RLC's (The Biotech Investor) "transcript" post of Algazi Conf. Call:
Listened to the call a couple times and typed this up (haha man do I miss Patti! She was amazing at getting super accurate transcripts out quickly). Started as notes but sort of turned into a transcript (haha). There were a few things I couldn't understand and/or interpret on the call (mostly some scientific terms said too quickly or quietly), it's not proofed and I paraphrased a few things.... But for the most part it's VERY accurate (I bolded some things in the Q&A that got me excited):
Punit's Intro
* Company feels IT-TAVO-EP is a viable solution for patients refractory to checkpoint inhibitor treatments
* Ipilimumab ORR following progression on Pembro is 13% and not all of those responses are durable (implying that cold tumors VERY rarely turn hot on their own... and even if they do, they don't have the immune environment needed to have a durable response. A solution is NEEDED)
Alain Algazi (Presentation)
* Combo trial is treating cold tumor population that's VERY unlikely to respond to Pembro mono-therapy
* A little discomfort upfront, but virtually zero side effects... very favorable to other injection approaches where you don't have the discomfort at treatment, but tend to have some severe side effects
* Tumor takes up plasmid expressing IL-12. Beauty is that it does this for a week or so at a time. IL-12 is expressed where the tumor antigens are, right in the tumor micro environment for a long period of time. You get long, focused exposure with very little circulating IL-12. This leads to regression of treated and untreated lesions.
* Of the 23 patients in this data set, 10 had prior anti-Pd1 treatment (Pembrolizumab/Keytruda) and 7 had prior anti-CTLA-4 treatment (Ipilimumab/Yervoy)
* In combo study population, we would’ve expected a ~6% ORR from these patients... but we saw a 50% ORR.
* We had a lot of CR’s. Durable CR’s and still in remission. One new lesion that was retreated and it’s gone now too. So these patients had durable remissions... a lot of deep responses... and a high ORR.
* One patient, a pig farmer & electrician, who was technically a progressor on Tavo+Pembro treatment according to RECISTv1.1 because he had some flare in tumors before eventually getting better... progressed on 2 differenent PD-1 checkpoint treatments (Nivolumab and Pembrolizumab). He couldn’t work or even walk because he had huge tumors on his heel, but he’s completely functional now. Counted as having PR bc of clinically relevant response. He grandfathered out of the trial... they’re trying to get him an extension bc he wants more treatments. "He looks great!"
* Another patient (CR) progressed on TVEC treatment
* Another patient (PR) progressed on Ipilimumab
* Didn’t have anybody falling out of remission after the 12 months, when we stopped treatment. So these are durable remissions and these people are still doing very, very well.
* Toxicity doens’t capture the whole picture. This side effect profile basically looks exactly like Pembro... it doesn’t add a lot of toxicity.
* Data suggest IT-TAVO-EP is an effective therapeutic modality in refractory anti-PD1 patients.
* People might question the biomarker... well the next step is PISCES. The best biomarker for non-response is non-response, so we’re using refractory anti-PD1 patients and we’re going to validate these findings in that study.
* Chris Twitty Has done a lot of translational work on this data so we have a lot of insight into what’s going on biologically.... some correlative data to support what we’re seeing clinically
Mechanistically:
* They see increase in cytokines levels, particularly in responders
* They see increase in natural killer cells (an innate immunity)
* They see an increase in proliferating CD8 positive cells, particularly with the combo therapy... so they think they’re seeing a synergistic effect where they’re seeing more proliferating CD8 positive t-cells in the tumor.
* They also see an increase in adaptive resistance... Regarding the melanoma score.... If you give IT-TAVO-EP monotherapy you see a significant net increase in PD-L1 staining suggesting adaptive resistance, and this is much more pronounced with the combo therapy. Of course in the combo therapy, you’re really addressing that adaptive resistance with the PD-1 antibody.
* You also see an increase in inflammatory gene expression, and this also appears to suggest synergies between IT-TAVO-EP and Pembrolizumab
* Pembro isn’t designed to turn tumors from cold->hot, but they’re getting a super robust increase in cold->hot tumors with Tavo+Pembro (over the IT-TAVO-EP mono), again suggesting a synergistic effect.
