RNAi therapies through ‘tough patch and here to stay’
RNAi arrived on the scene in the 1990s, after Andrew Fire and Craig Mello discovered the function of the system to control the activity of genes – the two later won the Nobel Prize for Physiology or Medicine for their work.
The pharmaceutical industry initially invested in the technology in the hope that it could bring about a new treatment modality for a variety of gene-related conditions. However, frustrations about its widespread utility led major companies to exit the space.
However, after Alnylam received a first-in-class approval for its RNAi treatment, Onpattro (patisiran), interest in the potential for the technology has resurfaced.
At the beginning of this week, Novartis exercised an option to license Ionis’ RNA-targeting drug candidate, TQJ230. While Sanofi paid $11.6bn (€10.1bn) for Bioverativ, in part, to acquire RNAi candidate, fitusiran.
In-PharmaTechnologist (IPT) spoke to Phio Pharmaceuticals’ current CEO (effective as of March 1), Gerrit Dispersyn (GD), as well as its former CEO and current member of the board, Geert Cauwenbergh (GC), about how RNAi development has managed to ride out its difficult early years to arrive with a promising future for immuno-oncology.
IPT: Could you outline the work Phio is carrying out?
GD: We have a proprietary self-delivering RNAi platform that we are using to develop immunotherapy treatments. The way we're using the platform is by reprogramming cells without having to use genetic modification. By doing so we can, for example, weaponise a patient's immune system – using the immune effector cells and getting them to better attack cancer. This is based upon the naturally occurring RNAi phenomenon that was discovered in the late 1990s and had, initially, somewhat of a difficult time being translated into therapeutics. However, the companies that persevered, including ourselves, have developed their own solutions, and ours is to make those RNAi molecules self-delivering by chemical modifications that are built into the oligonucleotide itself.
IPT: Could you expand on the self-delivering aspect?
GD: We don't require any delivering tools or delivery vehicles, such as lipid nanoparticles or electroporation, which makes us unique in our approach. We can very easily use its self-delivering properties to reprogram cells used in immuno-oncology therapeutics, such as adoptive cell therapy – where the cells are taken from a patient, expanded ex vivo and then giving back to the patient. We can also use our technology towards the tumour microenvironment directly, by injecting it into the tumour and, by lowering the physical, chemical, and biological barriers that a tumour typically has, we are able to keep out the immune effector cells. On the other hand, we can remove the barriers that they encounter in the tumour microenvironment, helping to get some significant therapeutic solutions for patients in the not too distant future.
IPT: How does this compare to competing forms of delivery?
GD: If you compare us with our direct competitors, they would require electroporation of cells, which essentially means blowing holes in the cell membrane temporarily, or going with lipid nanoparticles to fuse with the cell membrane and then deliver their contents. Needless to say, the cells don't like when holes are blown in their cell membrane neither do they like to be force-fed through lipid nanoparticles. We have some nice data to show that we have not only a good efficiency of delivery but also a very high level of cell viability – really setting us apart from any other delivery mechanism.
IPT: How did dermatology and ophthalmology come into Phio’s treatment targets?
GC: Initially, we focused on dermatology because that is very visible – when you treat a dermatological disease, you can take pictures before and after so that it's clear if something works. As we were doing that and we needed additional investment, we were able to get additional funds from a stakeholder with an interest in ophthalmology, and so we added ophthalmology activities to our business.
So, that's why we had clinical programs going in dermatology and ophthalmology showing that our approach really works and we can effect phenotypic changes in diseases.
IPT: What advantages does RNAi offer in immuno-oncology?
GC: The unique advantage for self-delivering RNAi is that it can be delivered in a variety of organs but also that it can be delivered into cells. This was at the same time that the adoptive cell transfer therapy in immuno-oncology became the approach at the forefront of cancer treatment. A little bit more work and it was clear to us that this was the unique diversifier making our technology unique. It's not permanent gene manipulation, as Geert pointed out, which is probably good in certain mono-genetic orphan diseases but I'm not so sure that it is perfect for immuno-oncology and tumour treatment.
We don't need to damage the immune cells to get into the cell, they spontaneously take up the therapy and that provides us with a situation where we are sitting over the nexus between classical immuno-oncology and adoptive cell transfer therapy.
IPT: How is this approach different to current work in immuno-oncology?
GD: A lot of focus has gone into chimeric antigen receptor (CAR)-T therapy, with the idea that we can isolate cells from a patient then we can genetically engineer them to recognise certain cancers better and see whether that helps. Obviously, the first CAR-T therapies are approved on the market but mostly only working for haematological cancers and not in solid tumours.
What we're trying to do, with both academic collaborators and industry collaborators, is to improve autologous T cells in a way that makes them much more efficacious. They're weaponized essentially and improve upon the tumour killing activities. The initial way that we're doing that is we're going after some targets that are already clinically validated, including certain checkpoints. As you know, the biggest market right now in the immuno-oncology world is checkpoint inhibiting antibodies, for example, towards PD-1, where the concept is the correct one and these antibodies work.
However, we go about that same concept a different way. We make the change into the T cell by just adding our PD-1, for example, checkpoint inhibiting RNAi molecules during the rapid expansion protocols of those T cells and therefore making it no longer required to have two very costly therapeutic modalities combined. Adoptive cell therapy is very expensive and then the antibodies are very expensive, so we feel that both from a clinical viewpoint and from a cost standpoint, we can improve upon that therapy very significantly. So, that's one of our key focus areas and is the focus of one of the programs that we have publicly announced that we're pushing forward into the clinic as soon as we can.
IPT: What does the future hold for the technology?
GC: If you look at the uniqueness of self-delivering RNAi, where you strip out a lot of the risk of the toxicity of the compounds or the vehicle, it positions this approach as an important method to treat a variety of diseases for a number of reasons.
First of all, it's a life and death situation. Secondly, antibodies are expensive as mentioned and our methods are a lot less expensive than making antibodies – if you think about the economics of healthcare, antibodies are not going to be the future, unless a better way is found to make them.
With RNAi, you can do it synthetically at a lower cost and it will give additional weaponry to physicians to treat patients in need. Yes, it has been a somewhat risky change for us [to refocus on immuno-oncology]; however, I believe that the risk will pay off not just commercially but also in terms of patient need. It's only a matter of a few years until we will see RNAi make this impact.
GD: All new technology goes through the hype cycle, right? It goes through an initial period of over-expectation, and then it goes through a sobering period, where a couple of things need to be fixed. Well, guess what? We went through that tough phase, along with some other companies, and we have found our own ways to make sure that RNAi therapeutics are here to stay.
Geert Cauwenbergh was elected president and CEO of Phio Pharmaceuticals when the business was spun-off from its parent company, then known as Galena Biopharma. He will step down from the role on March 1.
Gerrit Dispersyn has been appointed as the Phio Pharmaceuticals' new CEO, a position he will step into on March 1. Prior to this, he had worked as COO and president of the company.