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Aileron Therapeutics Provides Business Update and Outlines 2021 Strategic Priorities

On December 21, 2020 Aileron Therapeutics (NASDAQ:ALRN) reported a business update and outlined its strategic priorities for 2021, including announcing more details about the design and conduct of a Phase 1b randomized, double-blind, placebo-controlled clinical trial of ALRN-6924 in patients with advanced non-small cell lung cancer (NSCLC) undergoing treatment with first-line carboplatin doublet chemotherapy (with or without immune checkpoint inhibitors), planned to begin enrolling in the second quarter of 2021 (Press release, Aileron Therapeutics, DEC 21, 2020, View Source [SID1234573141]). Aileron is developing ALRN-6924 as a novel medicine to selectively protect healthy cells in patients with cancers that harbor p53 mutations to reduce or eliminate chemotherapy-induced side effects while preserving chemotherapy’s activity on cancer cells, a concept known as chemoprotection.

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"2020 has been a year of important progress for Aileron, most notably achieving clinical proof-of-concept for ALRN-6924 as a chemoprotective agent in patients with p53-mutated small cell lung cancer (SCLC) undergoing treatment with topotecan," said Manuel Aivado, M.D., Ph.D., President and Chief Executive Officer of Aileron. "In 2021, we aim to make further strides in our clinical development efforts by initiating a randomized, placebo-controlled trial of ALRN-6924 in patients with advanced NSCLC. This trial represents a key step toward advancing our vision to bring chemoprotection to all patients with p53-mutant cancer regardless of cancer type or chemotherapy. We believe chemoprotection has the potential to transform chemotherapy similar to the way anesthesia transformed surgery."

Dr. Aivado further commented, "February 2021 will mark a critical milestone for the emerging chemoprotection field – the first PDUFA date of a chemoprotective agent. While that therapeutic’s focus is myelopreservation, or the concept of protecting bone marrow cells from chemotherapy-induced toxicities, we view chemoprotection’s potential through a broader lens. We believe that, due to its mechanism of action, ALRN-6924 may have the potential not only to protect bone marrow cells from chemotherapy but also to protect other cell types, such as hair follicle cells and cells lining the oral cavity, among others. Currently there are no therapies to prevent hair loss or the painful mouth sores that patients undergoing chemotherapy often experience due to chemotherapy’s destruction of healthy cells."

Aileron Strategic Priorities and Anticipated Key Value Drivers in 2021

Initiate Phase 1b Randomized, Double-Blind, Placebo-Controlled Clinical Trial in First-Line NSCLC and Report Initial Data

Today, Aileron announced additional details about its planned Phase 1b clinical trial of ALRN-6924 in patients with advanced NSCLC. The company plans to begin patient enrollment in the second quarter of 2021, subject to obtaining funding for the trial, and expects that the randomized, double-blind, placebo-controlled trial will be part of a registration program designed to ultimately support approval for ALRN-6924 in NSCLC. Aileron anticipates enrolling approximately 40 patients with stage IV NSCLC undergoing treatment with first-line carboplatin doublet chemotherapy with or without an immune checkpoint inhibitor. Patients will be randomized 1:1 to receive either 0.3 mg/kg of ALRN-6924 or placebo. Endpoints will include the effect of ALRN-6924 to limit chemotherapy-induced bone marrow toxicities. Aileron anticipates reporting initial results from the trial late in the fourth quarter of 2021 and full results mid-2022.

