Good day, and welcome to the Protagonist Therapeutics PTG-300 Development Update Call. Please note that today's conference is being recorded. At this time, I would like to introduce Don Kalkofen, Protagonist's Chief Financial Officer. Please go ahead..

Thank you, operator. Good afternoon, everyone. Please note that a replay of today's call will be available at the Investors section of our website at protagonist-inc.com.

Before we begin, I'd like to remind you that today's discussion will include statements about the company's future expectations, plans and prospects that constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995..

PTG-300 for various blood disorders, most of which are rare disease; and oral GI-restricted targeted peptide PTG-200 and PN-943 for inflammatory bowel disease, or IBD. All of these assets have a multibillion-dollar potential in multiple indications.

PTG-300 peptide mimetic of the natural hormone hepcidin that serves as a master regulator of iron homeostasis storage and distribution in the body was being pursued in Phase II open-label proof-of-concept studies in beta-thalassemia, or beta-thal; polycythemia vera, or PV; hereditary hemochromatosis, or HH; and an investigator-sponsored study in myelodysplastic syndrome, or MDS.

As you may recall, a major objective for 2020 was to pick our first clinical indication for PTG-300 that we can progress towards a pivotal study in 2021. Today, we are pleased to announce initial but yet very robust clinical data from our polycythemia vera program.

And the selection and prioritization of polycythemia vera as the first indication for a pivotal study with 300. This decision is based on three criteria; strength and consistency of the clinical data, favorable regulatory path forward and the commercial opportunity. This is our major announcement today.

And while most of our discussion will be around 300 and polycythemia vera, let me also take this opportunity to talk briefly about our oral gut-restricted IBD assets, largely in the context of corporate update and cash runway..

Thanks, Dinesh. As Dinesh mentioned, we are really encouraged by the results we have seen in the ongoing Phase II study of PTG-300 in patients with polycythemia vera. Dr. Hoffman is going to walk you through the study results in detail, but I wanted to highlight why I believe this data has prompted us to focus on PV as the first indication for 300.

The majority of PV patients today are treated with phlebotomy, or phlebotomy in combination with cytoreductive therapies to control erythrocytosis and keep the hematocrit levels below 45%, as indicated in many treatment guidelines.

There is a large body of evidence that shows that managing hematocrit is challenging and regardless of best available therapy, they're a substantial portion of patient segments that have poorly controlled hematocrit and therefore, a higher mortality rate compared to age match controls.

The treatment paradigm of PV allows patients to enter what I call the danger zone before they get the next treatment. So even those people who are considered well-controlled have increased hematocrit leading up to their phlebotomy.

Self-administered 300 may reduce doctor visits and the anxiety associated with the uncertainty of phlebotomy at that time. Phlebotomy is those of donated blood know, is associated with acute symptoms and difficulties. But the real problem in these patients is the potential for chronic symptoms related to iron deficiency in phlebotomized patients..

Yes. Thank you very much, Sam. Thanks for the opportunity to present this really exciting data. So if we can go to Slide 7, I can educate the audience on what polycythemia vera is so they can have a better understanding of the potential for 300 and put this in context.

So as you can see here, this slide is entitled what is Polycythemia Vera? Well, polycythemia vera is a member of a group of chronic hematologic malignancies termed myeloproliferative neoplasms. And these neoplasms are unusual in that patients frequently live several decades. And these neoplasms occur at the level of the hematopoietic stem cell.

And unlike leukemia, they are characterized by increased production of mature blood cells. In polycythemia vera, the cell that's most destructive to the patients are really the increased production of red blood cells. And that's the term erythrocytosis that you've heard previously and we'll hear subsequently.

Now the interesting thing about this disease is that there are 100,000 cases of polycythemia vera in the United States. This disease occurs across races and age groups. And the critical diagnostic warning sign is that of an elevated hematocrit, which is the hallmark of the disease.

I think the importance of this drug is that although there's 100,000 cases of these patients, these patients, as I mentioned, live for several decades, so the usage of this drug would be quite prolonged over that period of time..

one, advancing PTG-300 in polycythemia vera as well as in hereditary hemochromatosis; two, advancing PN-943 to a Phase II study in ulcerative colitis; and three, working closely with our partner, Janssen, to continue Phase II development of PTG-200 in Crohn's disease.

As a result of our ability to limit our focus with 300 to PV and HH, we have organized our efforts to extend our cash runway for an additional 6 months. We have taken steps to manage and lower our operating costs and align our resources around our current studies.

As a consequence, we now have adequate financial resources to fund planned operating and capital expenditures through the middle of 2022. Finally, we are mindful of the impact that the current coronavirus outbreak may have on our local operations and global activities.

