CytRx Selects Four New LADR™ Ultra High Potency Drug Candidates for Advancement Toward Clinical Trials

LOS ANGELES, March 15, 2018 /PRNewswire/ -- CytRx Corporation (NASDAQ: CYTR), a biopharmaceutical research and development company specializing in oncology, today announced that it has selected four new, investigational LADR™ (Linker Activated Drug Release) candidates for advancement toward clinical testing in cancer patients. The candidates, preliminarily named LADR-7 (AE-Keto-Sulf07), LADR-8 (AE-Ester-Sulf07), LADR-9 (PP072) and LADR-10 (FN296), were created using CytRx's novel LADR™ technology which enables drug compounds to bind to albumin in the body's bloodstream and controls the release of the drug at the tumor site.  All four candidates are eligible to advance into Investigational New Drug (IND)-enabling studies with the goal of filing IND applications on one or more candidates in 2018.

Supportive data demonstrating the impressive in vivo antitumor efficacy of LADR-7, LADR-8, LADR-9 and LADR-10 will be presented at the American Association for Cancer Research (AACR) 2018 Annual Meeting taking place April 14-18, 2018 in Chicago. All studies submitted to AACR were selected for poster presentations.

"The posters being presented at AACR this year highlight the positive research supporting our decision to select LADR-7, LADR-8, LADR-9 and LADR-10 as LADR™ drug candidates which are eligible to advance toward IND-enabling studies," said Felix Kratz, PhD, CytRx's Vice President of Drug Discovery.  "For LADR-7 and LADR-8, the presented data will describe the greatly improved antitumor efficacy of these compounds compared to their parent compound auristatin E, along with their potential to induce statistically significant, long-term partial or complete remission in several tumor-bearing animal models.  For LADR-9 and LADR-10, the presented data document the synthesis of a spectrum of novel maytansinoid derivatives that were discovered to be as potent or more potent than the parent drug maytansine in inhibiting the growth in a panel of human cancer cells. Subsequently, two highly potent maytansinoid derivatives were selected for developing the albumin-binding drug candidates LADR-9 and LADR-10. Both LADR-9 and LADR-10 were well-tolerated and induced long-term partial and complete tumor regressions in a number of tumor-bearing animal models. These results are statistically significant compared to maytansine which was essentially devoid of in vivo antitumor activity. We are excited about this new research and the selection of the LADR™ ultra high potency compounds, which we believe may have breakthrough status against numerous solid tumors, and we look forward to sharing our data with the medical and scientific community at this year's AACR meeting."

Details for the poster presentations at AACR 2018:

Title: Superior efficacy of novel albumin-binding auristatin E-based prodrugs compared to auristatin E in a panel of human xenograft models in mice.

Abstract Number: 3703

Session Category and Title:  Cancer Chemistry; Drug Delivery
Session Date and Time: Tuesday, April 17, 2018 8:00 AM - 12:00 PM
Location: McCormick Place South, Exhibit Hall A, Poster Section 30
Poster Board Number: 3

Summary: Auristatins are a highly cytotoxic family of antimitotic tubulin-binding peptides. As a result, to date, only one auristatin antibody drug conjugate (Adcetris®) has been approved and marketed. Other auristatins have been investigated in Phase 1 and 2 clinical trials, but due to systemic toxicity and low antitumor activity they were discontinued. Due to the high cytotoxicity, CytRx researchers hypothesized that delivery of auristatins selectively to the tumor, avoiding premature release in the blood circulation, would be beneficial. In this study, CytRx researchers utilized the Company's novel LADR™ technology to synthesize auristatin E-derived prodrugs (AE-Keto-Sulf07 and AE-Ester-Sulf07) that are bound covalently to human albumin and is designed to be liberated in the acidic environment of the tumor. The researchers conducted a head-to-head comparison of AE-Keto-Sulf07 and AE-Ester-Sulf07 to parent compound auristatin E in human tumor xenograft models.

In this study, AE-Keto-Sulf07 showed excellent antitumor response over a wide dose range, with optimal dosage at 4.5 mg/kg twice per week over 4 weeks. AE-Ester-Sulf07 was also highly efficacious. In contrast, auristatin E was only marginally active. The results demonstrated that AE-Keto-Sulf07 and AE-Ester-Sulf07 successfully bound to circulating albumin, demonstrated promising antitumor efficacy and induced statistically significant long-term partial or complete remission.

