Since our goal for Hersiran, our Herpes therapeutic, is to help patients, it was very important for us to conduct further research about the admission process of drugs and how to follow the guidelines for good pharmaceutical practice. This way, we wanted to ensure a good quality, safety and a high efficacy of Hersiran.
Through our university studies, we were already familiar with the basics of the individual drug development phases. However, we wanted to know more about how to bring a drug like Hersiran to the market and wanted to get advice from experts. Therefore, we reached out to the leading company in the field of RNA interference (RNAi) therapeutics, Alnylam, that produced the first worldwide approved siRNA therapeutics, ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran) and AMVUTTRA™ (vutrisiran). We were very grateful to be able to talk with the General Manager Hannes Schmeil, Medical Manager Ondrej Novak and a Regulatory Affairs Manager about the different steps of market access. Additionally, we were able to get in contact with the R&D-Team via email to discuss the design and delivery of our siRNAs.
As Mr. Schmeil has been a general manager of Alnylam for the last 5 years, he has extensive experience in every aspect of complete organizational set-up and development, product launch and commercialisation including pricing & reimbursement in Germany and Switzerland.
In our meeting (Figure 1), Mr. Schmeil was enthusiastic to give us a broad overview on the organization of a pharmaceutical company and the roles of each department in the drug approval process. The major phases of this process is depicted in Figure 2. Additionally, he proposed important factors to contemplate at each stage. His experience was especially valuable to us as his focus was on orphan drugs, which would also include Hersiran, as herpes induced encephalitis affects roughly 2 in 10000 people and in Europe a disease is rare if fewer than 5 in 10000 are affected (Orphan Drug Regulation 141/2000).
By getting such a comprehensive insight into drug development and market access, we had a good and detailed foundation to establish our proposed implementation and formulate a detailed admission process for our drug, on which you can read more about here.
As Alnylam had already released a therapeutic with an siRNA encapsulated in lipid nanoparticles (LNP), we were interested in their experience with this delivery system. Thus, we met the Medical Manager, Ondrej Novak, online (Figure 3). Novak explained to us the mechanism of action of their drug “patisiran”, which was the first ever RNAi therapeutic. Patisiran is used to treat hereditary transthyretin-mediated amyloidosis that affects the liver. The medication is given as an intravenous infusion every three weeks. The disadvantages of this method are the high frequency of application (due to a lot of liposomes being filtered out of the system or reacting elsewhere before even reaching its target), that the infusion takes a long time (60 to 80 min) and the patients have to take premedication (cortisol steroids) to prevent immune responses and allergic reactions, because of the sheer amount of liposomes being introduced to the system. This process can be a burden to patients and severely decrease their quality of life. Therefore, we felt validated in develeloping a local application approach through aerosoles in the nose instead of a systemic application, such as injections.
Through Mr. Novak, we got in contact with two researchers of Alnylam who suggested to us following aspects we should consider: Firstly, they mentioned that siRNAs against viral targets have to be carefully selected to target highly conserved regions of the viral transcripts to minimize the risk of breakthroughs. In this method, the selected siRNAs have to be tested under conditions, which allow to determine the emergence of viral resistance. We kept the issue of quickly developing resistance due to high mutation rates in viruses in mind while looking for our production method of the siRNA. During our research, we found out that by producing siRNA in E.coli with RNaseIII various siRNAs are created, impeding a resistance against our entire drug. Thus, we preferred and eventually chose this approach over a solid phase synthesis of individual siRNAs with a single target sequence. They also recommended us to optimize our delivery method for metabolic stability, which is why we decided to additionally coat our liposomes with Chitosan, to both enhance their ability of nose-to-brain transportation, but also to increase their stability.