Any medicine can cause adverse events, or toxicities, and since less is known about experimental medicines than those on the market, the risks of drug-related toxicities is somewhat greater for an experimental medicine (drug).
To provide thoughtful commentary on the risk of a potential side effect of a drug, one must discuss the incidence, severity and strength of evidence that the drug is causal and know the dose and dose schedule that was used when the side effect, or toxicity was observed.
Because antisense oligonucleotides (ASOs) are members of the same chemical class and therefore share basic properties, we ask if an observed toxicity is unique to a particular ASO (Is this a toxic ASO?), is the observed toxicity a product of altering the target of the ASO (Is the altered target product causing toxicity?) or is the observed toxicity a “class effect”, (Is the toxicity shared by ASOs of that same chemical class?).
Whether a toxicity is unique to a particular ASO, the target of the ASO or a class effect, one must know a great deal more than simply the name of the toxicity to understand the toxicity in a way that is helpful.
Firstly, one must know the INCIDENCE of the toxicity. The incidence is the fraction of patients treated with the drug, in this case an ASO, who experience the toxicity. Obviously if one patient in a thousand have the toxicity, the potential impact on the heath of treated patients is much lower than if the incidence is 100%.
A second parameter of critical importance is the SEVERITY of the toxicity. Toxicities with the same name can vary widely in severity. Obviously a more severe version of a toxicity is of more concern than a mild version.
The third parameter of interest is how STRONG is the evidence that the adverse event was actually caused by the drug.
Finally, since drug effects are dose dependent, one must know the dose and the dose schedule of the drug in the patient(s) who experience the event.
To show how this works, let’s look at a complex adverse event.
Normal pressure hydrocephalus (NPH) is a change in the volume of the fluid that is used to provide nutrients and get rid of waste in the central nervous system. That fluid is called cerebrospinal fluid (CSF). NPH is noted in patients with degenerative neurological diseases and the INCIDENCE of NPH varies depending on the disease and how far advanced the disease is. NPH has also been associated with intrathecal administration of ASOs (injection of ASOs directly into the CSF). Given the background incidence of NPH in the degenerative neurological diseases in which ASOs are used, anecdotal reports of NPH in a single patient are difficult to interpret. We have more insight into this now due to recent results of well controlled trials of almost 800 patients with Huntington’s diseases, treated for more than 69 weeks at a dose as high as 120 mg/quarter an INCIDENCE of 0.6% compared to a background INCIDENCE of 0.4 % in untreated patents with the disease.
Obviously, though if an ASO caused NPH in every patient treated, an INCIDENCE of 100%, that would be very different and much more worrisome. Now in the Huntington’s study, simply discontinuing administration of the ASO was generally sufficient. Obviously, if the NPH were much more severe, possibly requiring the placement of a shunt to stop the progression of the NPH, that would be a very different situation.
The strength of evidence that an adverse event is drug related is often quite contentious because patients and diseases are complex and patients are often taking several medications. So, an INCIDENCE of 0.6% compared to a background incidence of 0.4% would not be terribly strong were the study not well controlled. On the other hand, if every patient treated experienced NPH and they experienced NPH at about the same total dose, that would be very strong evidence that the drug is responsible for the adverse event. Next, since the effects of drugs are dose related, you might expect that side effect or toxicities increase as the dose is increased and you would be right.
In summary, to really understand a toxicity, you would know the INCIDENCE, how SEVERE the toxicity was, the dose and dose schedule that was associated with the toxicity and how strong the evidence implicating the drug was. Clearly, whether a toxicity is unique to an individual drug or a “class effect”, if the incidence and severity of the toxicity are high, that is a very different situation than if the toxicity occurs rarely and is not severe.