As we disclosed in our financial results released today, we are suspending guidance for PN-943 Phase II initiation and PTG-200 Phase II data, and we are actively working to minimize impact on timelines and move as quickly as conditions would permit.

Our priority is maintaining the health and safety of our employees and those who are participating in our studies. We will continue to monitor changing conditions carefully and provide updates as appropriate. With that, we would like to now open up the call for questions.

Operator?.

Our first question comes from the line of Chris from Nomura..

This is Chris Marai from Nomura Instinet. Maybe the first one is for the physician on the line. Thank you so much for the overview of PV.

I was curious how you look at a therapeutic like PTG-300 in terms of clinical practice on sort of an everyday basis as you see PV patients? And how do you think it may fit, assuming this profile remains consistent in sort of the treatment lines of PV, how you may see its usage, in particular relative to drugs like Jakafi?.

Okay. I think that's a really terrific question. I think its use would be quite wise, wide. I think virtually all patients with PV would be candidates for this drug. We've, as you can see, we have treated young patients and also older patients with this drug. So it's been well tolerated.

I think the advantage, again, is that, especially with young patients, those individuals, we do not want to give life-long myelosuppressive therapy or interferon or Jakafi because of unanticipated, potential for unanticipated adverse effects.

So if they have an increased phlebotomy requirement, this would be an ideal treatment for those folks because basically, it would free them up from returning to the clinic as frequently as they do and requiring repeated phlebotomies.

When we risk-stratify these patients, those patients that go on the three treatments that I've discussed before, frequently, they still require phlebotomies, and it's been shown by European investigators, if you have additional phlebotomies during your administration of these drugs, that you are an increased risk of thrombosis.

So in that setting, this drug could be an adjunctive agent that would eliminate the needs for phlebotomy.

Alternatively, and I could see this developing quite quickly, patients are frequently unwilling to take any of these agents, especially hydroxyurea and interferon because of the potential of hydroxyurea and the concern about interferon essentially having systemic symptoms, problems with individuals about immune disease and also its effect to exacerbate depression in patients.

So in those individuals, I could see and even in those high-risk patients, if we can control their hematocrits with this drug, which I think we can easily do, and we've demonstrated that. That this drug would be a real competitor for any of those agents.

So I think it could be essentially utilized potentially for the broad swath of patients with polycythemia vera. So I think, and for long periods of time, that's the issue that I'd like to really emphasize to you.

For instance, like young females who have Budd-Chiari syndrome, and we usually put those young females on myelosuppressive therapy and interferon for life-long periods of time, and they can live several decades.

They would far prefer being on a non-chemotherapy, non-biologic agent like interferon, it would really liberate them, especially from the adverse effects..

Okay. That's very helpful. And then I was wondering if we could touch upon the data for a minute. Dr.

Hoffman, could you elaborate on some of the effects of spleen size that you may have observed in the trial, if any? What you would hope to see there on an endpoint like that in a patient population like this?.

Yes. So in this situation, what you have to understand is this is not myelofibrosis. So in reality, most patients with, or virtually all patients, I'll say most, the overwhelming majority of patients with patients with polycythemia that don't have symptomatic splenomegaly.

So the endpoints that have been used in the past, let's say, for Jakafi for reduction of spleen size are of minimal importance.

So these patients, even though some of them have high-risk disease, really didn't have -- they had minimal splenomegaly at all, only 40% of patients with polycythemia vera have splenomegaly and only for our advanced disease it's symptomatic. So the sample size is too small.

In animal models, when hepcidin mimetics were given, those are polycythemia vera animal models, the administration of a different hepcidin mimetic did lead to reduction in splenomegaly but we really were not able to assess this because none of these patients really had significant splenomegaly.

So we await treating patients like that to see if the data in the mice is recapitulated in humans as it relates to spleen size..

Our next question comes from the line of George Farmer of BMO. Your line is now open. .

Hi, everyone. This is Gobind Singh on for George. Congrats on making a decision and moving forward with those 2 indications. I guess we had 2 buckets of questions. The first 2, maybe for Dinesh. I know you guys were thinking about once-weekly dosing and possibly twice-weekly dosing in beta-thal.

I was wondering if maybe going forward, at least with PV, do you think you might be looking at twice-weekly dosing at all? And I was wondering since we are moving past beta-thal and MDS, if you'd be willing to comment at all as to what kind of data we're seeing in those indications? And I'll have a follow-up for Dr. Hoffman, if that's okay..

Yes. Gobind, thanks for the question. And I will have Sam Saks, our CMO, answer the first question..

Sure. So with respect to the use of 300, we think that it's going to be used widely. You were asking me--.

About the once-weekly..

