Excision BioTherapeutics
Use of CRISPR Cas9 Gene Editing Therapeutic Shown to Permanently Inactivate HIV-1 in Patient’s Blood for First Time
March 4, 2016
Excision BioTherapeutics
HIV Cure-Focused Excision BioTherapeutics Secures $10 Million in Seed Funding Led by ARTIS Ventures
September 6, 2017

Interview with OneMedMarket

Brett Johnson & Tom Malcolm
This interview was originally published by OneMedMarket.

Thomas Malcolm Ph.D is the CEO, President and Co-Founder of Excision BioTherapeutics, a company working in the area of gene editing and CRISPR technology, with a primary focus on HIV. Brett Johnson speaks with Dr. Malcolm to discuss the Company’s mission to use gene therapy to cure HIV, why the CRISPR space has exploded and the overall outlook. Continue reading for a full transcript of the interview.

Brett Johnson: Today I am with Thomas Malcolm. He is the founder, CEO and President of Excision BioTherapeutics, a Philadelphia biotech working in the area of gene editing. Thanks for joining us today, Tom.

Tom Malcolm: No problem. Thank you, Brett, for inviting me.

BJ: Tom, tell us, what does Excision do?

TM: Excision is working on gene editing approaches to eliminate permanently viral genes from human cells that cause infectious diseases. Right now, our main focus is developing gene editing therapeutics for HIV, JC Virus, and Herpes Viruses HSV1 and HSV2.

BJ: What is gene editing? How will you eradicate these viruses?

TM: Gene editing attacks the problem at the core cause of disease where the infections originate – the genetic level. For the first time, we are capable of doing this because the tools in the gene editing field have improved vastly over the past couple of decades. Gene editing has been around for a long time, but a lot of the nucleases that have traditionally been used are bulky, awkward and difficult to deliver to targeted regions in the body where viral infections reside. However, through the discovery of CRISPR-based nucleases, we’ve been able to utilize the gene editing approach far more efficiently. This is what we are working on – various types of the CRISPR systems to cut out or ‘excise’ viral genetic elements from host cells, thereby eradicating disease.

BJ: Where did the CRISPR system come from? What is the background on CRISPR?

TM: CRISPR has a history going back to the early 90’s. It was discovered during this time that clusters of bacterial genes were somehow contributing to their resistance from bacteriophage infection. Fast forward to 2011 when scientists defined the mechanics of the CRISPR-nuclease system and its versatile use in eukaryotic cells, and the rest is history. The ease of use of CRISPR nucleases, such as Cas9, has opened the door for various groups to look at different diseases and potentially treat them from the genetic level.

BJ: What has been the progress thus far with the CRISPR system? Have people started to accomplish their goals through it, or is it still early in terms of its efficacy?

TM: The CRISPR space has really exploded in the last year. I remember when I first learned about the technology and then discussed it with various people, they had no clue what I was talking about. Now, you have to be really out of touch with reality to have never heard of this medical breakthrough. The field has been moving very fast and this is reflected in the thousands of research papers published around the world. There has been tremendous progress in a very short period of time with improving the technology, allowing many groups to achieve their goals. For example, different versions of Cas9 have been invented to improve efficiency and new CRISPR nucleases have also been discovered. But I think one of the biggest challenges with the technology in relation to its efficacy is going to be therapeutic delivery. The Company’s scientific partners at Temple University and Stanford have developed new delivery technologies and approaches that we believe will allow us to address these challenges.

BJ: How did you get into the CRISPR field?

TM: I have been in the HIV field of research for a long time. Because of this, I have an understanding of the problem that is associated with the integrative nature of the viral genes into the human genome. When I saw the paper that was published from Dr. Kamel Khalili’s group out of Temple University three years ago, where they used this new nuclease (Cas9) to snip out the genetic elements of HIV and safely cure human cells in vitro, I knew that just by reading the abstract of the paper that this was an enormous breakthrough in the HIV field. 

I reached out to Dr. Khalili and we immediately had a great relationship and we decided that we were going to form this company and put our best efforts forward to help people by finally eliminating this virus once and for all. I think this is the best chance we have of doing it.

BJ: That’s really impressive. What has been the progress in HIV over the last few years? As I understand, it has evolved greatly over the past 20 years.

TM: It has. Outside of human hereditary disease, HIV is one of the most studied biological factors. There was a little bit of a lull about 10-15 years ago, but things have been picking up with new discoveries about how to block the virus from replicating by using next generation inhibitors and vaccines. Although these approaches show considerable advances and effectively block viral infection of new cells, they do not eliminate the latent reservoir of virus, and therefore a patient must remain on suppressive viral medications.  

I think there is a lot of very exciting things going on in the HIV field and the CRISPR system is a new adaptation that will allow us to eliminate the latent virus all together. We still have a lot of work to do, but it is very promising and we are in the process of completing in vivo studies that will allow us to move into human trials.

BJ: What is your sense of when you might be able to get into the clinic? What is the outlook in terms of when all this can happen?

TM: Dr. Khalili’s group is near the tail end of the animal studies and the scientists are getting very promising results. We will be working with the FDA to get IND status. If all goes well, we hope to be in the clinic by the end of 2017.