In the U.S. alone, there are nearly 200,000 new cases of NSCLC diagnosed each year, and an estimated 50% or more of patients with NSCLC have p53-mutated cancer.1,2 Across all cancer types, there are an estimated 1.8 million patients in the U.S. diagnosed each year, and an estimated 50% of all cancer patients have p53-mutated cancer.1,3

Report Data Readouts from Ongoing Phase 1b Clinical Trial of ALRN-6924 in SCLC and Ongoing Healthy Volunteer Study

In 2021, Aileron plans to report additional results from its ongoing Phase 1b clinical trial in patients with SCLC. In October 2020, Aileron presented positive clinical data from the trial demonstrating clinical proof-of-concept that treatment with ALRN-6924 resulted in a protective effect against severe anemia, thrombocytopenia and neutropenia in patients with p53-mutated SCLC treated with topotecan. The data set from this trial, which Aileron plans to announce in the first quarter of 2021, will include results across all dose levels evaluating ALRN-6924 administered 24 hours prior to topotecan administration ("24-hr schedule"), including an exploratory 0.2 mg/kg dose level, as well as results from a cohort evaluating 0.3 mg/kg ALRN-6924 administered six hours prior to topotecan administration ("6-hr schedule"), which has now completed enrollment, with a total of six patients. In addition, Aileron initiated a healthy volunteer study in November 2020 to characterize the time to onset, and magnitude and duration of cell cycle arrest in human bone marrow relative to ALRN-6924 administration. Due to COVID-19-related delays, Aileron is updating its guidance on the readout of the healthy volunteer study from the second quarter of 2021 to mid-2021.

"We expect that, taken together, these additional results from the Phase 1b clinical trial of ALRN-6924 in patients with small cell lung cancer and the results from the healthy volunteer study, will further inform and support future randomized, controlled trials of ALRN-6924 when given prior to various chemotherapies," said Dr. Aivado.

How ALRN-6924 Is Designed to Protect Healthy Cells from Chemotherapy

ALRN-6924 is being developed by Aileron as a novel chemoprotective medicine to selectively protect healthy cells in patients with cancers that harbor p53 mutations to reduce or eliminate chemotherapy-induced side effects.

Chemotherapy preferentially acts on cells that are cycling or undergoing the process of cell division. In cancer cells, the cell cycle is unchecked, which leads to uncontrolled cell proliferation, a hallmark of cancer. Certain types of healthy cells also naturally need to cycle, such as bone marrow cells, hair follicle cells, skin cells, and cells lining the oral cavity and the gastrointestinal tract. As a result, chemotherapy preferentially targets and kills both cycling healthy cells and cycling cancer cells. This, in turn, can lead to a spectrum of chemotherapy-induced side effects, from unpleasant to life-threatening and fatal.

ALRN-6924, an investigational first-in-class MDM2/MDMX dual inhibitor, is administered prior to chemotherapy to patients with p53-mutant cancers. ALRN-6924 is designed to activate normal p53 protein in patients’ healthy cells, temporarily and reversibly pausing cell cycling to selectively shield the patients’ healthy cells from chemotherapy. The protection is limited to healthy cells, as ALRN-6924 cannot work in p53-mutated cancer cells given that p53 has lost its function in those cells. Therefore, cancer cells continue to cycle uninterrupted and remain fully susceptible to destruction by chemotherapy.

BioInvent and Transgene receive CTA approval for Phase l/lla trial of oncolytic virus BT-001 in solid tumors

On December 21, 2020 BioInvent International AB ("BioInvent") (OMXS: BINV), a biotech company focused on the discovery and development of novel and first-in-class immune-modulatory antibodies for cancer immunotherapy, and Transgene (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapies for the treatment of cancer, reported they have received regulatory approval in Belgium for a clinical trial application (CTA) for a Phase l/lla study of the novel oncolytic vaccinia virus BT-001 (Press release, BioInvent, DEC 21, 2020, View Source [SID1234573129]).

BT-001 is a best-in-class oncolytic Vaccinia virus. It has been generated using Transgene’s Invir.IO platform and its patented large-capacity VVcopTK-RR- oncolytic virus, which has been engineered to encode both a Treg-depleting human recombinant anti-CTLA4 antibody generated by BioInvent’s proprietary n-CoDeR/F.I.R.S.T platforms, and the human GM-CSF cytokine. By selectively targeting the tumor microenvironment, BT-001 is expected to elicit a much stronger and more effective antitumoral response. Delivering the anti-CTLA4 antibody directly to the tumor microenvironment will allow a local therapeutic activity and will thus greatly increase the safety and tolerability profile of the monoclonal antibody by reducing systemic exposure. BT-001 is being co-developed through a 50/50 collaboration between BioInvent and Transgene.