The once-weekly in beta-thal, we don't anticipate that we'll need to go to twice-weekly based on this data. The patients are having a robust response to once-weekly therapy. We can always consider that in patients who max out with respect to the effect.

But at least so far, once-weekly dosing in the range that we're studying has been adequate, which is why we're confident about moving for into a pivotal study, because it looks like we're in the active range and we understand how to titrate the drug..

Gobind, you may recall that in the beta-thal data, the transfusion-dependent data, the TSAT levels are at 100% near saturation. So that was our toughest population that demanded high doses and twice-weekly dosing to get the TSAT levels into the normal ranges.

In comparison to that, diseases like HH, and especially PV, the TSAT burden is incredibly lower, right? So we had always hypothesized that then logically, one would assume that for all these other indications, you may note lower doses and lower frequency of dosing. So all the data that you have seen today, that is once-weekly dosing.

And you can see, we are oscillating anywhere between 20 to 40 milligrams over here. And sorry, Gobind, can you repeat your -- the second question for Dr.

Hoffman?.

Sure. Yes. I didn't say it, but it would be great if Dr. Hoffman. I know you mentioned that the spleen sizes is not something you guys typically look at. I believe in the protocol, you guys are looking at a PV-specific kind of symptom score.

I was wondering if maybe you'd be willing to comment to how maybe the trend is looking in the patients that you've seen so far? And then I guess the second part of that question was, especially since there's a blinded phase, that a blinded component to this trial, how are you guys using hydroxyurea or Jakafi and whether it's past history or in combination? Or what's the protocol for how people can give these other medications in addition to PTG-300?.

Okay. I can speak to these questions. One is, let's take the second question, and then I'll probably ask you to repeat the first one. But in the second question, let's say, for instance, we have one patient in the protocol. And then I think this guy is emblematic.

The, many of, this fellow is on maximal doses of hydroxyurea, if we put him on higher doses of hydroxyurea, we'd make him thrombocytopenic and put him at a risk of having a bleeding event.

So what we've done with him is we've kept him on a fixed-dose of hydroxyurea and to that fixed-dose of hydroxyurea, we've added 300, and that's eliminated the phlebotomy requirement. Many of the patients who are on the clinical trial have been reluctant to go on myelosuppressive therapy.

So a lot of patients are not that interested in going on myelosuppressive therapy because of the toxicities associated with myelosuppressive therapy or interferon. There's also a concern with some of the patients about Jakafi, about secondary malignancies, also increased incidents of shingles that is associated with that drug.

And so that's the context that we've been administering the drug. We have not had somebody who have, we have concurrently treated with interferon. We've only had a patient who have been treated concurrently in a small sample with hydroxyurea..

This is part of our goal in expanding the study is to open it up to accrue additional patients with a wide variety of approaches that are used in these patients. But it's too early for the symptom score, just to comment on the symptom score..

Go ahead..

The system score is really well established. It's been used in the registration of Jakafi. It's really well accepted by the field. We're using the standard scoring system and we'll be able to report that out later when we have more data..

Yes. Let me comment on the symptom score. I mean the symptom score is of value. In the patients with polycythemia vera, we've done, I have a large program project ramped from the NCI. We've used that symptom score, for instance, to assess the efficacy of interferon and also hydroxyurea, and it is useful, but it's not as robust as it is in myelofibrosis.

Anecdotally, I can tell you that they're one of the patients in our cohort had intractable pruritus, which was eliminated by the use of this drug. And that was very satisfactory. But again, that's one anecdotal indication. The patients do experience a sense of well-being, but that's really just a global assessment.

And I think to really get a good feeling of the results of the symptom score would require a much more, a much greater group of patients being studied with that tool, quality life tool..

That's perfect. That's really helpful. And sorry, Dinesh, I might have missed this. Is there, can you, are you guys, can you comment at all about any data that you've seen with PTG-300? And I think it was an IST with myelodysplastic syndrome..

So that study has been discontinued. We decided not to begin that study with a focus on PV. We've had such a strong reaction to the positive data in PV, our feeling was that we wanted to focus our efforts where we saw such great results..

Our next question comes from the line of Mr. Joe Schwartz..

Joe, we can't hear you if you're on..

Maybe operator, we go to the next question on the interim..

Hello?.

Yes..

Can you hear....

Hello?.

Joe, you are breaking up. There are technical difficulties. Well, why don't we....

We now have the line of Mr. Joe Schwartz of Leerink. We are having some technical difficulties..

Yes.

Are you guys able to hear me?.

Yes..

Yes..

Okay. Great. I'm not sure what happened there.

So I was just wondering if you could talk at all about any of the other blood compartment components like leukocytes, reticulocytes, whether there were any notable changes there and whether you can tie any of that to the targeted mechanism of action?.

