Re: Farmas USA
SGMO
La entrevista entera a SM. La ha colgado Liquid Biopsy. Adjunto también una nota de Jefferies en la que explica que al EVP de R&D lo han largado porque el nuevo CEO quiere una estructura más horizontal y tener contacto más directo con el desarrollo. Una buena noticia aparentemente en la que creo que el mercado se precipitó.
Sandy Macrae at Wells Fargo on September 7, 2016
Sept. 14, 2016
I had a few hours free today and decided to share my very rough transcription of what Sandy Macrae had to say last Wednesday at the Wells Fargo Healthcare Conference. I am a relatively large holder of Sangamo stock both personally and in a small investment partnership that I manage. I have held some shares for over 8 years now. This year has been quite a disappointing and big down year, to put it mildly. But I am optimistic that Sandy can turn things around. One big potential hiccup that may be coming is that Sangamo could end up canceling the HIV program later in 2016. The will no doubt wash out a lot of shareholders.
For future reference, Sangamo closed at $4.50 and the S&P 500 closed at 2186.48 on Tuesday Sept. 6, the day before Sandy spoke. The presentation was in the form of a question and answer session. This is rather long and inexact, but I think that it conveys accurately the gist of what Sandy believes and his philosophy of "underpromising and over delivering" in the future (a huge and welcome change from the Edward Lanphier years):
WF (Wells Fargo analyst): We are very fortunate to have with us Sangamo's new CEO, Sandy Macrae. Sangamo is a pioneering company in the field of gene editing and gene therapy. Why don't we start there Sandy. You have a novel platform in zinc finger nucleases. What was it about the technology in the gene editing space that drew you to Sangamo?
SM (Sandy Macrae): It's a fascinating company. It's been on the go for 20 years. For many of those years it was the only and pioneering company doing gene editing and published many of the landmark publications in this area. In many ways we defined what gene editing should look like and had many of the original and initial interactions with the agency (FDA). It is a company that today is moving into the clinic with gene editing. I have a long background in molecular biology. It had everything a molecular biologist could want. It (zinc fingers) had the specificity, the sensitivity and the ability to recognize and edit any part of the genome. It truly gives us the tools to control and change genes.
WF: When you think of Sangamo's platform within the context of the broader context of the gene editing space with regard to CRISPR, how do you position your platform?
SM: I looked also at the CRISPR companies and made the decision to come to Sangamo. In 10 to 20 years in the future I expect that gene editing will become a standard way of doing medicine, and it will be almost invisible like the plumbing in your hotel or the engine in your motorcar. I hope that there will be several ways of doing gene editing and I hope that zinc fingers will be one, and that CRISPR's will also fulfill their promise. But there is a long way between doing something in a test tube (CRISPR's currently) and doing something on clinical scale. This is something that I have only begun to appreciate since I have come to Sangamo. The ability we at Sangamo currently have to do things at clinical scale, editing specifically with minimal off target hits, it will take some years for CRISPR companies to get there. As they do they will get more effective and more able to hit the targets they want. One of the most impressive things about zinc fingers is that we can hit almost any base in the genome. We have an accuracy down to 1.7 bases. So if you want to give me a target, the scientists at Sangamo - these are remarkable people who have spent 20 years doing this science - they almost go to the cupboard now and pull out a set of modules that can create zinc fingers for any target - putting them through a series of phage displays, tweaking them and purifying them - with minimized off target hits. To move ahead you need to go through tox studies, safety studies and manufacturing preparation.
We will have 4 things in the clinic next year and a number of others have the potential to move in also. People ask: Why has Sangamo taken so long to get there? In the past Sangamo made some bold and brave choices. With diabetic neuropathy, that study did not work. For the past 3 or more years, it was a truly an audacious way to go, addressing an important disease like HIV. We are going to be telling you what we are seeing in our T-cell (clinical trial) work in HIV late this year. And we have an ongoing stem cell HIV (clinical) study. In the past 3 years (before Sandy started at Sangamo on June 1, 2016), we put together a a promise and a proposal to start 8 IND's(clinical trials) by this year. What I found when I came to the company was that to do 8 IND's with 140 people was impossible. I have been here 3 months. The Board has asked me to refocus the company, to create a clinical and development team and to bring new transparency to Sangamo. We want people to understand what we can and will do. We want to under promise and over deliver.
