- U.S. Patent and Trademark Office publishes Arrowhead's latest patent application on αvβ6 integrin ligands. - αvβ6 integrin ligands enable high affinity extrahepatic delivery of RNAi trigger sequences to multiple tissues. - Arrowhead cornering the market on its patent pending extrahepatic compositions for targeting αvβ6 integrin ligands.
- The company that is able to move RNAi outside of the liver will create a ton of value.
Arrowhead Pharmaceuticals Inc (NASDAQ: ARWR) business model of going after extrahepatic targets and establishing first mover advantage has the potential to be amplified by gaining patent protection for an extrahepatic targeting ligand composition. Arrowhead’s patent application is looking to exclude, or require a license with, others in targeting a number of different tissues outside of the liver for the life of a patent (around 17 years).
Arrowhead indicated at its last Analyst Day meeting in New York on October 16, 2018 that since there will be more RNAi competitors going after liver targets, it believes that targeting indications outside of the liver will be more productive in building a long-term valuable company.
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RNAi drugs from the three main RNAi companies: Arrowhead Pharmaceuticals Inc (NASDAQ: ARWR), Alnylam Pharmaceuticals (NASDAQ: ALNY), and Dicerna Pharmaceuticals (NASDAQ: DRNA) currently target the liver. They are able to target the liver by conjugating a high-affinity targeting ligand to an RNAi trigger sequence. This targeting ligand acts like a magnet by being able to bind itself to receptors found on the liver. The result is specific delivery of an RNAi drug directly within the liver.
The process is quick and efficient and has shown to provide incredible results, as once the trigger sequence is delivered to the liver, its biological effects of knocking down specific genes can last for over 3 months, but its plasma half-life is such that the drug gets eliminated from the bloodstream within approximately 24 hours. This is a big win for the present state of RNAi platforms with regards to safety, as most safety issues arise while the drug remains in the bloodstream.
Identifying an effective targeting ligand to get an RNAi drug to a specific tissue is a major challenge. The well-known method of targeting the liver is by using a synthetic triantennary N-acetylgalactosamine (GalNAc) ligand. The GalNAc is designed to bind with high affinity and specificity to the asialoglycoprotein receptor (ASGPR) found in the liver. In short, the GalNAc ligand has become a very effective tool in delivering an RNAi trigger sequence to the liver.
The GalNAc structure itself, however, is not proprietary, therefore any RNAi company is free to use it by conjugating it to its own proprietary RNAi trigger sequence. The conjugation of the GalNAc ligand to an RNAi trigger sequence can be done via a variety of means, including both proprietary and non-proprietary structures. The GalNAc is currently actively being used by a number of RNAi companies, including competing RNAi drugs that are designed to treat HBV and Alpha-1 antitrypsin deficiency.
Identifying extrahepatic targeting ligands to target other tissues outside of the liver is the next big challenge RNAi companies are facing. Arrowhead has been working hard in being able to advance its RNAi TRiM™ platform to the next level by going extrahepatic. The Company is currently guiding on the delivery of two new extrahepatic drugs in the clinic, ARO-HIF2 (2019) for the treatment of clear cell renal cell carcinoma (ccRCC), and ARO-ENaC (1H2020) for the treatment of cystic fibrosis.
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Arrowhead Pharmaceuticals Inc (NASDAQ: ARWR) has been able to identify high-affinity targeting ligands that can target cancerous tumors, as well as the lungs. On August 15, 2019 the U.S. Patent and Trademark Office published Arrowhead’s latest patent application, Publication No. 20190248832 for Alpha-V Beta-6 Integrin Ligands and Uses Thereof.
This patent application seeks to protect new high-affinity targeting ligand compositions that allow RNAi trigger sequences to be delivered to extrahepatic targets. The compositions comprise αvβ6 integrin ligands that have serum stability and a high affinity for αvβ6 integrins. Arrowhead is claiming in its patent application that its new compositions can target the following cell types:
- type I and II alveolar epithelial cell, - goblet cell, - secretory epithelial cell, - ciliated epithelial cell, - corneal and conjunctival epithelial cell, - dermal epithelial cell, - cholangiocyte, enterocyte, ductal epithelial cell, - glandular epithelial cell, - renal tubule, and epithelial tumors (carcinomas).
These cells can be found in various tissues throughout the body including: the lung, cancer tumors, bile ducts, intestines, breasts, glands, and kidneys. Based on Arrowhead’s corporate presentations, it is believed that Arrowhead’s ARO-ENaC drug uses the αvβ6 integrin ligands to target the lungs with high specificity.
If the developed compositions of the αvβ6 integrin ligands turn out to be as successful as Arrowhead Pharmaceuticals Inc (NASDAQ: ARWR) is beginning to show in its preliminary data for ARO-ENaC, this patent application can potentially have profound implications for extrahepatic targeting of RNAi. An issued patent would provide Arrowhead with a legal monopoly and allow it to corner the market with its newly developed extrahepatic targeting compositions for around 17 years.
If Arrowhead can establish a monopoly with its newly developed extrahepatic compositions, this new patent application has the potential to be a blockbuster.
Author: Robert Toczycki, J.D., MBA
Robert Toczycki, J.D., MBA is an independent analyst. His primary experience is as an Intellectual Property Attorney focusing on the development, management and monetization of IP portfolios in the high-tech arena. Toczycki founded bioboyscout.com, the world’s first online biotech valuation calculators that help eliminate bias and challenge private valuation models of Wall Street analysts.
Disclosure: long ARWR.