Title: Structure-activity relationship studies and biological evaluation of novel maytansinoids, a class of highly selective tubulin inhibitors

Abstract Number: 1657

Session Category and Title: Cancer Chemistry; Target Based Drug Discovery
Session Date and Time: Monday, April 16, 2018; 8:00 a.m. to 12:00 p.m. CT
Location: McCormick Place South, Exhibit Hall A, Poster Section 30
Poster Board Number: 12

Summary: Maytansine is a potent microtubule-targeting compound that inhibits proliferation of cancer cells, but its narrow therapeutic window prevents most clinical application and to date only one maytansinoid antibody (Kadcyla®) has been approved for use in resistant breast cancer. Prior research has shown that the potent cytotoxic activity of maytansinoids is related to the nature of the substituent at the C3 acyloxy chain. In this study, CytRx researchers synthesized a library of novel maytansine analogs that can be attached to serum albumin in vivo via an acid-sensitive linker which releases the maytansinoid at the tumor site, thereby diminishing dose-limiting side effects. Each of the novel maytansine analogs were analyzed in vitro for potency and cytotoxicity against 11 cancer cell lines, compared to maytansine. Of the 32 newly synthesized maytansinoid analogs, seven were found to be more potent than the parent drug maytansine in inhibiting the growth of human cancer cells. Clear structure-activity relationships were identified. Based on these results, lead compounds have been selected for creating albumin-binding derivatives and their further in vivo evaluation. 

Title: Novel albumin-binding maytansinoids inducing long-term partial and complete tumor regressions in several human cancer xenograft models in nude mice.

Abstract Number: 2661

Session Category and Title: Cancer Chemistry; Antitumor Agents
Session Date and Time: Monday, April 16, 2018 1:00 PM - 5:00 PM
Location: McCormick Place South, Exhibit Hall A, Poster Section 30
Poster Board Number: 1

Summary: The goal of this study was to determine if novel maytansinoids could be created using CytRx's LADR technology that would carry the same potent cell killing properties as maytansine, while reducing cytotoxic side effects. In this study, CytRx researchers synthesized a library of potent maytansinoids that were attached to a water-solubilizing hydrazone linker utilizing the Company's novel LADR™ technology. Maytansinoid-linker derivatives selectively bind to human albumin and are designed to be liberated in the acidic environment of the tumor. The researchers conducted a head-to-head comparison of the novel albumin-binding maytansinoids with parent drug maytansine in human tumor xenograft models.

Treatment with CytRx's novel albumin-binding maytansinoids was better tolerated than with maytansine and maximum tolerated doses were 4 to 7 times higher showing no significant body weight loss (<5%). The novel albumin-binding maytansinoids demonstrated a significantly higher antitumor activity compared to both the control-group and the group treated with maytansine and induced long-term partial and complete tumor regressions in all experiments.

Following the conclusion of the poster presentations, PDF copies of the posters will be available at http://cytrx.com/investors/presentations.

About the LADR™ Technology Platform

CytRx's innovative LADR™ (Linker Activated Drug Release) technology employs a broad portfolio of novel linker molecules that selectively bind to circulating albumin and can be linked to a wide variety of anti-cancer payloads. The Company's research efforts currently center on creating new molecules from the combination of ultra-high potency cytotoxic payloads with tunable linkers. The molecules that CytRx is currently evaluating concentrate at the tumor site providing targeted delivery of the cell killing payloads.

About CytRx Corporation

CytRx Corporation (NASDAQ: CYTR) is a biopharmaceutical company specializing in research and clinical development of novel anti-cancer drug candidates that employ linker technologies to enhance the accumulation and release of drug at the tumor. CytRx is rapidly expanding its pipeline of ultra-high potency oncology candidates at its laboratory facilities in Freiburg, Germany, through its LADR™ (Linker Activated Drug Release) technology platform, a discovery engine designed to leverage CytRx's expertise in albumin biology and linker technology for the development of a new class of potential breakthrough anti-cancer therapies. Aldoxorubicin, CytRx's most advanced drug conjugate, is an improved version of the widely used anti-cancer drug doxorubicin and has been out-licensed to NantCell, Inc.

About AACR

AACR is the oldest and largest scientific organization in the world focused on every aspect of high-quality, innovative cancer research. Its reputation for scientific breadth and excellence attract the premier researchers in the field. The organization's programs and services foster the exchange of knowledge and new ideas among scientists dedicated to cancer research, provide training opportunities for the next generation of cancer researchers, and increase public understanding of cancer. Presentations at the AACR Annual Meeting will cover the latest basic, translational, clinical, and prevention-focused research in the field, including important areas such as early detection, cancer interception, and survivorship in all populations. 

Forward-Looking Statements

This press release contains forward-looking statements. Such statements involve risks and uncertainties that could cause actual events or results to differ materially from the events or results described in the forward-looking statements, including risks and uncertainties relating to the ability of NantCell, Inc., to obtain regulatory approval for its products that use aldoxorubicin; the ability of NantCell, Inc., to manufacture and commercialize products or therapies that use aldoxorubicin; the amount, if any, of future milestone and royalty payments that we may receive from NantCell, Inc.; our ability to develop new ultra-high potency drug candidates based on our LADR^TM technology platform; and other risks and uncertainties described in the most recent annual and quarterly reports filed by CytRx with the Securities and Exchange Commission and current reports filed since the date of CytRx's most recent annual report. All forward-looking statements are based upon information available to CytRx on the date the statements are first published. CytRx undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

Investor Relations Contact:
Argot Partners
Michelle Carroll/Sean Augustine-Obi
(212) 600-1902
[email protected]
[email protected]

SOURCE CytRx Corporation

Related Links

http://www.cytrx.com