* TIL’s increased in treated and untreated lesions, in responders you see an increase in the effect to regulatory t-cell ratios vs the non responders you don’t. See they think the difference between the two is whether you’re increasing those ratios. Dr. Algazi is working on an investigator sponsored trial where they’re adding up a catostat which will help to deplete some of those regulatory cells. So because this is well tolerated, they can do triplet combo and he expects they’ll be well tolerated... and we’ll find that out soon.
* Data demonstrates IT-TAVO-EP promotes innate and adaptive cellular responses triggering adaptive resistance and a partially exhausted immune response that Pembro is able to reinvigorate, suggesting clinical synergy and potentially a really effective comination.
Q&A
* Q( Chris Twitty): In your practice, how do you decide when to give anti-PD1? Do you do testing or just throw everyone on anti-PD1 treatment immediately?
* A (Dr. Algazi): The standard has been everyone goes on anti-PD1 antibody... that’s the most common practice. We’re in an academic center so we feel comfortable using these assays because we feel they’re useful and can identify patients. But the standard has been to use PD-1 monotherapy. The alternative in standard of care is to use Nivolumab-Ipilimumab combo which can be extraordinarily toxic.
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* Q (Chris Twitty): Do you use the biomarker assay when patients come in looking for treatment options?
* A (Dr. Algazi): It’s not a validated assay so technically we can’t use it for clinical decision making. So we have limitations because it’s not an FDA approved assay.
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* Q (Chris Twitty): So in the bigger context then, of all the patients that come in and you put them on a PD-1 inhibitor about a third will be the rapid progressors, about 40% will be subjective, and then the ones that respond. So in the greater context, where does this data fit into the current practice of patients with metastatic melanoma in terms of response rate and ability to respond when you combine Tavo and Pembro?
* A (Dr. Algazi): With the data we have now, if you’re looking at the first line... you could potentially stratify your patients and that’s what we did. Patients who had high partially exhausted t-cell proportions... we just put them on Pembro mono therapy. That was the standard while we were running the trial. And those patients tended to respond. And the patients less likely to respond we put them on TAVO+Pembro and half went into remission. So now just by stratifying patients by selection, we’re increasing the remission rate so that the majority of patients are going into remission without getting any of the severe side effects of the current alternative in standard of care (Nivo-Ipi combo)
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* Q: (Robert Andtbacka?) Of course predicted responders weren’t included in the combo study, so assuming this therapy was used on the total population what would you expect the ORR to be?
* A (Dr. Algazi): I would say 75%. The caveat is we’re looking at patients with accessible lesions. So I think there’s still a technological front where you can actually make devices and I know Punit and the OncoSec team has been working on refining devices and working on ways to access more lesions. I gave a similar talk at a Merck meeting at ASCO and there was a lot of interest in saying “Can I do a pancreas using this techinology?”... and you can’t right now, but why not? You could actually have an endoscopy... there may be ways to adapt this so it can be used in other settings.
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* Q (Robert Andtbacka?): Chris you did a lot of work on the immune signature and we’re looking at the biopsies and so on... Can you comment on the cold profile that you see and how that converts to a hot profile... and how that relates to the clinical response that we subsequently see?
* A (Chris Twitty): The TIL assay does a really good job in that we can look at the patients that were enrolled, add the low PD1, CTLA-4 population and contrast that with the patients that were excluded from the trial that have high PD1, CLTA-4 population and we see a pretty clear division, in terms of not only PD-L1 expression but gene expression. And this gets modulated with the combo therapy, so we see these levels really jump up on the gene sets in the volcano plots. So certainly that classic gene signature is there, but then if you look these other broader immune markers are there as well, so we see clinality that a lot of people are becoming to understand being an important player in terms of how it fits into immune responses... so we see a significant increase in clinality after treatment and we also see peripheral effects as well and all of this seems to cut with the responders suggesting that as you would expect this is an immune based therapy, so phenotypes by flow... memory markers, slack markers and the peripherally proliferating exhausted t-cells as well. So it all supports this concept of a signature up-regulated in the responding population. In terms of prediction, it wasn't really something we were trying to focus on. One of the interesting things that's going to be highlighted in Alain's SITC poster is that the clinality in the blood does seem to really, at screen, seem to separate between the responders and the non-responders so that's a higher clinality in the non-responders and a lower clinality in the blood and we're going to drill into that a little deeper and see what we can understand there, but that's the one thing that's teasing at something that we might be able to predict coming into this.
