Opportunities, benefits and risks are not so different from each other
Adverse drug reactions that compromise the safety of drugs do not necessarily mean that the development of a pharmaceutically active agent is immediately stopped. The case of a pharmaceutical agent initially developed by Tübingen-based c-a-i-r biosciences GmbH shows how an undesired event can actually lead to new opportunities. The original agent is now being further developed on a different basis from the original plans.
Applied research does not necessarily always go to plan and unexpected discoveries can often occur, and the drug discovery process is no exception. The c-a-i-r biosciences GmbH team has developed an active compound with an anti-inflammatory effect that is in principle suitable for the treatment of autoimmune diseases. The compound’s mechanism of action is based on the inhibition of a key enzyme that leads to certain immune cells releasing inflammatory factors (cytokines).
"In 1999, we initiated the project on the chemical synthesis and pharmacological characterisation of active compounds that were able to selectively inhibit the aforementioned enzyme, and we have since continued our work under the BioProfile funding programme. In 2005, at c-a-i-r biosciences GmbH we identified a promising compound as a clinical development candidate and developed it further in close cooperation with the Institute of Pharmaceutical Chemistry at the University of Tübingen," said Prof. Dr. Stefan Laufer, co-founder and board member of c-a-i-r biosciences GmbH. Based on results obtained from non-clinical disease models, the drug developers hope that they will eventually be able to use the new substance (laboratory code CBS-3595) for the treatment of rheumatoid arthritis, psoriasis and inflammatory bowel diseases.
CBS-3595 worked well and showed a promising safety and efficacy profile despite the moderate enzyme activity in inflammation models. "In addition, the first clinical Phase I study involving healthy volunteers was successful," said c-a-i-r biosciences GmbH CEO Dr. Wolfgang Albrecht explaining that well tolerated doses of the drug led to a considerable decrease in the inflammation parameter TNF-alpha ex vivo. However, higher doses led to gastrointestinal incompatibilities similar to those observed in animal models, which could not be deduced from the compound's mechanism of action. Such adverse drug reactions might be acceptable if the drug is used for life-threatening diseases such as cancer, but are completely unacceptable for the indication for which the drug is being developed. "People suffering from chronic inflammatory diseases would certainly be willing to take the drug over long periods of time if the drug had both the desired effect and an acceptable side effect profile. A drug that causes nausea, even if only for a short period, does not fulfil the drug requirement profile," said Albrecht.
Drug safety comes first, effect second
Luckily, the researchers did not hide the new drug away in the back of a drawer, but decided to carry out a detailed investigation of its mechanisms of action. “Our clinical candidate targets two different reaction pathways which lead to the inhibition of TNF-alpha production in the cell,” said Laufer. It is a dual inhibitor of the enzyme p38-MAP kinase and of the enzyme phosphodiesterase-4 (PDE-4) activation pathways. The researchers were therefore looking for substances that are able to inhibit p38-MAP kinase. It was already known that PDE-4 inhibitors led to the inhibition of TNF-alpha formation and clinical testing has shown that they are suitable for the treatment of chronic-obstructive pulmonary diseases (COPD) and psoriatic arthritis, a condition that is associated with skin inflammation. However, at high doses, all the PDE-4 inhibitors led to stomach problems such as those observed for CBS-3595. The optimisation of the drug dose has its difficulties, which is why only one PDE-4 inhibitor has so far been granted marketing authorisation for the treatment of COPD.
In acute inflammation models, CBS-3595 exhibits a greater inhibitory effect on TNF-alpha production than the PDE-4 inhibitor. Albrecht therefore believes that the dual inhibition of p38-MAP kinase and PDE-4 has an additive therapeutic effect. "The gastrointestinal incompatibility of CBS-3595, which was initially regarded as very problematic, might in retrospect be a piece of luck," said Albrecht explaining that the simple comparison of indications for which pure p38-MAP kinase and PDE-4 inhibitors have been tested suggests that the simultaneous inhibition of both signalling pathways might have a therapeutic advantage.
Albrecht and his team are now looking for an optimal drug effect compromise that will lead to an effective drug and potentially to a completely new class of drugs. The researchers are testing many ways to combine the two mechanisms of action in an effort to elucidate the synergistic or additive effect of the two inhibitors. So far, the team has come up with four new drug candidates, each of which containing a different proportion of the two mechanisms of action, and which have been shown to be more efficient on the molecular level than the original substance. "We are investigating whether a moderate PDE-4 effect leads to a better effect in the treatment of inflammatory diseases such as COPD. In such cases, the PDE-4 pathway plays a more important role than in the previously targeted indications," said Albrecht.
Adverse drug reactions might also decrease during permanent medication
The dose-effect investigations in animal models have already revealed a highly interesting aspect: “With regard to gastrointestinal incompatibility, our drug candidate leads to the development of tolerance when repeatedly administered – an effect that is also known from other PDE-4 inhibitors,” said Albert. As to how far this might turn out to be an additional advantage in clinical development still needs to be investigated. However, it might turn out that the most important adverse drug reactions are likely to decrease during long-term permanent drug administration. In terms of drug safety, the dual effect of the inhibitor might therefore make the drug candidate even more acceptable.
At present, the c-a-i-r researchers are focusing on the further development of their substances, the production of analogues, on additional toxicity tests and on the further development of suitable drug formulations. c-a-i-r is currently looking for suitable cooperation partners to test the drug candidates in Phase II trials. “We are currently looking for development partners to commence Phase II trials for testing promising candidates and hope to find an SME in the pharmaceutical industry that will work with us to develop follow-up molecules with improved properties,” said Laufer commenting on the company's plans.
c-a-i-r biosciences GmbH
Dr. Wolfgang Albrecht
Prof. Dr. Stefan Laufer