Sangamo Therapeutics, Inc. (SGMO) Earnings Call Transcript & Summary

[Audio Gap] Therapeutics for fireside chat as part of our 2024 Global Healthcare Conference representing the company, we have Sandy Macrae, President and CEO. Sandy, thanks so much for joining us. How are you doing today?

I'm doing well. Thank you. It's a pleasure to be here.

Great. Great. So we have a long list of questions here, but maybe before we ask some of the questions into the individual programs. Can you just maybe big picture, talk about what progress has the organization made over the last few months. And most importantly, what's ahead here for Sangamo.

Yes. I literally just come here direct from ASGCT. And ASGCT, we showed our new capsid, which is, without a doubt, we believe, best-in-class. And we showcased the first-ever presentation of our integrase, which allows the recombination of large pieces of DNA. And what it does is it reflects Sangamo's belief that being at the front of the science is always important. And it allows us to dedicate our future to neurology. And to do that, you need both the cargo, the zinc fingers or the integration at one point in the future, but you also need a way to deliver it. And that's one of the key takeaways from ASGCT this year. It's about delivery. And there is a limit to the number of times people go after the same disease in the liver. And what's exciting is new ways to deliver either with LNPs or with new capsids as we've shown. That takes real scientifical focus, and that's what Sangamo has chosen to do. We've made some great medicines. The hemophilia product with Pfizer, they will show the results of the Phase III in the summer, and they're tracking to file a BLA in beginning of next year. And once we do that, we get $220 million worth of milestones and then 14% to 20% royalties. We've got beautiful data on Fabry. And the agency has given us this remarkably thoughtful way forward with the Phase III design that they've agreed with us allows us to get registration with as few as 25 patients. It really is one of the moments where you realize it's a partnership between the companies and the FDA to bring medicines to patients. And that allows Sangamo's as an entity to focus on the science and bringing new medicines and new -- into new frontiers for genomic medicine.

That's awesome. That's a greater review Sandy here. Maybe staying big picture. I think some investors may actually argue that zinc finger proteases maybe don't have the same versatility than CRISPR-Cas9 and some of the more novel approaches that the field more broadly was able to develop the last few years. What would be your pushback to that?

I've been doing this job for nearly 8 years now. And when I started, there was CRISPR, Editas, Intellia. Now I count 27 companies, and I'm not sure what each one brings is different from the other. And people still come back and use zinc finger and there was an article as -- an independent article from the Lombardo Group, recently showing the zinc finger repressors are better than CRISPR, and that's an independent bake-off. Why do I like to zinc fingers? I like them because they're natural. You and I have hundreds of zinc fingers controlling our genes. I like them because they're small. They're in [ 1/8 ] of the size of the CRISPR. They're 1/4 of the size of the mammoth small CRISPR. They're used in the body, so there -- what they do, the repressors is they control the expression at the promoter level. So they don't cause double-stranded breaks. And then we can add a whole series of functionalities onto it and choose what it is that we do based on the disease that we're trying to control. For the brain because the cells don't divide there are pressors and activators are actually very useful tools. We -- the zinc finger repressors is something we've been talking about for some time. And at ASGCT, we showed activator -- unique activators to turn genes back on again. So I'm very happy that I have the zinc fingers and I'll watch the rest of them squabble over, which is the best CRISPR. And then with the integrate, we showed that we can once again pioneer the field. David Liu, great respected scientists. I sat in a panel with him once and he said, what -- the dream is recombination at greater than 10% efficiency. And what we showed was 30% to 50% efficiency with the recombinanators. And what that will do eventually will let us put whole genes into the genome and correct for a whole variety of errors. And I think that is where the field is going to go.

Got it. Got it. That's actually very helpful. You mentioned your new focus, obviously, on CNS. Can you maybe just talk about that a little bit? And maybe in the context of the route of administration, how are you thinking about prioritizing key route of administration, you have 3 programs I think for one of your programs, you're actually using intrathecal delivery versus for the other one. You're hoping to use, obviously, IV with your novel approach that crosses the blood-brain barrier. Can you just maybe just expand a little bit on how you're thinking about routes of administration here?