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* Q (Robert Andtbacka): How soon can you see changes in the blood or tumor biopsies after initiation of therapy?
* A (Chris Twitty): Clinically it happens pretty quick... as early as cycle 4. But immunologically we tend to see changes after cycle 2, so after 1 cycle of therapy we see immunological changes that... I'd be cautious to say we can identify the responders... but certainly they're changes that tend to support the concept that they will become responders.
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* Q (Robert Andtbacka?): And with that then can you also determine the depth of the response, because you had mentioned something about that Alain, saying if you develop a certain signature you're more prone to a CR than a PR or is the data still too early to determine this?
* Follow up Q (Punit): Do you want to put it into the context of the recent publication you guys did? There's now 2 publications that really highlight the predictive capability of this assay and I think that's worth noting.
* A (Dr Algazi): It's pretty robust... I think you can give a pretty good prediction. You don't get the level of granularity you need to determine who will be CR vs PR, but the assay does a good job predicting responders vs non-repsonders.
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* Q (Robert Andtbacka?): So moving onto the PISCES trial we're doing now, which is taking patients that have failed a PD-1 inhibitor and then putting them on this combo therapy to try to change these cold tumors to hot tumors. What about the patient populations in the existing Phase 2b combo study and the upcoming PISCES study... are they different or are they similar?
* A (Dr. Algazi): The prediction would be that they're the same. But personally, if I'm investing in something or thinking about doing something, you always want to maintain a healthy skepticism. I think it's going to be exactly the same. It's really a validating study. Because I think the assay is a good one. But when you see the data, it's kind of a done deal. If you're seeing a great remission percentage in that population, these are demonstrated refractory patients because they didn't respond. Clinically, if you give someone a PD-1 antibody, you don't see people magically responding at week 30. For the most part, you see what's going to go on within the first 12 weeks... 18 max. And we're going to wait long enough to make sure they're truly non-responders, but I predict we're going to see exactly the same thing. From an investment perspective... if you wait for this data, that would be like saying I'm going to invest in Merck because Permbrolizumab is a hot drug... well you should have done that a few years ago. And I don't know anything about the investment side... I have a 401-k and that's it.
* A (Punit): The interesting thing in the existing combo study, is that while we've had a mix of post and pre PD-1 patients, in the PISCES trial we're only enrolling post PD-1 patients. There are 11 patients that will be highlighted on the poster that had prior checkpoint therapy.
* A (Robert Andtbacka?): It's one thing to have an assay that's highly predictive, it's another to have actual non-responding patients and that's why we're doing the PISCES now.
* A (Dr. Algazi): It's really a validation. It's a really robust validation. We talked a lot about how the trial is designed and I think it's going to be a really robust test of the technology and I think this is going to be pretty definitive.... It's almost like the subsequent Phase 3 is almost like an anti-climax because if we see good signal in this... I think this is the proof.
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* Q (Robert Andtbacka?): So you didn't show median PFS... we showed PFS but I didn't see median PFS.
* A (Dr. Algazi): That's because we don't know the median PFS because everybody is still in remission. We haven't had anybody fall out of remission yet and I see these people in clinic on a regular basis. The most common complaint is "Do I have to keep getting scanned and coming in?" But they're all doing really well.
* A (Robert Andtbacka?): One thing I'll say about the treatment itself, is we have a patient who has been on multiple therapies and had progressed on all of those therapies... and that patient has had universally CR to the Tavo+Pemrbo. It's interesting to see that because you're expecting that since he progressed on so many therapies he'd progress here, but he didn't... he had a CR.
