One of the biggest concerns in developing an entirely new class of drugs is whether they will be well tolerated. At the height of the TLR scare, it almost seemed that just looking at an siRNA would cause you anaphylactic shock. Nevertheless, after several hundreds of patients have been dosed with probably around 1000 siRNA administrations for diseases affecting the eye, lung, skin, blood cells, liver, solid tumors, and kidney, RNAi Therapeutics have shown a very promising safety profile.
When RNAi Therapeutics candidates have been abandoned, it was mostly not because of safety issues, but for factors such as lack of efficacy, doubts about the mechanism of action of observed therapeutic effects, or changes in the commercial attractiveness of compounds (e.g. wet AMD candidates by Allergan/Merck and Opko). In one case, Tekmira’s ApoB SNALP for hypercholesterolemia, the decision to voluntarily abandon this first-generation ApoB candidate after one patient experienced mild flu-like symptoms, may well have had to do with the fact that much more potent LNPs had already been developed by then and there was thus no point to tempt fate and further dose escalate.
It is not surprising that side-effects related to the innate immune stimulatory potential of nucleic acids were the most frequently cited safety issue in clinical trials. In the case of nanoparticles, complement activation seems to be another area where attention needs to be paid. However, even when formulated with lipids, the currently most potent systemic delivery agents but which are known for their potential to amplify immune responses, patient lives have not been needlessly put at risk and the potencies of both Silence’s cationic lipoplexes and Tekmira’s (neutral) LNPs, especially in light of the significantly improved potencies of 2nd generation LNPs, may be well within the therapeutic windows for a number of indications.
The most demanding test for the safety of RNAi Therapeutics are the ongoing cancer trials where the ability to dose escalate is the name of the game. Here, all 4 nanoparticle-formulated candidates by Calando, Silence, and Alnylam, seem to be still dose-escalating after having reached dosages of between 0.1 and 1.25mg/kg, dosages where anti-cancer efficacies may be expected based on animal models.
With this type of record, RNAi Therapeutics does not have to hide behind the more established classes of drugs. Even protein-based therapeutics which are highly sought after by Big Pharma and investors these days (well, all is relative) have to deal with a number of immune-related issues, both direct responses of the immune system to their introduction (anaphylaxis, antibody formation) as well as target-based toxicities as most of these drugs work by suppressing the immune system. And similar to protein-based therapeutics, and maybe even more so because they are likely to resemble each other more than protein-based therapeutics resemble each other, with experience the rate of attrition of RNAi Therapeutics due to safety should only decrease over time.