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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Summary of TROPION-PanTumor01 Results

Efficacy Measure

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

ORR, %iii, iv

43% (n=9)

CR/PR (confirmed)

n=5

CR/PR (pending confirmation)

n=4

DCR, %v

95% (n=20)

PD, %

5% (n=1)

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

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

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

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

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

v DCR is CR+PR+SD.

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

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

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

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

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

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

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

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

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

On May 7, 2021 Applied DNA Sciences, Inc. (NASDAQ: APDN) ("Applied DNA" or the "Company"), a leader in Polymerase Chain Reaction (PCR)-based DNA manufacturing, reported that it will report fiscal 2021 second quarter financial results after market close on Thursday, May 13, 2021 (Press release, Applied DNA Sciences, MAY 7, 2021, View Source [SID1234579454]). The Company’s management will discuss the results during a conference call and simultaneous webcast at 4:30 p.m. ET that same day. Presentation slides will also be posted to the ‘IR Calendar’ section of the Company’s corporate website and embedded into the live webcast.

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Conference Call and Webcast Information – Replay
A telephonic replay of the conference call will be available for one week beginning one hour after the end of the live conference call.

Webcast: View Source

Availability: Telephonic replay: until Thursday, May 20, 2021; webcast replay: 1 year

The webcast and accompanying PowerPoint presentation will also be archived on the ‘IR Calendar’ page listed under the Investor Relations drop-down menu on the Company’s website.

On May 7, 2021 Cytokinetics, Incorporated (Nasdaq: CYTK) reported financial results for the first quarter of 2021. Net loss for the first quarter was $47.1 million, or $0.66 per share, compared to net loss for the first quarter of 2020 of $39.4 million, or $0.66 per share. Cash, cash equivalents and investments totaled $460.2 million at March 31, 2021 (Press release, Cytokinetics, MAY 7, 2021, View Source,million%2C%20or%20%240.66%20per%20share. [SID1234579474]).

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"We continued to execute well in the first quarter against our ambitious plans. We recently convened a meeting with FDA related to omecamtiv mecarbil and GALACTIC-HF and are proceeding towards additional planned meetings this quarter with an expected NDA submission in the second half of the year," said Robert I. Blum, Cytokinetics’ President and Chief Executive Officer. "We look forward to the presentation of a secondary analysis from GALACTIC-HF which will shed further light on the impact of ejection fraction on patient outcomes. Additionally, we were pleased to complete enrollment in Cohort 2 of REDWOOD-HCM and more recently begin enrollment in the open-label extension study. We expect results from REDWOOD-HCM mid-year and are planning to initiate a pivotal Phase 3 trial by year-end."

Q1 and Recent Highlights

Cardiac Muscle Programs

omecamtiv mecarbil (cardiac myosin activator)

Met with the U.S. Food and Drug Administration (FDA) in Q1 and anticipate additional regulatory interactions in Q2 to inform plans to submit a New Drug Application (NDA) for omecamtiv mecarbil in 2H 2021. The planned regulatory filing is expected to be based on a single pivotal trial, GALACTIC-HF, which demonstrated a positive effect on the primary composite endpoint of cardiovascular death or heart failure events in patients receiving standard of care plus omecamtiv mecarbil

Announced that data from a secondary analysis of GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) assessing the effect of omecamtiv mecarbil on clinical outcomes in relationship to patient baseline ejection fraction will be presented in a Late Breaking Clinical Trial session at the American College of Cardiology 70th Annual Scientific Session & Expo (ACC.21).

Continued conduct of METEORIC-HF (Multicenter Exercise Tolerance Evaluation of Omecamtiv Mecarbil Related to Increased Contractility in Heart Failure), the second Phase 3 trial of omecamtiv mecarbil. Expect to complete enrollment in Q2 and report results in early 2022.

Conducted market research, forecasting and other planning activities in support of the potential commercialization of omecamtiv mecarbil.

Published a manuscript entitled, "Effect of Varying Degrees of Renal Impairment on the Pharmacokinetics of Omecamtiv Mecarbil" in Clinical Pharmacokinetics.
CK-3773274 (CK-274, cardiac myosin inhibitor)

Dosed the first patient in Cohort 2 of REDWOOD-HCM (Randomized Evaluation of Dosing With CK-274 in Obstructive Outflow Disease in HCM), the Phase 2 clinical trial designed to determine the safety and tolerability of CK-274 in patients with obstructive hypertrophic cardiomyopathy (oHCM). We subsequently completed enrollment in Cohort 2 of REDWOOD-HCM in Q1.

Opened enrollment in Cohort 3 of REDWOOD-HCM for patients whose background therapy includes disopyramide.

Activated the first site for enrollment in REDWOOD-HCM OLE, the open label extension clinical study designed to assess the long-term safety and tolerability of CK-274 in patients with symptomatic oHCM who have participated previously in REDWOOD-HCM.