"This clinical trial approval sets the stage to further broaden BioInvent’s promising clinical pipeline. BT-001 is our fourth program in clinical development. We are very excited to move forward this unique oncolytic virus which combines multiple, clinically proven mechanisms of action into a single drug. This clinical study will allow us to test BT-001’s potential to treat a range of solid cancer indications. Regulatory approval of this agent demonstrates the excellent performance of our teams," said Martin Welschof, CEO of BioInvent.

Philippe Archinard, PhD, Chairman and CEO of Transgene, said: "We are pleased that we have received a first approval to initiate the Phase l/lla trial of BT-001. This oncolytic virus has induced long-lasting antitumor immune responses and abscopal effects in several tumor models, and its activity is further enhanced through combination with an anti-PD-1 antibody treatment. Thanks to its unique mode of action and the results seen so far, we believe it has the potential to make a significant difference to cancer patients."

This multicenter, open-label, dose-escalation Phase l/lla trial evaluating BT-001 alone or in combination with pembrolizumab will first be including patients in several countries in Europe and then in the USA. The Phase l, which is expected to begin within the next few weeks, will be divided into two parts. Part A will enroll up to 36 patients with metastatic/advanced solid tumors, who have already been pretreated, including with immunotherapies. Patients will receive single agent, intratumoral administrations of BT-001, in cutaneous or palpable subcutaneous lesions or easily injectable lymph nodes, to select the recommended dose and best regimen. Part B will explore the combination of intratumoral injections of BT-001 with pembrolizumab, an anti-PD1 targeting agent in 12 patients. The Phase lla will evaluate the combination regiment in several patient cohorts with different tumors types. These expansion cohorts will offer the exciting possibility of exploring the activity of this approach to treat other malignancies not traditionally addressed with this type of treatment.

Peptomyc steps forward as a Clinical Stage Biotech company

On December 21, 2020 Peptomyc S.L., a biotech company specialized in the development of protein and peptide therapeutics for cancer treatment, reported that it has officially transitioned from pre-clinical to Clinical Stage, having filed its first Clinical Trial Application in Europe (Press release, Peptomyc, DEC 21, 2020, View Source [SID1234573128]). The company has recently completed the pre-clinical safety studies for its first-in-class MYC inhibitor, OMO103. MYC is an oncoprotein deregulated in most –if not all- types of cancer. Accordingly, OMO103 has demonstrated potent anti-tumor activity in multiple preclinical models of cancer, and is now ready to be tested in Phase I/II clinical studies. The treatment of the first patient with is expected to start in Q1, 2021.

Manuela Niewel, MD, PhD, as Chief Medical Officer of the company, will assume the responsibility for leading Peptomyc’s clinical development, regulatory and medical affairs activities. "I am really excited about this important step and look forward to seeing OMO103 successfully acting in patients", Dr. Niewel says. " With OMO-103, we will address three major unmet medical needs in the oncology field: Non-Small-Cell Lung Cancer, Triple Negative Breast Cancer, and Colorectal Cancer.

The Phase I dose-escalation will start in three Spanish sites and later, in Phase II, we will expand the study to additional European sites".

Marie-Eve Beaulieu, PhD, co-founder and Chief Scientific Officer of Peptomyc adds: "The demonstration of our product’s quality, safety and stability, clearly represents a key milestone in our efforts to develop potentially life-saving cancer drugs. We are definitely thrilled to continue advancing Myc inhibition towards marketing approval".

Tagrisso approved in the US for the adjuvant treatment of patients with early-stage EGFR-mutated lung cancer

On December 21, 2020 AstraZeneca reported that Tagrisso (osimertinib) has been approved in the US for the adjuvant treatment of adult patients with early-stage epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after tumour resection with curative intent (Press release, AstraZeneca, DEC 21, 2020, View Source [SID1234573127]). Tagrisso is indicated for EGFRm patients whose tumours have exon 19 deletions or exon 21 L858R mutations as detected by an approved test.

