions were thrombocytopaenia, haemorrhage, bacterial infection, fatigue, dizziness, diarrhoea, and nausea.[19]

Kapila Viges, Chief Executive Officer, MPN (Myeloproliferative Neoplasms) Research Foundation, said: "We are thrilled to see momelotinib reach the clinic, giving patients and their physicians another option to help manage myelofibrosis. Any new treatment that takes steps toward unlocking the mysteries of this complex and chronic blood cancer represents great progress for the field."

Momelotinib is currently not approved in any other market.

About Ojjaara (momelotinib)

Ojjaara has a differentiated mechanism of action, with inhibitory ability along three key signalling pathways: Janus kinase (JAK) 1, JAK2, and activin A receptor, type I (ACVR1). [2],[6], [20],[21] Inhibition of JAK1 and JAK2 may improve constitutional symptoms and splenomegaly.[6],[21] Additionally, inhibition of ACVR1 leads to a decrease in circulating hepcidin, which is elevated in myelofibrosis and contributes to anaemia.[2],[6],[20],[21]

Please see accompanying US Prescribing Information.

About myelofibrosis

Myelofibrosis is a rare blood cancer that results from dysregulated JAK-signal transducer and activator of transcription protein signalling and is characterised by constitutional symptoms, splenomegaly, and progressive anaemia. Myelofibrosis affects approximately 25,000 patients in the US.[1],[5],[6]

About the pivotal MOMENTUM clinical trial

MOMENTUM was a phase III, global, multicentre, randomised, double-blind study investigating momelotinib versus danazol in patients with myelofibrosis who were symptomatic and anaemic and had been previously treated with an approved JAK inhibitor. The trial was designed to evaluate the safety and efficacy of momelotinib for treating and reducing key hallmarks of the disease: symptoms, blood transfusions (due to anaemia) and splenomegaly.2 Results from the 24-week treatment period were presented at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and subsequently published in The Lancet.[22],[23]

About the SIMPLIFY-1 clinical trial

SIMPLIFY-1 was a multicentre, randomised, double-blind, phase III study that compared the safety and efficacy of momelotinib to ruxolitinib in patients with myelofibrosis who had not received prior treatment with a JAK inhibitor. Safety and efficacy results for SIMPLIFY-1 were based upon a subset of patients with anaemia (haemoglobin <10 g/dL) at baseline. The efficacy of momelotinib in the treatment of patients with myelofibrosis in SIMPLIFY-1 was based on spleen volume response (reduction by 35% or greater).

On September 15, 2023 Deciphera Pharmaceuticals, Inc. (NASDAQ: DCPH), a biopharmaceutical company focused on discovering, developing, and commercializing important new medicines to improve the lives of people with cancer, reported that in connection with the hiring of Dashyant Dhanak, Ph.D., Executive Vice President and Chief Scientific Officer, the Compensation Committee of Deciphera’s Board of Directors approved the grant of a stock option to purchase 65,900 shares of Deciphera’s common stock, 65,900 restricted stock units ("RSUs") and a special grant of 75,000 RSUs ("Special RSUs") to Dr. Dhanak with a grant date of September 15, 2023 (Press release, Deciphera Pharmaceuticals, SEP 15, 2023, View Source [SID1234635180]).

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The equity awards were granted under the Company’s 2022 Inducement Plan and were made pursuant to Nasdaq Listing Rule 5635(c)(4). The grants were an inducement material to Dr. Dhanak accepting employment with the Company. The options have a ten-year term, and the exercise price of the options is $13.42, equal to the fair market value of the Company’s common stock on the Nasdaq on September 15, 2023. The shares subject to the option vest over a four-year period, with 25 percent of the shares subject to the option vesting on the first anniversary of Dr. Dhanak’s date of hire and the remainder vesting in equal monthly installments over three years thereafter. The 65,900 shares underlying the RSU grant will vest in equal annual installments over a three-year period, beginning on or about the one-year anniversary of the grant date. The 75,000 shares underlying the special grant vest over a two-year period, with 50 percent vesting on or about the first anniversary of the grant date and the remainder vesting on or about the two-year anniversary of the grant date. The awards are subject to the terms and conditions of their applicable equity award agreements, including having a continued relationship with the Company on the vesting date.

On September 15, 2023 BeyondSpring Pharmaceuticals presented its corporate presentation (Press release, BeyondSpring Pharmaceuticals, SEP 15, 2023, View Source [SID1234635179]).

