Altamira in strategic repositioning to develop RNA therapeutics

Altamira Therapeutics (NASDAQ:CYTO) is using its recent acquisition of closelyheld Trasir Therapeutics as a steppingstone for a strategic repositioning to focus on development of RNA therapeutics, while in the medium term aiming to spinoff or divest its legacy assets in neurotology, rhinology and allergology to unlock their value for the Company’s shareholders.


“We aim to be a leading company for effective delivery of RNA payloads to tissues beyond the liver,” said chairman and CEO, Thomas Meyer, Ph.D.


As part of the repositioning, Altamira will become involved in oncology indications, which are particularly well suited for its RNA delivery technology. Dr. Meyer likened the potential of RNA therapeutics in oncology to the breakthroughs provided by monoclonal antibodies which started to make inroads from the 90s. In both cases, it took about 20 years between the actual innovation and the approval of the first drug. The first RNA therapeutic was approved by the FDA only in 2018 – hence the RNA breakthrough has now barely just got started.


Trasir is the brainchild of Samuel Wickline, M.D., a pioneer in extrahepatic delivery of nucleic acids. Dr. Wickline did the majority of his Trasir work while at Washington University in St. Louis and a few years ago, he moved to University of Southern Florida at Tampa. Dr. Wickline, who is now CSO of Altamira, did more than 15 years of NIH-funded research to deliver RNA payloads inside cells that are not in the liver.


Dr. Meyer explains that Altamira is developing a versatile peptide-based platform called OligoPhore or SemaPhore, for the safe and effective delivery of nucleic acid payloads, such as small interfering ribonucleic acid (siRNA) and messenger ribonucleic acid (mRNA) into target cells, using systemic or local administration.


siRNA is one type of oligonucleotide, which can be used therapeutically to silence disease-related genes. mRNA can be used therapeutically to translate genetic code from DNA into proteins, which then can be used to replace abnormal or deficient proteins or make proteins to fight or prevent disease.


Dr. Meyer points out that the global market for RNA therapeutics has been growing fast, exceeding $1-billion in 2020. However, appropriate delivery technologies have remained a key rate-limiting step for unlocking their potential.


For example, Dr. Wickline says viral-based delivery vectors suffer from lack of transduction efficiency and target specificity, and lipid nanoparticles and currently available ligand conjugates preferentially target the liver, which is fine if that’s the target, but tend to have a suboptimal therapeutic index delivering RNA to other tissues.


On the other hand, he points out that Trasir’s ground-breaking OligoPhore technology has the potential to effectively deliver RNA payloads to tissues beyond the liver, which is inadequately addressed with current delivery approaches. “We look forward to applying OligoPhore for the development of truly innovative RNA therapeutics and advancing them to clinical proof of concept,” he adds.


According to Dr. Wickline, OligoPhore’s mechanism of action enables a stable peptide-siRNA polyplex to be taken into the cell through a process called macropinocytosis. Once inside the cell, the endosome is acidified and as the pH drops, the polyplex is disassembled, and the peptide helps the RNA sequence to get outside the endosome, he adds.


OligoPhore enables delivery to target tissues outside the liver, creating the potential for developing RNA-based therapies for a range of indications with substantial unmet need.


In various mouse models of disease, OligoPhore and its mRNA SemaPhore have been shown to protect either the siRNA or mRNA payloads from degradation in the circulation. Proof-of-concept for efficient delivery and target knockdown of undesired genes has been demonstrated for various gene targets, enabling a preclinical development pathway for several oncology indications, rare diseases and various inflammatory conditions.


Based on work of Dr. Wickline and collaborators, Altamira has selected mutant KRAS-driven colorectal cancer as the first therapeutic indication for its OligoPhore oligonucleotide delivery platform. The Company intends to develop the treatment under project code AM-401, targeting an IND submission by the end of 2022.


Colorectal cancer is the fourth most diagnosed cancer and the second leading cause of cancer death in the U.S. Mutations in KRAS alone account for some one million deaths per year worldwide. Approximately 40% to 50% of patients with colorectal cancer harbor mutations of the KRAS gene, which are known to contribute to the development and metastasis of colorectal cancer.


Although the role of KRAS mutations in cancer has been known for decades, they have remained a challenging target for therapeutic treatments. Only recently two small molecule inhibitors of single KRAS mutations were approved by FDA for the treatment of non-small cell lung cancer. Besides colorectal cancer, KRAS mutations are frequently observed in pancreatic cancer and lung cancer.


In parallel with AM-401, Dr. Meyer says Altamira will explore further potential applications of the OligoPhore platform for delivery of siRNA, mRNA, and gene editing constructs, and seek to leverage the platform’s potential through strategic partnering.


“We are not interested in becoming purely a platform company but intend to develop our own program of RNA therapeutics as well,” he adds. The initial focus is on existing siRNA data, while advancing research on mRNA and other payloads, and upscaling manufacturing and developing a safety package for an IND.


“Our key message is that we are a diversified company now that will become a pure play RNA-focused company over time, unlocking shareholder value in the process,” concluded Dr. Meyer.