Discussions of gene-editing have mostly focused on the dramatic promise of CRISPR-cas9 technology.
A number of high-profile biotechs are pushing forward with development of CRIPSR-based therapies and some are expected to begin clinical development as early as next year. Another company, Sangamo BioSciences, is currently evaluating zinc fingers nucleases as an editing platform.
But other approaches are gathering steam as well. Last month, a startup called Homology Medicine launched with $44 million in venture money to fund research into homologous recombination, a naturally-occurring mechanism which promotes genetic diversity. The process involves a sequence of DNA essentially “flipping” from one chromosome to another.
Homology, which is headed up by a team of former Shire executives, believes it can harness homologous recombination to more effectively edit genes and “leapfrog” its competition. Its approach, however, is still in development and none of its research has yet been published.
BioPharma Dive spoke with Arthur Tzianabos, CEO of Homology, earlier this month on the sidelines of the BIO 2016 conference in San Francisco about his company’s efforts in gene-editing and his outlook for the space.
The following Q&A has been condensed and lightly edited for clarity.
What are some of the differences between CRISPR-cas9 and homologous recombination?
Tzianabos: With CRISPR, you are going in with a multi-component system. You have got to take cells out and then you have to cut the DNA basically through both strands. You are cutting it in two places and then you are counting on non-homologous end-joining to pop another gene in from another vector into that correct site. What happens is you get a lot of off-target break events.
In the case of homologous recombination, you have this already evolved mechanism for a billion years of human evolution that really nicely targets that one site because you have 800 base pairs to the left, 800 base pairs to the right.
What we are seeing with homologous recombination mediated by this novel family of adeno-associated viruses (AAVs) is very high efficiency, in vitro and en vivo. Tens of percent. With CRISPRs, it is in single digits of efficiency.
Homologous recombination has been known about for a while. Has anyone else in the past tried to look at this as a gene therapy?
Tzianabos: David Russell has published a number of papers, and actually has a company where he described AAV-inducing homologous recombination. The issue is he was using AAVs that have very low efficiency of homologous recombination.
He is stuck with the same problem CRISPR guys are stuck with. He has to take cells out, induce this very low frequency event, take those cells and grow them up, then put them back in. So it really limits what kind of diseases you can go after.
From a practical standpoint, when you try to commercialize something like that the cost of manufacturing is huge versus just a single injection of a virus en vivo, correcting with very high efficiency.
This is not a brand new thing we are describing. It is just that this new family [of AAVs] really does this at a very high frequency. That is the non-obvious patentable component to this.
And you license this different type of AAVs, correct?
Tzianabos: We license it from the City of Hope and from the founder. Saswati Chatterjee is her name, who is a long time AAV expert and very focused on AAVs and discovering novel AAVs and stem cells.
How would characterize the therapeutic space that you are looking at?
Tzianabos: We think because of the really good bio-distribution of this kind of class of AAVs that we can go after inborn errors of metabolism in the liver, such as PKU. Great target. Very developable target with great animal model, great endpoints in the clinic.
Huge unmet need in rare central nervous system disorders that we all worked on at Shire and know the development pathways for those as well.
Obviously diseases of hematopoietic stem cells - so sickle cell, beta-thalassemia, the hemoglobinopathies are a natural target because these viruses obviously hone right to those sites in the bone marrow.
Those are three areas we can work in and there are a lot of diseases we can target. We are going to stay pretty focused on a few diseases and prove out the platform in clinical models. That is what the Series A will do for us.
With the financing, that is to fuel the preclinical work? And then you'd be looking for other opportunities post-preclinical?
Tzianabos: Exactly. That is why I'm here at BIO talking to many companies who want to talk to us because I think that would be the easiest way to expand the platform and prove it out and have companies have access to the technology which is very differentiated.
I will tell you that because of the diseases we are picking, and they are rare, the timelines for that are typically shorter in drug development. And because the team we have that has done that, I would imagine we are going to be on a shorter timeline than a lot of folks who have wandered into the space.
I think our expertise there is really going to help us leapfrog a lot of players in the field.
CRISPR Therapeutics, Editas Medicine and others are working to bring gene-editing therapies forward. Say one of them made it to market. How would that change things for you?
Tzianabos: I root for those guys because we are all in this together to help patients. I think ultimately commercialization based on an ex vivo approach of editing is just going to be so crippling from a manufacturing cost point of view. I can speak from experience there because I have been in cell therapy manufacturing mode before in the previous company I was at.
Costs are going to be a huge issue. If you are able to deliver something that does something better, you are giving it IV and it is a one-time administration, your manufacturing costs are potentially a lot lower. You can offer something to patients that is much more convenient. Your cost-benefit is going to look a lot better than what I would imagine the other guys are going to have to deal with.
Even with the gene therapies out there, the cost of conducting treatment is pretty significant.
Tzianabos: It’s pretty significant. In biologics you want your margins to be 60-80% and that is what you try to shoot for. That is what we shot for at Shire.
Achieving that with an ex vivo approach is pretty much impossible.
What do you think of the regulatory environment for gene therapies and gene editing?
Tzianabos: I think it comes down to a couple of things.
It is educating the regulators. It is being very vigilant in your non-clinical safety package in showing you are doing exactly what you’re saying you are doing in the genome.
Then there is going after diseases where there is a huge unmet need and no cure. The benefit-risk ratio looks different there. So it is just like when rare started and companies had to work with regulators to educate them about what you should be looking for and get there together. I see that is going to be very important in building those kind of ties with FDA and EMA.
Pricing and value have been a dominant conversation in the industry this year. How do you think the discussion might shape the space for gene-editing?
Tzianabos: I think if you continue to see therapies that come out of companies that make a huge impact on high unmet need diseases that we will figure out how to pay for it.
There are different models that have been proposed. But I think if you are bringing that value to the healthcare system and you are showing that you are saving the healthcare system money by a one-time treatment that is potentially curative - your pharmacoeconomic argument is pretty strong.