On December 8, 2022 Dantari, Inc. ("Dantari"), a clinical-stage biotechnology company developing best-in-class targeted therapeutics for the treatment of cancers and other diseases, reported that its emergence from stealth mode with $47 million Series A financing (Press release, Dantari, DEC 8, 2022, View Source [SID1234624938]). The Series A financing was led by Westlake Village BioPartners ("Westlake") and included participation from Corner Ventures, Alexandria Venture Investments, and Caltech. The Company also announced the appointment of Richard A. Markus, M.D., Ph.D., as president and chief executive officer (CEO), and its board of directors, chaired by Sean Harper, M.D., a co-founding managing director at Westlake.

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Proceeds from the financing support the advancement of Dantari’s differentiated antibody-drug conjugate (ADC) and chemotherapeutic platforms. Dantari’s platform of T-HDC (Targeted High-capacity Drug Conjugate) technology enables a significantly higher drug-antibody ratio (DAR) and tunable-release of chemotherapy compared to today’s ADCs. The Company’s next-generation targeted therapeutics can deliver larger payloads with a DAR of 60 for greater efficacy, and their biodistribution reduces bone marrow exposure, providing broad therapeutic potential.

The Company’s lead clinical investigational product is DAN-222, a novel HDC chemotherapeutic agent with a topoisomerase 1 inhibitor (topo1) payload. The use of topo1 products is often limited due to bone marrow toxicity. Because of its low bone marrow exposure in preclinical models, DAN-222 has the potential to broaden indications and provide new utility as a combination therapy with PARP inhibitors and other agents. DAN-222 is being evaluated in a Phase 1/2 clinical trial for the treatment of metastatic human epidermal growth factor receptor (HER) 2-negative breast cancer. Early results from the dose-escalation portion of the study will be presented today in a poster session at the 2022 San Antonio Breast Cancer Symposium (SABCS). The study is ongoing and full results will be presented in a future scientific forum.

Dantari’s pipeline also includes several next-generation ADC programs leveraging the T-HDC platform. The Company’s next program, DAN-311 for HER2-positive and HER2-low breast cancer, is planned to enter the clinic in the second half of 2023. Dantari’s other T-HDC product candidates combining validated targets and payloads for a variety of solid tumors including prostate cancer are progressing through preclinical development.

"We are excited to announce Dantari’s launch and initial clinical data. Our vision is to deliver groundbreaking next-generation targeted high-capacity therapeutics with enhanced efficacy and safety," said Dr. Markus. "DAN-222, our lead program in HER2-negative breast cancer, has significant commercial potential while also substantially de-risking our T-HDC platform technology. We look forward to sharing our dose-escalation data today at SABCS which demonstrate excellent translation from preclinical species into patients. We will continue to progress our pipeline as rapidly as possible, including advancing our lead T-HDC candidate DAN-311 in HER2-positive and HER2-low breast cancer into the clinic in 2023. We look forward to bringing much-needed new options to patients who have failed current therapies including traditional ADCs."

Dantari’s HDC and T-HDC platform technology originated at the California Institute of Technology (Caltech) with more than 20 years of research and uses standard organic chemistry manufacturing. Dantari’s T-HDC platform uses chemically defined polymers with a high degree of control and flexibility to optimize performance of targeted drug conjugates and leverages validated targets across a broad range of therapeutic payload options. Payload conjugation enables tunable-controlled release, with no ‘burst release’ and the high drug load enables more payload for greater bystander effect killing of tumor cells including in heterogenous tumors.

Dr. Harper commented, "The Dantari team has made great progress in building a world-class platform for oncology drug innovation. Dantari’s proprietary T-HDC platform provides significantly enhanced capabilities for targeted delivery of therapeutics, which I believe will usher in a step-change in the treatment of solid tumors. With Richard at the helm and this outstanding team, we look forward to the exciting future for this company and the medicines it will advance for patients."

As part of the Series A financing, Mark Davis, Ph.D., Warren and Katherine Schlinger Professor of Chemical Engineering at Caltech, and Pascal Touchon, president and CEO of Atara Biotherapeutics, join Drs. Harper and Markus on the Company’s board of directors.