* A (Dr. Algazi): One of the lessons I think I've learned in Melanoma is that if you have a focal intervention it's just like (inaudible?)... you don't see responses because.... here with IT-TAVO-EP it's very clean. You're doing one thing... expressing IL-12. As opposed to trying to develop a virus construct or somethign like that, that's doing multiple things. And even some of the things that you'd think would be more focal like a TLR agonist you get a lot of systemic inflamation of the protein based therapy. Here you're really just targeting the therapy where you need it and getting an extended delivery, so it really is doing exactly what you want in a measured way.
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* Q (Dan O'Connor): Can you talk a little more about the patients that had prior checkpoint experience and what occurred with those patients?
* A (Dr. Algazi): The one that's the most striking is the one I showed where he had 50 lesions throughout his lower extremity and groin nodes and he initially had a flare but ultimately his tumors got smaller and smaller over time and you saw this really robust response. He's actually been off for 3 months after sort of graduating and the tumors are smaller than they've ever been. And that's true of other patients that had prior checkpoint inhibitor therapy... some of them had very rapid remissions. So we are seeing some sign of refractory patients responding. But this is a smaller group of people than will be on the 48 patient PISCES Phase 2.
* A (Robert Andtbacka?): And to add to Dr. Algazi,many times we find these patients when we start these therapies, it's not uncommon for them to have progression... whether that's true progression with new lesions forming or just having the existing lesions increasing in size, but then the patients respond. The other thing we often see, especially since we're treating patients with in transit disease, many times you still see the pigmentation... and we've done this so many times that we still see pigmentation and we wonder why there's any residual tumor at all but it's just pigmentation.
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* Q (Dan O'Connor): So when you look at the totality of the safety profile... to me it seems incredibly remarkable... there's really extremely little side effects associated with the therapy. Can you comment from your point of view on that?
* A (Dr. Algazi): The big thing is the injection you have to deal with the electric current. We use local anesthesia and most tolerate it well... it's often transient. We were taking these 5 minute time points... asking what kind of pain do you have every 5 minutes and it was almost always invariably zero. So the only thing is just dealing with the procedure, but between the procedure you just don't see a lot of side effects which makes it really easy for people to do. It also makes it combinable, so one thing I'm exciting about is doing a triplet combo therapy here and there's triplets being done, but you know those are all likely going to be riddled with nasty side effects. I think it's going to be tolerable and possible to do a lot of things with this and there's a lot of potential for growth. And I think we're seeing corroborating data... in Brisbane, Australia I gave a talk about the systemic effects of the priming therapy and we're seeing that you really do get systemic effects so I think this really could be a real wave of the future because it's combinable and well-tolerated.. and the only thing is dealing with the minor discomfort with the procedure itself... and I know OncoSec is working on reducing the discomfort involved with the procedure.
* A (Robert Andtbacka?): We're currently just using TAVO right now, but really this is a platform and it lets us consider other plasmids and so on we can electroporate in as well.
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* Q (Dr. Algazi): An interesting question academically is do you need systemic therapy? Do you need to give drugs through IV to get an immune response?
* A (Robert Andtbacka?): That's a really good point Alain and I think that with some of the things we're seeing right now, I'm not convinced you'll need systemic therapy. I think there's more data needed but depending on how you do the local therapy, you may be able to get enough of a systemic response but the jury is still out. As we've learned more about intratumoral therapies, it used to be we saw minimal systemic effects, but we're seeing more systemic effects now.
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* Question about dosing change/escalation:
* A (Dr. Algazi): Almost everyone is responding so I think we have a good dose. We're seeing really robust clinical effect We're seeing abscopal effects, we see what appears to be synergy and we're going to validate that synergy so it appears to be a an effective dose. Maybe we could go a little higher but I'm not sure what the added benefit would be because we're already seeing pretty robust effects clinically.
* A (Robert Andtbacka?): To add to that, with seeing the robust results we're seeing, it also becomes a matter of practicality... how many times do we want to bring patients in for treatment and so on.
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Intro of New CEO, Dan O'Connor:
Dan: We ran a little bit over time so I'll make this brief. The data that you saw here this morning is the reason why I joined this company... plain and simply. I really appreciate everyone's work on this technology. I think we have a really important data set in front of us. I'm looking forward to amplifying this data set to the public in the months and weeks to come. And I really appreciate your support. I'm looking forward to the PISCES study which is open and now screening for patients.