BJ: In terms of a regulatory perspective, what are the big challenges? Is it because it is so new that it is challenging for the FDA? What do you see as the biggest challenge for getting approval?

TM: We have to take a lot of care and be thorough. The FDA is here to help us and make sure we develop safe medicines for people. The last thing we want to do is hurt people – our objective is to help them. I believe CRISPR gene editing approaches will be safe and any technological challenges that arise will be addressable. 

It should be noted that this is not the first gene editing approach to be in the clinic. Sangamo Therapeutics has been using Zinc Finger Nucleases to alter the human CCR5 gene to block HIV from entering cells.

One of the biggest challenges for getting approval may relate to potential off-targeting concerns associated with CRISPR Cas9, so patients will need to be monitored frequently during clinical trials. However, Excision is focused on the eradication of viral genes, which have different characteristics from human endogenous genes. These differences, have allowed for the careful design of the targeting RNAs in manner where the scientists do not see any abnormalities in human cells so far. A lack of off-targeting using this approach has been confirmed using very thorough and state of the art deep sequencing techniques.

BJ: Can you discuss what you have learned in your animal studies and the types of research you’ve been doing on animals?

TM: On the surface, we have a checklist of very detailed in vivo experiments to ensure that our therapeutics are safe and efficacious. We are in the process of completing these studies. Dr. Khalili has published a couple of papers in top peer-reviewed journals that show, for the very first time, that we can excise the virus from various tissues invivo. This is a huge breakthrough, that has not been accomplished on this level previously. We are pretty excited about it. 

BJ: Are other companies with whom you are completing that are doing the same thing, and are perhaps at the same juncture?

TM: Good question. It is likely that there are groups out there working on the same thing. That’s a good thing, because different approaches might occur, and the goal is to help people by curing this virus.

BJ: Can you talk a bit about the scientific and management team that you have assembled and their backgrounds?

TM: We have a really great scientific advisory group. Collectively, our advisors have thousands of publications from tenured and experienced individuals. Our management team is excellent. Excision has a terrific Chief Development Officer and Chief Medical Officer, each with over 30 years of experience taking various molecules from conception to market. Everything is moving along very efficiently and it is an exciting time for the team.

BJ: Can you discuss your capital needs to develop the company and what your financing plans are going forward?

TM: We are currently seeking additional funding and the company is getting a lot of attention from various investors. As you know, it is a journey, being on the money trail. Building a therapeutics-based company is a cash demanding process, but based on the Company’s management history we are well-equipped to overcome challenges and meet our objectives. As such, what we are looking for are the right investors who understand and want to partake our vision to cure infectious disease.

BJ: Why are investors taking an interest in this project?

TM: It kind of swings back to one of the first questions you asked, and I think it is because the gene editing space is really hot and has very big implications in healthcare.

BJ: What are some key takeaways for investors? How would you summarize the key points that people should be tuned into?

TM: I think that the most important takeaway for investors is an opportunity to be a part of history with what we are going to accomplish, that, and joining great group of hard working people from the management to the scientists – this is really what I like to hit home with people.

I truly believe that Excision BioTherapeutics is going to change the world by making it a better place and I think we will be able to tackle a considerable number of viruses through our capabilities.

BJ: One last thing – can you discuss a bit about the pipeline? You discussed HIV, but what are some of the other potential applications?

TM: One of our programs that is closely paralleling HIV is the JC Virus project. JC Virus is a virus that has infected up to 85% of the population, but is relatively benign in healthy individuals. However, individuals with Multiple Sclerosis or Rheumatoid Arthritis have to take immunosuppressant drugs on a regular basis in order to minimize the symptoms of these diseases. These drugs suppress the immune system and thereby triggering, in some patients, JC Virus replication, which starts destroying nerve cells such as oligodendrocytes. The destruction of these cells leads to a condition called Progressive Multifocal Leukoencephalopathy, or PML. 

You may have heard of this when you watch TV and you see some of the drug commercials that list PML as a potential side effect. By using this gene editing system and our approach, we can eliminate the JC Virus problem so that patients can be administered these very effective medications for Multiple Sclerosis, Rheumatoid Arthritis or anything else where an immunosuppressant is needed to improve their lives. 

We are also working on a gene editing approach to eradicate permanently HSV1 and HSV2.

BJ: Do you have a sense of the market is in terms of the practical economics of this treatment? Would this be a drug or an injection of some sort? 

TM: For our current indications, it would be an injectable therapeutic. When it comes to market size, there is a lot of finger-waving because you will come up with different numbers, depending upon whoever does the analysis. So, this does not concern me too much. What immediately concerns me is reaching our goals on the scientific side and getting to human trials to help people.

BJ: What do people currently spend on HIV treatments? Isn’t it pretty substantial?

TM: I believe, on average, in the U.S., it runs about $2,000 a month. A lot of that is subsidized through insurance.

BJ: Is it your hope that you will have something comparable in terms of price?

TM: We want to make sure that these medicines are available for everyone, and that the Company can continue to develop curative therapeutics to help people. I think that is what is most important.

BJ: Thank you for joining us, Tom. 

TM: Thanks a bunch, Brett. 

This interview has been edited and condensed.