These are the 4 things we are going to focus on rather than 8. We are going to move our Hemophilia Factor 9 into the clinic - our first IVPRP program (In Vitro Protein Replacement Platform) in which we insert a transgene into the albumin locus of the liver. In Hemophilia Factor 8 we will do gene therapy and in MPS 1 (Hurler's) and MPS 2 (Hunter's) the first patients will be treated at the beginning of 2017. I want to come back: We are about to put a transgene into the albumin locus in vivo (inside the body). This is the first time that anyone has done anything like this. This is the first time that a human being will have a new gene dropped into their liver(or any other part of the body) in vitro. This is a landmark moment not just for Sangamo but for the field of gene editing. We need to take time to do it right. We need to chose the right patients and do it safely. The whole field depends on the pioneers doing it right and not harming patients.
WF: With Sangamo's focus in Hemophilia Factor 9 on co-opting the albumin locus in the liver, can anyone else do this?
SM: I don't think that anyone else can. The CRISPR tech is improving every day with so many people working on it. I am sure that someone is trying similar things. We have the advantage that we can hit any base or base and a half in the genome so we have that accuracy. At the moment the CRISPR technology can hit in the ZIP code, perhaps to within 8 to 32 base pairs. Some targets they can hit and sometimes that is OK, but other times the accuracy of zinc fingers is our therapeutic advantage. My challenge to our discovery team is not just to copy CRISPR but find things that only we can do, and not just to edit genes but to alter their transcription which is our secret sauce. That's what we want to do in the future. I want to do things that only we can do. For instance our Hemophilia Factor 8 is "just" a gene therapy (not gene editing) but is the best gene therapy there is. If you compare Non Human Primate data it's about 1 log better than the others (Biomarin and Spark) data. This is somewhat the overflow of all the time spent at Sangamo over the years becoming experts at gene manipulation. Brigit Reilly, a remarkable woman in our laboratories, has managed to squeeze Factor 8, or part of it, into a vector. She has optimized the codons, she's got the best expression, and she's put in the best promoter. Until we are in humans we can't say we are the best, but if non-human primate holds up, we will be the best. We will file an IND this year and get into testing patients in the clinic as quickly as possible early next year. We may not be first but we believe we will be the best.
WF: You mentioned with Hemophilia B as your lead program you want to do it right. How much risk to delivery is there? What percent of delivery do you need to transfect to get efficacy? Speak to what are the risks.
SM: We are using the delivery vector AAV-6. We feel it is the best. There are antibodies to AAV-6 vectors as all viral vectors. With regard to this, all the gene therapy companies shouldn't be competing. We should be sharing what works and whether to give steroids or not. Steroids are appropriate in some situations. Our way of thinking is that we will give the AAV-6 vectors and treatt afterward in the beginning lower doses. For higher doses including in both MPS trials we will treat with steroids at the outset. For Hunters and Hurlers patients their doctors tell us that they so much want some solution that they are willing to undergo such steroid treatments, whereas Hemo patients may not. It is the patients and the doctors who will lead us on this.
WF: What is the benchmark for success in Hemo B to tell you that you have a competitive product? What are the timelines for data that may affirm that you have a product?
SM: Next year we will have at least 4 products in the clinic. In Hemo B (Factor 9) the first patient will be dosed this year and we could have data in 2017 towards the end of the year. In Hemo A (Factor 8) the IND will be filed this year and the first patients will be dosed next year. Our hope is to also have data next year (2017). MPS 1 and MPS 2 will start early next year. Hopefully we will have clinical data in 2017 or early 2018 on all three albumin locus programs. We don't want to release data patient by patient. We're going to hold off until we have enough data to say meaningful things to the community.