DAN-222 Phase 1 dose-escalation data at San Antonio Breast Cancer Symposium
Poster Title: A Dose-escalation Study of the Safety and Pharmacology of DAN-222 in Subjects with Metastatic Breast Cancer (NCT05261269)
Presenter: Tim Hagerty, Ph.D., vice president of translational sciences, Dantari
Poster ID: OT3-28-01
Session: Ongoing Trials Poster Session 3
Date/Time/Location: Thursday, December 8, 2022; 5:00-6:15 PM CT, Henry B. Gonzalez Convention Center

DAN-222, a novel clinical investigational product, has complementary mechanism of action with PARP inhibitors and can be used in combination since it has demonstrated reduced bone marrow risk in preclinical models. Importantly, the complementary enhanced efficacy is independent of tumor homologous repair deficiency (HRD) status, including BRCA status.

This is an open-label, multicenter, dose-escalation study designed to assess the safety, tolerability, and pharmacokinetics (PK) of intravenously (IV) administered DAN-222 and includes a dose-escalation of DAN-222 in combination with niraparib in patients with HER2-negative metastatic breast cancer.

Results from the first three cohorts showed that the PK profiles of DAN-222 are linear and dose proportional, and that DAN-222 is stable and releasing the payload with consistent kinetics with very low variability between patients (CV% = 7.1 – 20.5). The PK profile of DAN-222 is consistent with and without niraparib.

"These early data on DAN-222 are encouraging as they show this novel platform with high chemotherapy capability appears to be delivering as expected and is well tolerated by patients," said Sara A. Hurvitz, M.D., associate professor at the David Geffen School of Medicine at University of California, Los Angeles (UCLA), medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit, co-director of the Santa Monica-UCLA Outpatient Oncology Practices, director of the Breast Cancer Clinical Trials Program at UCLA, and clinical consultant and principal investigator of the study.

On December 2, 2022, Arrowhead Pharmaceuticals, Inc. (the "Company") entered into an open market sale agreement (the "Open Market Sale Agreement") with Jefferies LLC (the "Agent"), pursuant to which the Company agreed to issue and sell up to 7,807,620 shares of common stock (the "Shares"), par value $0.001 per share (the "Common Stock") (Filing, Arrowhead Research Corporation, DEC 8, 2022, View Source [SID1234624937]). The Company estimates that gross proceeds from the offering will be approximately $250 million, after deducting the Agent’s discounts and commissions and estimated offering expenses payable by the Company.

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The offering is being made pursuant to the Company’s automatically effective shelf registration statement on Form S-3 (Registration No. 333-268665), which was previously filed with the Securities and Exchange Commission.

The offering closed on December 2, 2022. Pursuant to the Open Market Sale Agreement, the Company has agreed to indemnify the Agent against certain liabilities, including liabilities under the Securities Act of 1933, as amended, or to contribute to payments that the Agent may be required to make because of such liabilities. The Open Market Sale Agreement contains other customary terms and conditions, including representations and warranties, covenants, and indemnification obligations in favor of each party.

The foregoing descriptions of the Open Market Sale Agreement do not purport to be complete and are qualified in their entirety by reference to the full text of the Open Market Sale Agreement, a copy of which is attached hereto as Exhibit 1.1. A copy of the opinion of Gibson, Dunn & Crutcher LLP relating to the legality of the issuance and sale of the of the Shares is attached to this Current Report on Form 8-K as Exhibit 5.1.

On December 8, 2022 Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies, reported that it has commenced an underwritten public offering of American Depositary Shares ("ADSs"), each ADS representing one ordinary share (Press release, Autolus, DEC 8, 2022, View Source [SID1234624934]). All ADSs to be sold in the proposed offering will be offered by Autolus. Autolus also intends to grant the underwriters a 30-day option to purchase up to 15 percent of the ADSs sold in connection with the offering at the public offering price, on the same terms and conditions. The offering is subject to market conditions, and there can be no assurance as to whether or when the offering may be completed or the actual size or terms of the offering.