So we made this decision 3, 4 years ago, that this is where we're going to go. And we made the decision that Fabry was the last liver-targeted gene therapy. And we had a long-term plan because that's what you need to do. And we have a long-term plan that we would take Fabry into Phase III, and that would finish there and then the company will focus on neurology. The finances over the past couple of years, brought that to Crescendo sooner than we'd expected, and that's how we're going to partner Fabry. We're making great progress with those conversations. We looked at where the zinc finger represses particularly work well and neurology seemed to be the place. We looked at where there was unmet medical need. Neurology seems to replace. And we believe that we could invent or discover a capsid that allows us to cross the blood-brain barrier. But before we did that, I told Amy and her team to find me things that existing capsids would be able to address. And that's where Nav1.7 came because Nav1.7 uses an existing capsid, it's given intrathecally. It goes to the dorsal root ganglia and that's where the pain circuitry is controlled, and it turns down or turns off Nav1.7, which is a very well-understood target that everyone is trying to be drug for tens of years. And because as a small molecule given systemically, it has cardiac side effects, nobody could make into medicine. We've now med -- we believe, into medicine because we could administer intrathecally and turn off the pain signal in patients with intractable pain. We should have an IND for that. We're literally completing the GMP tox studies at the moment. There should be an IND this year in the clinic next year and hopefully results by the end of next year.

Got it. Got it. That's very helpful. Can you just maybe talk about the nonhuman primates data? And what you're seeing there for Nav1.7, particularly the histopathology findings? Is that...

It is good. And there has been a concern -- there has been a discussion with dorsal root ganglion. And I think it usually is when people put a very active promoter usually GFP and high doses. And they see inflammation in the dorsal root ganglion. We see none of that because we're using zinc fingers, which are natural, and we're using a sensible promoter. And in all of our histopathology, it's looked absolutely fine. And we've had good conversations with the agency, and they agree with our assessment.

Great. Great. Great to hear. Let me talk about indication selection and indications prioritization. Why for Nav1.7, you think the chronic neuropathic pain is the lowest hanging fruit, if you will, why you're prioritizing that as your first indication that you're pursuing for that target?

I get asked this usually in the context of Vertex and Nav1.8. And that's a [ tablet ], and it's being used for bunionectomy and tooth pain and daily pain indications. Whereas what we're looking for is the 30,000, 40,000 patients that have -- that their lives are dominated by pain. And it's small fiber neuropathy, sometimes it's diabetes. But other times, it's mutations in the Nav1.7 channel itself or other pain indications. And for those patients, if you ask them, they say, I would rather be [indiscernible] pain limits. And many -- and there's a cohort of them that even take their own life. So this is a very horrible intractable disease that is treated with antiepileptics and the whole series event of psychiatric medicines even that don't take the pain away. And we feel that if our medicine works, it will make an enormous difference to those patients.

Got it. Got it. That's helpful. How should we think about duration of effect. This would obviously be potentially one and done, right, which I think has its own positives. But is that potentially a double-edged sword? Like do we want to maybe have an ability to pharmacologically modulate that pathway? Or how are you thinking about that part...

Gene therapies have to be -- genomic medicines have to be considered as you give them and they don't go way. And therefore, the choices we make and all the other companies make has to be thoughtful in choosing diseases where there isn't really an alternative where the benefit of the gene therapy outweighs any risk. And under the assumption that it's going to be once and done. And I think it's not that, that's a two-edged sword that is that something one has to accept and navigate and choose diseases that are significant. One of the most interesting things about ASGCT was a number of companies doing PCSK9. It's now replaced sickle as the place to go for the CRISPR companies. And I'm sure there are some people with very rare hereditary forms of hyperlipidemia for which a gene therapy may be correct. But you and I, with our bulk standard hyperlipidemia should never be taking a genomic medicine to address something that can be treated either with statins or even with the PCSK9 antibodies. And I think that's a very good example of understanding where the place of genomic medicines is and where other treatments are the right thing to use.

Yes. Certainly, are you advertising indications with larger medical need is critical for genetic medicine more broadly, and we've seen that pendulum kind of swinging one way and maybe now it's coming back the other way...

There may be a time in the future once we've tested it and bear intractable pain. The people understand its safety and its utility and can gradually increase the patient population. But I'm going to be very careful to start with the most deserving the most suffering -- the highest suffering patients and then gradually go from there.