Okay. If we go back to the, go ahead..

Go ahead, Dr. Hoffman..

Yes. I mean we have some appendix slides, which if you can go to slide, the appendix slide starts on Slide 18. And the next slide basically, which I guess is Slide 19 is essentially the platelets and you can see that there they've been essentially steady in response to the, in those patients receiving the drug.

So the platelet count has not gone dramatically up. But I'd like to emphasize to you that although many clinicians have used platelet numbers as a trigger to treat patients with polycythemia, I think the literature well justifies that it basically, it does not, the platelet numbers does not correlate with the thrombotic risk.

Hematocrit makes the biggest difference. So we, if those people are sort of treating patients with polycythemia vera essentially don't go after the platelet count. And we've not had people who have had platelet counts over 1.5 million where you develop a Von Willebrand disease. So as you can see, they remain level.

If you go to the next slide, which is reticulocytes, that's not what you're interested in. You're interested in the next slide, which shows the leukocytes. And you can see that those levels have also remained steady during the treatment period.

I should also emphasize to you that none of the patients that received the drug had any thrombotic episodes during the administration of the drug or any evidence of evolution of the disease to myelofibrosis or to acute leukemia.

And that's, the reason I'm mentioning that to you is because frequently, patients have elevated leukocyte counts when that occurs. So the other lineages have remained stable during the period of administration..

Great. That's helpful. Thanks.

And then for the company, what are the next updates we should look for from this trial? And how quickly do you think you can get a pivotal trial ongoing? And what would be design and an endpoint analysis that you'd target there look like?.

So thanks for that question. And I will have Sam Saks elaborate on the answer to the question..

Sure. So we're currently in the process of working with thought leaders to design pivotal studies. So we can't say much more about that until we get that design. We're going to move that forward and discuss it with FDA as soon as we finalize that. The current study is going to continue and expand.

We expect the first part of it is, of course, open-label, so we'll be aware of the data as it evolves. The randomized portion will be starting. And we expect that there'll be further data updates in the last half of the year at the various medical meetings in this field that occur that people are well aware of..

And what I would like to add is that clearly, even in these difficult times, we are very satisfied rate of enrollment. Today, we showed you data on 7 patients. We also mentioned that now there are 8 patients that are enrolled and the data speaks for itself.

So we believe the enrollment will strengthen in the coming weeks and months, and it will be our intent to share the data and share as much information as we gather from this expanded study..

One of the things that Dr. Hoffman mentioned is these patients have to be phlebotomized. So they have to seek medical care. They can't just stay in their house and hunker down. So that's one of the things that's advantaged us is we actually give them the possibility of administering at home. So that's working in our favor.

These patients can't just avoid care altogether. They run the risk of thrombotic events..

And then, Sam, as you mentioned during the call, obviously, the next steps are getting together with the thought leaders, with the KOLs and then collect more data and have a good dialogue with the FDA to finalize the next pivotal study..

Our next question comes from the line of Douglas Tsao of HCW. Your line is now open. .

Hi, everyone. Chris Bialas on for Doug Tsao. Congrats on the data.

And I was just wondering if you guys could give a little more color about what you saw in the beta-thalassemia trial that made you decide to discontinue?.

So all along, our guidance has been that, look, we are doing multiple open-label proof-of-concept studies with the intent of picking a winner. Today, we have picked a winner by a huge margin, and that is what we are able to share. As far as beta-thal is concerned, obviously, we got incredible safety data in 50-plus patients with 1000-plus injections.

We got excellent pharmacodynamic data, as you recall, that we shared during our last December call. And we, of course, cannot share any more information right now because we are under embargo. And -- but we will be presenting beta-thal at an upcoming medical conference in this quarter..

But I want to incorrect your impression. This is not a matter of us reacting to thal. This is a matter of us reacting to the fact that PV is so outstanding. We really want to emphasize that, as Dinesh said, we were investing in these 4 things in parallel that are open label. We get to see the data all the time.

When we saw this data, there was no question in our mind that this needed to be the focus of the company. So I just wanted to make sure you understood that we were really reacting to the positive here..

I'm showing no further questions at this time. I would like to turn the conference back to Dinesh..

Great. So in summary, we are pleased to have delivered on our promise to select an indication for the initial pivotal development of PTG-300, which was a major objective for this year. In addition, we would like to thank Protagonist shareholders, the patients who participated in our studies and the investigators who support these studies.

In these difficult times, I want to specifically emphasize how thankful and proud I am of the Protagonist employees that have brought us to where we are today. Thank you all for joining us..

Ladies and gentlemen, this concludes today's conference call. Thank you all for joining. You may now disconnect. .