WF: You mentioned the MPS 1 and MPS 2 programs. One of the first things you did was to reset expectations. How will that benefit Sangamo long term?
SM: It's been an interesting 3 months. We are striving for transparency. What we are doing is so important for patients that we need to bring the world along with us. We found an organization that was absolutely passionate about what it was doing but was going to fast for the organizational structure that we have. When you corner at high speed in a Prius sometimes you have to slow down. The 3 things I have found are fixable. The 3 things I have been talking about are:
1) In Factor 9 we had said that we would start in the first half of 2016. Now we are saying the second half of 2016. We had some supply chain issues. I am embarrassed to say this delay was solely because of a shortage of phosphate buffered saline solution. We are very much a discovery company. In the lab you dilute with this solution. We had to make sterile phosphate buffered saline solution. In the future this will have more clinical oversight. This problem is now solved.
2) We had previously had our MPS 1 and MPS 2 IND's approved by the FDA. As part of this entire process we had done a very early study in animals in which we had been using the wrong (amino acid?). Thomas came to me to tell me about this problem. On our own we went to the agency (FDA). They asked us to repeat the early animal experiments with the correct amino acid. and come back to show them the results. These are now done and we are confident that we will get into the clinic at the beginning of next year wit MPS 1 and MPS 2.
3) We were about to submit an IND to the FDA for the hemoglobinapathies in Beta Thalassemia with BIogen. I looked at the data and the zinc finger that we were proposing, and I said that we can do better. And we now have a new better zinc finger and I looked at the data just last night, and it's absolutely beautiful what they (Sangamo's lab scientists) have done. It's an understanding of the binding interactions and how to optimize gene editing. Hopefully this will move us ahead and make us the leader in gene editing.
WF: How will these changes effect your relationship with Biogen?
SM: We talk to them regularly. They are company with an intensity of purpose. I met with George (Scangos, Biogen CEO?) and the senior Biogen team. They agreed with our proposal. I am confident that it will move ahead. We are ready to go back to Biogen with a whole new package. I would expect an IND early next year.
WF: One area we have been hearing a lot about is leveraging gene therapy experience in immuno-oncology and the engineering of T-cells and NK-cells. Any thought that you will partner with one of the adoptive cell therapy companies? What can you bring to this area?
SM: It's a good question, Chris. When you come to a company you discover some bad things (as Sandy has discussed), but also some surprisingly good things. One scientist in our lab came to me with an idea that was not supported in the previous regime to do T-cell editing to take out the HLA receptor and to drop in a gene in the middle. Our T-cell editing is significantly better than anything that has been reported by CRISPR companies. Now Sangamo did try to get a partnership in this area but was caught up in companies being bought and sold and it did not advance. This is something that we need to find a partner for. Our success with double gene knockouts is about 80% for zinc fingers. Tis success is better than anybody else has reported. With our HIV work we have real experience with T-cell editing. We are the only company that has patients in the clinic with T-cell editing. 70 to 80 patients have been treated in the clinic in our HIV trials. We understand how to do it. Immuno-oncology is the next step forward for us.
WF: Do you anticipate that you will secure a partnership in immuno-oncology in the next 12 to 18 months? Is this a strategic imperative?
SM: I'd love to. I'd really love to recognize and make available the quality of the work we have done.
WF: You started off by talking about the great science at Sangamo and trying to address the clinical deficiencies. What should we see over the next 12 months? Prominent hires? How should we benchmark your success?
SM: I've said to the board that we all do these (5?) things: 1) We will create a clinical development group that is professional and reliable. We have already hired a head of clinical operations. We are interviewing others for the head of clinical development. 2) We will refresh the discovery organization bringing it back to ground-breaking science. 3) Ward is doing great work talking to people outside to understand how we look from outside. We my see some changes there.
WF: What about the competition from Megatals?
SM: They work. The key is what can they do time after time in the clinic. We can't chase after CAR-T work everyone else is going after. Though my desire is to realize our potential, we need to make sure that we are not late to the game.