The approval was granted under the US Food and Drug Administration’s (FDA) Real-Time Oncology Review (RTOR) pilot program. Five other countries participated in a concurrent submission and review process through FDA’s Project Orbis.

While up to 30% of all patients with NSCLC may be diagnosed early enough to have potentially curative surgery, disease recurrence is still common in early-stage disease and nearly half of patients diagnosed in Stage IB, and over three quarters of patients diagnosed in Stage IIIA, experience recurrence within five years.1-4

The approval was based on results from the ADAURA Phase III trial where Tagrisso demonstrated a statistically significant and clinically meaningful improvement in disease-free survival (DFS) in the primary analysis population of patients with Stage II and IIIA EGFRm NSCLC, and also in the overall trial population of patients with Stage IB-IIIA disease, a key secondary endpoint.

Roy S. Herbst, MD, PhD, chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT and principal investigator in the ADAURA Phase III trial, said: "Adjuvant Tagrisso has demonstrated an unprecedented disease-free survival benefit for early-stage lung cancer patients with EGFR mutations who face high rates of recurrence even after successful surgery and subsequent chemotherapy. This approval reinforces how critical it is to test all lung cancer patients for EGFR mutations before deciding how to treat them and regardless of their stage at diagnosis. This will help ensure as many patients as possible can benefit from this potentially practice-changing treatment."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: "For the first time, a targeted, biomarker-driven treatment option is available to patients in the US with early-stage EGFR-mutated lung cancer. This approval dispels the notion that treatment is over after surgery and chemotherapy, as the ADAURA results show that Tagrisso can dramatically change the course of this disease. We remain committed to treating cancer patients earlier, when they may still have a chance of being cured."

Adjuvant treatment with Tagrisso reduced the risk of disease recurrence or death by 83% in the primary endpoint of DFS in patients with Stage II and IIIA disease (hazard ratio [HR] 0.17; 95% confidence interval [CI] 0.12-0.23; p<0.0001). DFS results in the overall trial population of patients with Stage IB-IIIA disease showed Tagrisso reduced the risk of disease recurrence or death by 80% (HR 0.20; 95% CI 0.15-0.27; p<0.0001). At two years, 89% of patients treated with Tagrisso remained alive and disease free versus 52% on placebo after surgery, the current standard of care. The safety and tolerability of Tagrisso in this trial was consistent with previous trials in the metastatic setting.

Tagrisso was recently granted Breakthrough Therapy Designation for patients in the early-stage disease setting by the US FDA. In April 2020, an Independent Data Monitoring Committee recommended for the ADAURA trial to be unblinded two years early based on a determination of overwhelming efficacy. Investigators and patients continue to participate in the trial and remain blinded to treatment. The results from the ADAURA trial were presented during the plenary session of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program in May 2020 and were recently published in The New England Journal of Medicine.

The US regulatory submission was reviewed under the FDA’s RTOR pilot program which aims to ensure that safe and effective treatments are available to patients as early as possible. Five national health authorities collaborated with the FDA on this review through Project Orbis, an initiative of the FDA Oncology Center of Excellence, which provides a framework for concurrent submission and review of oncology medicines among international partners. These included Health Canada, the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency (Anvisa), Swissmedic, and Singapore Health Sciences Authority. The UK Medicines and Healthcare products Regulatory Agency participated in the review as an observer.

In China, Tagrisso is under priority review for the adjuvant treatment of patients with early-stage EGFRm NSCLC based on the ADAURA Phase III trial. This indication is also under regulatory review in the EU and additional global submission discussions are ongoing.

Tagrisso is a once-daily oral tablet approved for the 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC and for the treatment of locally advanced or metastatic EGFR T790M mutation-positive NSCLC in the US, Japan, China, the EU and many other countries around the world.