I mean, super helpful. Maybe staying with Nav1.7. You mentioned, obviously, you're making progress with the IND, you have the GLP talks ongoing. Walk us through how you're thinking about the clinic? Once you enter the clinic, what are some of the biomarkers that maybe you can track to actually see potential for initial proof of concept? Like any thoughts on that front?

Patients will tell us there's more pain. I mean that's why we're doing this. I get asked often about how difficult pain studies are in the placebo response. And in milder forms of pain, absolutely. I've done pain studies in previous lives. But these are patients for whom their lives are dominated. They get up in the morning and think about pain and they go to bed and think about pain at the end of the night. And so we will be very careful to do this study well. And then within 4 to 6 weeks of administration, the virus will be -- the AV will be producing the zinc finger repressor -- and if it's anything like the Fabry studies, where the patients see benefit 4, 6 weeks into the treatment, that's the kind of time line that we should see in effect. Now we're going to start at low-dose because that's what you do and then gradually increase till we get to the highest dose for which we have over...

We have a sentinel cohort of patients? Do you have a stagger...

We'll do it very carefully like that.

Okay. Okay. That's helpful. Maybe switching to your novel capsids to have the ability to kind of cross the blood-brain barrier, some of the early evidence that you've shown there. Can you maybe just expand on why these capsids are differentiated? And again, how you're thinking about indications prioritizations there?

So we've been working on that for 4 years of creating large libraries of mutated caps, it's based on the kind of capsids that you've all heard of. And then we select for them by going into monkeys, into nonhuman primates. Each capsid has a barcode on it. So the once it gets through the blood-brain barrier and found in the brain, you can identify them at autopsy. And then you select for them and you enrich through 3 rounds of selection. And we came up with the capsids like BBB that is head and shoulders above all of the existing capsids. And when people patent their capsid, the sequence becomes known, and therefore, you can make other people's capsids and put them into the experiment. So you can see that you're doing better than the other capsids that are -- have been spoken about and traded on -- and so we think that our capsids, it gets to all the brain regions. It gets to a significant number of cells in each region. And we have the advantage because we're also putting our cargo in it. And so we see not just that the capsid gets there, but it works. It produces the zinc fingers -- in the zinc fingers and repressed out. And we were seeing for tau and prion disease that 50%, 80% of sales were almost complete shutdown of their -- the gene of interest. And then slightly more [indiscernible]. We are thinking of the capsid, it's very manufacturable. And that's one that is not usually talked about. And there's 2 parts to that. One is, if you put it in one of those big bats, can you make a lot of it. And yes, the answer is yes. But the other one is all the process of purifying and assaying it can use existing methods, which you can't do for all capsids. And yes, again, this is one that we'll be able to purify and make and make available. So we're very pleased with it. We showed data at ASGCT that we think we found how it crosses the blood-brain barrier. So we have identified a protein that binds to the capsid and allows it to cross the blood-brain barrier, which is very pleasing. And then we've shown that this is preserved between mouse, monkey and human. And when we talk to -- we're talking to many companies and were trying to license this capsid, and that's one of the first questions. Do you know what's the receptor? And once you have that, the conversation changes dramatically.

Can you potentially optimize that in some sort of -- it sounds to me that you screen a number of capsid to find the capsid that had the ability to cross the blood-brain barrier and now that you have discovered the way the capsid cross the blood-brain barrier, is there a way to further optimize that and develop rationally novel capsid that have better ability to craft the blood-brain barrier?

Yes. But this cap is so good. I'm not in a hurry to do that. There's no way that I would stop the development of the programs I've got to wait for another capsid because each round of selection in nonhuman primates takes about 6 to 9 months. So future generations of capsids could be created with this, as you just rightly described it rational drug design. And we will continue to do that. But STAC-BBB is a great capsid. It's everything we would have wanted.

Got it. Got it. To wrap up maybe pivoting to going back, I should say, to Fabry, you already mentioned, it was great to see a faster path to potential approval here. You mentioned 25 patients. You don't have to run a trial head-to-head versus Fabrazyme, sounds to me that you've been looking for a partner for quite some time. What is holding pharma back here?

