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Tuesday, April 25, 2023

Oligonucleotides Break Through to the Lung

It is days like today that I live forDays when new platform technology data is revealed that will change the practice of medicine and benefit patients for a number of diseases of high unmet need. In this case asthma, IPF, COPD etc. 


Almost a decade after GalNAc started to revolutionize oligonucleotide therapeutics delivery to the liver (hepatocytes) and turned oligonucleotides into the important therapeutic modality it has become today, Arrowhead Pharmaceuticals just reported the equivalent for the lung (lung epithelial cells to be precise).

Employing inhaled delivery of αvβ6 integrin-targeted stabilized RNAi triggers in healthy volunteers, the company found robust, -80% mean maximum target gene (RAGE) knockdown after 2 doses spaced a month apart. 

Since the knockdown reading was based on RAGE protein in serum (sRAGE), the true knockdown in the desired lung epithelium is likely higher.  This is also supported by the observation that more direct bronchoalveolar lavage measurements revealed -75% knockdown after just a single 92mg dose when the corresponding reading in the serum indicated -56%.  Further dose escalation to 184mg is ongoing and there are first indications that the long-lived pharmacodynamic response observed in animals will hold up in the clinic.

RAGE is a key player in pro-inflammatory signaling in the lung and thought to play a central role in related pulmonary disorders such as asthma.

In addition to clearing the efficacy hurdle, safety seemed excellent, or in the words of the company ‘no patterns of adverse changes in any clinical safety parameters’.

As some may remember, an earlier RNAi candidate targeting the lung (ENaC for Cystic Fibrosis) was shelved by Arrowhead due to preclinical findings in chronic tox studies in the rat.  The reason is thought to be that the sheer amount of material delivered to rat lungs overwhelmed and inflamed the macrophage-based particle clearance system.

What is different this time is that ARO-RAGE utilizes improved stabilization chemistries and therefore only a fraction of the overall tissue exposure is required to achieve the same knockdown. 

This is reminiscent of the early days in GalNAc conjugate-based delivery to the liver when a first-generation GalNAc-TTR RNAi trigger had to be discontinued by Alnylam due to adverse safety in the clinic.  Improved GalNAc RNAi drugs of increased metabolic stability (and reduced 3'-fluoro content) are now well established medicines.

Beyond RNAi Therapeutics, today’s results have important implications for oligonucleotide therapeutics applications in the lung in general, including RNA Editing. 

Most importantly, they establish αvβ6 integrin as a valid target receptor for oligo conjugates.  Moreover, some of the chemistries should be directly translatable for stabilization purposes and together with ARO-ENAC Arrowhead should now have good insights into the chemistry-safety relationship. 


3 comments:

Steve_382 said...

Thanks for the article. The lung has been a long wait.

Alnylam
In November 2005, the company announced the submission of its first IND application to the FDA to initiate a human clinical trial for its lead candidate RNAi therapeutic, ALN-RSV01,for the treatment of RSV infection. Pending clearance of the IND application by the FDA, the company plans to initiate a Phase I safety study in healthy adult volunteers by the end of 2005, and is also preparing to initiate a Phase I clinical trial in Europe.

Dirk Haussecker said...

Steve...thanks for your comment. As you will remember, ALN-RSV01 was really a shot in the dark at best, a preclinical innate immune artefact masquerading as RNAi knockdown at worst. Hence no immediate follow-up to that compound.

Anonymous said...

guess there is a typo, you wrote 3'-F content instead of 2'-F content

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