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Jefferies LLC, William Blair & Company, L.L.C. and Wells Fargo Securities, LLC are acting as joint bookrunners for the offering.

The securities are being offered pursuant to an effective shelf registration statement that was previously filed with the Securities and Exchange Commission ("SEC"). The offering will be made only by means of a written prospectus and prospectus supplement that form a part of the registration statement, which, for the avoidance of doubt, will not constitute a "prospectus" for the purposes of the Regulation (EU) 2017/1129 and has not been reviewed by any competent authority in any member state in the European Economic Area. A preliminary prospectus supplement relating to the securities will be filed with the SEC and will be available on the SEC’s website at www.sec.gov.

When available, copies of the preliminary prospectus supplement and the accompanying prospectus relating to these securities may be obtained for free from the joint book-running managers for the offering, Jefferies LLC, Attention: Equity Syndicate Prospectus Department, 520 Madison Avenue, 2nd Floor, New York, NY 10022, by telephone at (877) 821-7388 or by email at [email protected]; William Blair & Company, L.L.C., Attention: Prospectus Department, 150 North Riverside Plaza, Chicago, IL 60606, by telephone at (800) 621-0687, or by email at [email protected]; or Wells Fargo Securities, LLC, Attention: Equity Syndicate Department, 500 West 33rd Street, New York, New York, 10001, at (833) 690-2713 or email a request to [email protected]. For the avoidance of doubt, such prospectus will not constitute a "prospectus" for the purposes of Regulation (EU) 2017/1129 and will not have been reviewed by any competent authority in any member state in the European Economic Area.

This press release does not constitute an offer to sell or the solicitation of an offer to buy securities, and shall not constitute an offer, solicitation or sale in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of that jurisdiction.

On December 8, 2022 Astrazeneca reported Detailed results from the CAPItello-291 Phase III trial showed AstraZeneca’s capivasertib in combination with Faslodex (fulvestrant) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) versus placebo plus Faslodex in patients with hormone receptor (HR)-positive, HER2-low or negative, locally advanced or metastatic breast cancer, following recurrence or progression on, or after, endocrine therapy (with or without a CDK4/6 inhibitor) (Press release, AstraZeneca, DEC 8, 2022, View Source [SID1234624932]). Results will be presented today in an oral presentation at the 2022 San Antonio Breast Cancer Symposium (SABCS).

Results showed capivasertib in combination with Faslodex demonstrated a 40% reduction in the risk of disease progression or death versus placebo plus Faslodex in the overall trial population (based on a hazard ratio [HR] of 0.60, 95% confidence interval [CI] 0.51-0.71; p=<0.001; median 7.2 versus 3.6 months).1 In the AKT pathway biomarker-altered population, capivasertib plus Faslodex reduced the risk of disease progression or death by 50% versus placebo plus Faslodex (HR of 0.50, 95% CI 0.38-0.65; p=<0.001; median 7.3 versus 3.1 months).1 Alterations within the AKT pathway (PI3K/AKT/PTEN) occur frequently in breast cancer, affecting up to 50% of patients with advanced HR-positive breast cancer.2-4

Nicholas Turner, MD, PhD, Professor of Molecular Oncology at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, London, UK, and principal investigator in the CAPItello-291 Phase III trial, said: "These data demonstrate the practice-changing potential of capivasertib as a new treatment option for patients with advanced HR-positive breast cancer. Critically, this potentially first-in-class treatment has shown it delays disease progression for those who have progressed on, or become resistant to, endocrine therapies and CDK4/6 inhibitors."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Capivasertib brings important progress to an area with persistent treatment gaps as the first therapy of its kind shown to be effective in a Phase III trial in patients with advanced HR-positive, HER2-low or negative breast cancer. We believe these results which showed benefit in all-comers and biomarker positive populations can reshape HR-positive breast cancer treatment, and that capivasertib can become an important new option for patients."