Well, what was holding pharma back was lack of clarity of the regulatory pathway. So the -- if you think -- we only found our novel capsid in March. We only got regulatory clarity in February. So it's been a very interesting spring for us because all of a sudden, all the barriers have been taken away. Fabry, they wanted to see length. As with all AAV in the [ liver ], particularly we wanted to see sustained effect. So we've now dosed 33 patients. The longest is out nearly to 4 years, I think, and there's no sign of decline. We have taken 14 patients off ERT, none of them want to go back. And all of them, the Alpha-Gal remains in all of them, there is no sudden rise in lyso-Gb3. We have seen that in those patients that have came into the study with antibodies to Alpha-Gal, those antibodies have disappeared. It's remarkable. It's what everyone spoke about for so long about the tolerizing effect of low doses coming from the liver in contrast to the almost like vaccination effect that you get from ERT. And those antibodies were eventually abrogating the effect of the ERT. Well, we've now shown that if you get gene therapy, they disappear. So 14 are off and don't want to go back on it. The remaining 4 that are still on ERT have already planned their date when they're coming off. And so now we have a very -- the SF-36 is statistically significant. The FOS-MSSI is statistically significant. The very interesting GFR results that I think will contrast with what you see for ERT. On Friday, I just saw the next batch of data 6 months later of data, and it continues to show everything that we've been seeing, we've been saying. So -- we're in discussions with a number of pharma companies, significant discussions. And what appeals to them is now that there's a very agreed upon route with the agency to get to registration shows those 25 patients come back sooner if the results are compelling was what the agency said. And it speaks to the leadership of Peter Marks because what he said is, I'll get this wrong sometimes. And I think this is remarkable for someone in government in that position to see so there'll be times when I approve a drug on its biomarker, and it doesn't -- isn't confirmed by a clinical study. And that's okay. Because by doing that, I get it into patients and give -- bring benefit to people with rare diseases that wouldn't otherwise get it because companies like those pharma companies were avoiding this large study that they thought they were going to have to do. And because of what he's done and his team at the agency, the pharma companies now seeing there's a way forward for Fabry disease.

Okay. That's super helpful. I will not ask you about Peter Marks and Sarepta. That could be a whole different conversation, I guess. But maybe just sticking to Fabry, when I look at the biochemical response that you have shown, I thought it was interesting in some cases, you've seen impressive elevations of Alpha-Gal but that not always corresponded to actually a decrease in lyso-GB3 or not all the time. Is this just the natural variability of the data? Is there anything to read into it? Well, how -- what's the best way to rationalize that dichotomy?

I think it's -- there is variability with only a small number of patients. But I think it's clear that if you come in with the high lyso-Gb3, it will go down. And if you're already at a low lyso-Gb3 either because your mutation only produces results in a low lyso-Gb3 or you're already on ERT that the effect of the gene therapy isn't as pronounced on that measure. But what's more important, I think, is that patients that were in -- had this effect. Patients that were on ERT feel better on gene therapy. The objectively report -- sorry, they seek us out to tell us how much better they feel. They come up to us at conferences and talk about the benefit that they've had. The patient support group has been active in writing to these pharma companies that you referred to, to say, listen, here's a benefit. We don't want ERT. Can we be clear. ERT means I have to go to the clinic every second week for an infusion for many hours. And it doesn't give me the benefit of the gene therapy. And so we are delighted with this as a medicine. It will make an enormous difference to patients.

Great. We're running out of time, but maybe one last question, probably a big elephant in the room, if you will. And I think you already touched upon it, ways to potentially partner, Fabry? You remind us the economics around your program for Pfizer partner with Pfizer on hemophilia. But like walk us through big picture how you're thinking about extending your runway at this point?

I will -- we will extend our runway because we have remarkably valuable assets. We have a Fabry medicine that is now best-in-class, first-in-class with the clear pass through registration and people in the data room and talking to us about it as a partnerable product. We have 10 companies talking to us of accessing the capsid, and it is best-in-class and capsids are valuable. And we showed this integrase and have another cohort of companies talking to us about the entries. We have funded Sangamo in the time I've been there. I've raised $1.5 billion, of which half of it has been on equity and half of it has been in partnerships. And we will continue to do those partnerships and successfully fund the company. I'm confident for that.

Terrific. Sandy, thanks so much for joining us. We're out of time. Thanks, everyone, for joining us for this conversation. And we'll talk soon.

I look forward. Thanks again.