Received orphan drug designation for CK-274 for the potential treatment of symptomatic HCM from the FDA.

Prepared for regulatory interactions with FDA to occur in Q2 and continuing into the second half of 2021 to inform preparations for a pivotal Phase 3 clinical trial of CK-274 in HCM, expected to begin by year-end.

Recently presented data related to the optimization of CK-274, including the first disclosure of its chemical structure, at the American Chemical Society Spring 2021 Virtual Meeting.

Enrolled the first patient in a Phase 1 study of CK-274 in China under the License and Collaboration Agreement between Cytokinetics and Ji Xing Pharmaceuticals Limited.
Skeletal Muscle Program

reldesemtiv (next-generation fast skeletal muscle troponin activator (FSTA))

Conducted start-up activities, including regulatory and institutional review board submissions, for COURAGE-ALS (Clinical Outcomes Using Reldesemtiv on ALSFRS-R in a Global Evaluation in ALS), the planned Phase 3 clinical trial of reldesemtiv in patients with ALS, in preparation for the potential opening of the trial to patient enrollment in 2H 2021.

Completed joint research program under collaboration with Astellas directed to the discovery of next-generation skeletal muscle activators.

Published a manuscript entitled "Reldesemtiv in Patients with Spinal Muscular Atrophy: A Phase 2 Hypothesis-Generating Study" in Neurotherapeutics.
Pre-Clinical Development and Ongoing Research

Continued to advance new chemical entities and to conduct IND-enabling studies with expectation of our potentially advancing 1-2 potential drug candidates in development over the next year.

Continued research activities directed to our other muscle biology research programs.
Corporate

Conducted planning activities related to the termination of the Collaboration and Option Agreement with Amgen and the transition of rights to develop and commercialize omecamtiv mecarbil, effective May 20, 2021.

Joined with the European Organisation for Rare Diseases (EURORDIS) and the National Organization for Rare Disorders (NORD) to recognize Rare Disease Day, an international campaign elevating the public understanding of rare diseases.

Awarded Cytokinetics Communications Fellowship Grants to patient advocacy organizations serving the heart failure, HCM, ALS and SMA communities to support increased capacity in communications, disease awareness and community engagement.

Convened inaugural Heart Failure Advisory Council meeting with patients and caregivers with heart failure to inform the ongoing development of the company’s heart failure directed pipeline.
Financials

Revenues for the first quarter 2021 increased to $6.5 million from $3.8 million for the first quarter 2020 due to increased research and development revenue from our collaborations with Amgen and Astellas.

Research and development expenses for the first quarter 2021 increased to $31.6 million from $21.7 million for the first quarter of 2020. The changes were primarily due to increases in spending for COURAGE-ALS and our clinical development activities for our cardiac muscle inhibitor programs.

General and administrative expenses for the first quarter of 2021 increased to $15.6 million from $12.4 million for the first quarter in 2020, due primarily to an increase in personnel related costs including stock-based compensation and higher outside spending for commercial readiness.

We expect to revise our financial guidance mid-year once we finalize strategies and potential commercial launch plans for omecamtiv mecarbil. Executing on those strategies and plans may result in our incurring significant additional expenses that were not included in our current financial guidance. We expect that some or all of those potential expenses could be covered by our accessing additional capital through strategic partnership(s) with near term cash infusions or by equity and/or debt financings if deemed appropriate.

Conference Call and Webcast Information

Members of Cytokinetics’ senior management team will review the company’s first quarter 2021 results via a webcast and conference call today at 4:30 PM Eastern Time. The webcast can be accessed through the Investors & Media section of the Cytokinetics website at www.cytokinetics.com. The live audio of the conference call can also be accessed by telephone by dialing either (866) 999-CYTK (2985) (United States and Canada) or +1 (706) 679-3078 (international) and typing in the passcode 6097958.

An archived replay of the webcast will be available via Cytokinetics’ website until May 20, 2021. The replay will also be available via telephone by dialing (855) 859-2056 (United States and Canada) or +1 (404) 537-3406 (international) and typing in the passcode 6097958 from May 6, 2021 at 7:30 PM Eastern Time until May 20, 2021.

On May 7, 2021 Anavex Life Sciences Corp. ("Anavex" or the "Company") (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, reported that its President and Chief Executive Officer, Christopher U. Missling, PhD, will give a presentation titled, "Clinical Trials for Rare Diseases: Challenges and Opportunities", at the Precision in Clinical Trials Virtual Summit (East Coast) on Monday, May 10that 9:35 a.m. EDT (Press release, Anavex Life Sciences, MAY 7, 2021, View Source [SID1234579429]). The Precision in Clinical Trials Virtual Summit (East Coast) takes place May 10th – 11th 2021.

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