Summary of results: CAPItello-2911

Capivasertib plus Faslodexn=355
Placebo plus Faslodex
n=353
Median PFS in overall population (months)

7.2
3.6
HR (95% CI)

0.60 (0.51-0.71)
p-value

p=<0.001
Median PFS in the biomarker-altered population (months)

7.3
3.1
HR (95% CI)

0.50 (0.38-0.65)
p-value

p=<0.001
ORR in overall population

22.9%
12.2%
ORR in biomarker-altered population

28.8%
9.7%
HR, hazard ratio; CI, confidence interval; PFS, progression-free survival; ORR, objective response rate

Confirmed objective response rate (ORR) was 22.9% for the capivasertib plus Faslodex arm versus 12.2% for the placebo plus Faslodex arm in the overall trial population, and 28.8% versus 9.7%, respectively, in the biomarker-altered population.1 Although the overall survival (OS) data were immature at the time of the analysis, early data are encouraging.1 The trial will continue to assess OS as a key secondary endpoint.

The safety profile of capivasertib plus Faslodex was similar to that observed in previous trials evaluating this combination.1 In the overall trial population, the most frequent any grade adverse events (AEs) with capivasertib plus Faslodex occurring in 20% or more of patients were diarrhoea (72.4%), nausea (34.6%), rash (group term including rash, rash macular, maculo-papular rash, rash papular and rash pruritic; 38%) fatigue (20.8%) and vomiting (20.6%).1 The most frequent Grade 3 or higher AEs occurring in 5% or more of patients were diarrhoea (9.3%) and rash (12.1%).1

Notes

HR-positive breast cancer
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.5 More than two million patients were diagnosed with breast cancer in 2020, with nearly 685,000 deaths globally.5

HR-positive breast cancer (expressing estrogen or progesterone receptors, or both), is the most common subtype of breast cancer with approximately 70% of breast cancer tumours considered HR-positive and HER2-low or negative.6

The growth of HR-positive breast cancer cells is often driven by estrogen receptors (ER),7 andendocrine therapies that target ER-driven disease are widely used as 1st-line treatment in the advanced setting, and often paired with cyclin-dependent kinase (CDK) 4/6 inhibitors.8,9 However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease.9 Once this occurs, treatment options are limited9 – with chemotherapy being the current standard of care10 – and survival rates are low with 30% of patients anticipated to live beyond five years after diagnosis.6

Optimising endocrine therapy and overcoming resistance for patients with ER-driven disease at all stages of treatment as well as identifying new therapies for those who no longer have ER-driven disease are active areas of focus for breast cancer research.

CAPItello-291
CAPItello-291 is a Phase III, double-blind, randomised trial that is part of a larger clinical programme focused on capivasertib, an investigational AKT (serine/threonine kinase) inhibitor. CAPItello-291 is evaluating the efficacy of capivasertib in combination with Faslodex versus placebo plus Faslodex for the treatment of locally advanced (inoperable) or metastatic HR-positive, HER2-low or negative breast cancer.

The global trial enrolled 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer whose disease has recurred or progressed during or after aromatase inhibitor therapy, with or without a CDK4/6 inhibitor, and up to one line of chemotherapy for advanced disease. The trial has dual primary endpoints of PFS in the overall patient population and in a population of patients whose tumours have qualifying alterations in the AKT pathway (PIK3CA, AKT1 or PTEN genes). In the trial, approximately 40% of tumours had these alterations.

Capivasertib
Capivasertib is an investigational oral treatment currently in Phase III trials for the treatment of multiple subtypes of breast cancer, prostate cancer and a Phase II trial for haematologic malignancies. A potent, selective adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3), capivasertib is being evaluated as a monotherapy and in combination with existing therapies in tumours harbouring alterations in the AKT pathway (PI3K/AKT/PTEN), and in tumours reliant on signalling via this pathway for survival. Capivasertib 400 mg is administered twice daily according to an intermittent dosing schedule of four days on and three days off. This was chosen in early phase trials based on tolerability and the degree of target inhibition.

The capivasertib clinical research programme is investigating the safety and efficacy of capivasertib when used alone and in combination with established treatment regimens.

Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).

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On December 8, 2022 Arvinas presented its clinical trial results for ARV-471 Veritac trial (Presentation, Arvinas, DEC 8, 2022, View Source [SID1234624931]).

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