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On September 15, 2023 AstraZeneca and Daiichi Sankyo reported that Enhertu (trastuzumab deruxtecan) has been recommended for approval in the European Union (EU) as monotherapy for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) whose tumours have an activating HER2 (ERBB2) mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy (Press release, AstraZeneca, SEP 15, 2023, View Source [SID1234635178]).

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

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency based its positive opinion on the primary results from the DESTINY-Lung02 Phase II trial, which were presented at the IASLC 2023 World Conference on Lung Cancer and simultaneously published in the Journal of Clinical Oncology.

In the trial, Enhertu (5.4mg/kg) demonstrated a confirmed objective response rate (ORR) of 49.0% (95% confidence interval [CI] 39.0-59.1) and a disease control rate (DCR) of 93.1% (95% CI 86.4-97.2), as assessed by blinded independent central review (BICR), in patients with previously treated advanced or metastatic HER2-mutant (HER2m) NSCLC. One (1.0%) complete response (CR) and 49 (48.0%) partial responses (PR) were observed. The median duration of response (DoR) was 16.8 months (95% CI 6.4-not estimated [NE]). Median follow-up was 11.5 months at time of data cut-off of 23 December 2022.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "HER2-mutant non-small cell lung cancer is an aggressive form of lung cancer that often affects younger patients and has a poor prognosis, with limited approved therapies. This milestone recognises the unmet need in the European Union and if approved, Enhertu will provide the first targeted treatment option for these patients."

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "Enhertu is the first therapy to demonstrate a strong and durable tumour response in patients with previously treated HER2-mutant advanced non-small cell lung cancer, validating HER2 as an actionable target in lung cancer and supporting the potential to provide a much-needed option for these patients. This CHMP opinion is a positive step forward in advancing this HER2-directed antibody drug conjugate for these patients and we look forward to the European Commission decision."

The safety profile of Enhertu in the DESTINY-Lung02 trial was consistent with previous clinical trials with no new safety signals identified.

Notes

HER2m NSCLC
Lung cancer is the second most common form of cancer globally with more than two million cases diagnosed in 2020.1 In Europe, lung cancer is the third most commonly diagnosed cancer with more than 477,000 cases diagnosed in 2020.2 Lung cancer is also the leading cause of cancer-related deaths in Europe, with nearly 400,000 deaths reported in 2020.2 Prognosis is particularly poor for patients with metastatic NSCLC as only approximately 9% will live beyond five years after diagnosis.3

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including lung, breast, gastric and colorectal cancers. Certain HER2 (ERBB2) gene alterations (called HER2 mutations) have been identified in patients with non-squamous NSCLC as a distinct molecular target, and occur in approximately 2-4% of patients with this type of lung cancer.4,5 While HER2 gene mutations can occur in a range of patients, they are more commonly found in patients with NSCLC who are younger, female and have never smoked.6 HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.7 Next-generation sequencing has been utilised in the identification of HER2 (ERBB2) mutations.8,9

Although the role of anti-HER2 treatment is well established in breast and gastric cancers, there were no approved HER2-directed therapies in NSCLC prior to the approvals of Enhertu by the Israel Ministry of Health (MOH) Pharmaceutical Division, the Japan Ministry of Health, Labour and Welfare and the accelerated US Food and Drug Administration (FDA) approval of Enhertu in unresectable or metastatic HER2m NSCLC.10,11

DESTINY-Lung02
DESTINY-Lung02 is a global, randomised Phase II trial evaluating the safety and efficacy of Enhertu in patients with HER2m advanced or metastatic NSCLC with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained a platinum-based chemotherapy. Patients were randomised 2:1 to receive Enhertu 5.4mg/kg (n=102) or Enhertu 6.4mg/kg (n=50).

The primary endpoint of the trial is confirmed ORR as assessed by BICR. Secondary endpoints include confirmed DCR, DoR and PFS assessed by investigator and BICR, OS and safety.

DESTINY-Lung02 enrolled 152 patients at multiple sites, including Asia, Europe and North 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 topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

Enhertu (5.4mg/kg) is approved in more than 50 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a (or one or more) 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 40 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 Israel, Japan and under accelerated approval in the US 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 trial. Continued approval for this indication in the US may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/kg) is approved in more than 30 countries for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 and/or DESTINY-Gastric02 trials.