Lung cancer
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.5 Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.6 The majority of all NSCLC patients are diagnosed with advanced disease while approximately 25-30% present with resectable disease at diagnosis.1-3

For patients with resectable tumours, the majority of patients eventually develop recurrence despite complete tumour resection and adjuvant chemotherapy.4 Early-stage lung cancer diagnoses are often only made when the cancer is found on imaging for an unrelated condition.7-8

Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.9-11 These patients are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which block the cell-signalling pathways that drive the growth of tumour cells.12

ADAURA
ADAURA is a randomised, double-blinded, global, placebo-controlled Phase III trial in the adjuvant treatment of 682 patients with Stage IB, II, IIIA EGFRm NSCLC following complete tumour resection and adjuvant chemotherapy as indicated. Patients were treated with Tagrisso 80mg once-daily oral tablets or placebo for three years or until disease recurrence.

The trial enrolled in more than 200 centres across more than 20 countries, including the US, in Europe, South America, Asia and the Middle East. The primary endpoint was DFS in Stage II and IIIA patients and a key secondary endpoint was DFS in Stage IB, II and IIIA patients. The data readout was originally anticipated in 2022. The trial will continue to assess overall survival.

Tagrisso
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with clinical activity against central nervous system metastases Tagrisso 40mg and 80mg once-daily oral tablets have received approval in the US, Japan, China, the EU and many countries around the world for 1st-line EGFRm advanced NSCLC and EGFR T790M mutation-positive advanced NSCLC.

AstraZeneca in lung cancer
AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage development for the treatment of different forms of lung cancer spanning different histologies, several stages of disease, lines of therapy and modes of action.

AstraZeneca aims to address the unmet needs of patients with EGFRm tumours as a genetic driver of disease with the approved medicines Iressa (gefitinib) and Tagrisso, and its ongoing Phase III trials LAURA, NeoADAURA, and FLAURA2.

AstraZeneca is committed to addressing tumour mechanisms of resistance through the ongoing Phase II trials SAVANNAH and ORCHARD which test Tagrisso in combination with savolitinib, a selective inhibitor of c-MET receptor tyrosine kinase, along with other potential new 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 seven 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.

By harnessing the power of six scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics, and Cell Therapies – 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.

Astellas Reports XOSPATA® (gilteritinib) in Combination with Azacitidine Did Not Meet Endpoint of Overall Survival in Newly Diagnosed FLT3 Mutation-Positive Acute Myeloid Leukemia Patients Ineligible for Intensive Induction Chemotherapy

On December 21, 2020 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") reported that a Phase 3 trial of XOSPATA (gilteritinib) plus azacitidine versus azacitidine alone in newly diagnosed FLT3 mutation-positive (FLT3mut+) acute myeloid leukemia (AML) patients who were ineligible for intensive induction chemotherapy did not meet its primary endpoint of overall survival at a planned interim analysis of the LACEWING trial (Press release, Astellas, DEC 21, 2020, View Source [SID1234573126]). An independent Data Monitoring Committee recommended terminating the study for futility, concluding results are unlikely to show a statistically significant increase in overall survival. Astellas has stopped enrollment in the trial and is reviewing the results for other action as needed.

"Although we are disappointed by the primary outcome of LACEWING, we are conducting a thorough review of the data and plan to share detailed results at a later date," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head, Astellas. "These results do not affect other ongoing gilteritinib trials. We remain committed to our comprehensive program investigating gilteritinib across a wide range of AML patients with a positive FLT3 mutation, building on gilteritinib’s earlier, positive data in patients with relapsed or refractory FLT3 mutation-positive AML."

AML, a cancer of the blood and bone marrow, is one of the most common types of leukemia in adults.1 It has the lowest survival rate of all types of leukemia.2 Approximately one-third of people with AML have a FLT3 mutation.3,4 This mutation is associated with worsened disease-free survival and overall survival, and a higher risk of getting the disease more than once.3,4,5 Among patients with FLT3mut+ AML, an estimated 30-40 percent are not candidates for intensive chemotherapy regimens because of age, performance status, and/or comorbid conditions.6