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

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On September 14, 2023 Auransa, a clinical-stage, AI-native biopharma that mines massive data for therapeutic gold, reported dosing of the first patient in its Phase 1 clinical trial to evaluate AU-409 as a treatment for patients with advanced liver cancers or solid tumors affecting the liver (Press release, Auransa, SEP 14, 2023, View Source [SID1234635626]). The patient was treated at the USC Norris Comprehensive Cancer Center where Anthony El-Khoueiry, MD is the principal investigator on the trial.

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Specifically, the Phase 1 trial will evaluate the safety and pharmacokinetics of single agent AU-409 in cancer patients and help define potential doses for follow-on Phase 2 studies. For more information you can view the trial on ClinicalTrials.gov here.

"Our focus is on advancing novel therapies that raise the standard of care for cancer patients, leveraging AI and massive, available data," said Pek Lum, PhD, Founder-CEO, Auransa. "Too many patients are still treated with drugs that were not designed for them, will not completely reverse their cancer, and can lead to dangerous side effects. With the first patient dosed in our Phase 1 clinical trial for liver cancer, we take one step closer to helping these patients and proving the AI platform that discovered AU-409 will generate more novel treatments for cancer and cancer-related diseases."

Patients with advanced liver cancer, such as hepatocellular carcinoma and biliary tract cancer, continue to have limited survival rates and despite advances in treatment. For hepatocellular carcinoma, immunotherapy combinations, such as atezolizumab and bevacizumab, have become standard, first-line treatment options. Historically tyrosine kinase inhibitors (TKIs) were the standard of treatment.

"Despite the higher response rates seen with immunotherapy combinations, when compared to TKIs, most patients will develop resistance to treatment," said Dr. El-Khoueiry. "In second line treatment and beyond, TKIs like sorafenib offer limited efficacy and the potential for significant toxicity. This leaves a substantial gap for new, improved therapies for liver cancer. We look forward to seeing how the AU-409 program progresses to address these unmet patient needs."

Beyond AU-409 for liver cancer, Auransa has a growing pipeline of therapies for cancer and cancer-related diseases, with the goal of advancing towards the investigational new drug application stage, a critical entry point for FDA trials. This includes programs for heart-safe chemotherapy, late-stage prostate cancer, triple negative breast cancer, and head and neck cancer.

To build its pipeline, Auransa takes a fundamentally different approach from other TechBio companies using AI to decode biology. Instead of generating its own data on which to train algorithms, Auransa harnesses publicly available human disease data, applies algorithms that separate "signal from noise" by looking for recurrent disease signatures, and discovers novel compounds, targets, and disease models for the patient populations that will respond best. The goal is smarter, more efficient drug discovery that maximizes the chances of success in clinical trials and generates precision medicines for patients in need of a better standard of care.

For more information on Auransa, its pipeline and partnerships, please visit www.auransa.com.

About AU-409 for liver cancer

AU-409 is a novel small molecule with oral activity in models of liver cancer. In preclinical studies, AU-409 has been shown to modulate transcription of certain genes thereby altering the gene expression profile of liver cancer cells. The mechanism of action of AU-409 is distinct from that of current drugs approved for liver cancer, including tyrosine kinase inhibitors (TKIs) such as sorafenib or regorafenib. Non-clinical safety, toxicology and genetic toxicology studies support the first in-human clinical studies of AU-409.

About the AU-409 clinical program

AU-409-Clinical-2022-01 is the first-in-human study titled: First in Human Dose Escalation Study of AU-409 in Patients with Advanced Primary Liver Cancers or Advanced Solid Tumor with Liver Predominant Metastatic Disease, now being conducted at the USC Norris Comprehensive Cancer Center with Principal Investigator Anthony El-Khoueiry, MD. Primary objectives of the study include: (1) determine the maximum tolerated dose of AU-409 and the recommended Phase 2 dose and (2) characterize the safety and tolerability of AU-409 by assessing toxicities. Secondary objectives include: (1) determine the pharmacokinetics of AU-409 in patients with advanced-stage solid tumors treated with AU-409 and (2) obtain a preliminary assessment of anti-tumor activity of AU-409. If the trial is successful, USC may receive royalty payments under the collaboration agreement with Auransa.

For more information you can view the Phase 1 trial on ClinicalTrials.Gov here.