Hello, everyone. My name is Mitchell Kapoor. I'm a senior biotech analyst at H.C. Wainwright. I cover Rani Therapeutics, and I'm lucky today to have the CEO from Rani, Talat Imran, join us today. Thank you for joining.
Mitchell, thank you for having us, and thank you to H.C. Wainwright for putting this on and allowing us to be a part of it.
Of course, always a pleasure. So I always like to start these fireside chats for those who are maybe not as intimately familiar with Rani as I am, with just a basic overview of the story and kind of where we are today with the pipeline.
Sure. So Rani Therapeutics is a clinical-stage biotech, and we've developed a platform technology for the oral administration of virtually any biologic with bioavailability that's comparable to a subcutaneous injection. We've completed three Phase 1 studies, two with short peptides and one with a monoclonal antibody that we released data on earlier this year, RT-111. In terms of our pipeline, it kind of speaks to it. We have an osteoporosis program with the teriparatide, RT-102, a biosimilar of Stelara, ustekinumab, RT-111, that we are developing in partnership with Celltrion. They're our supplier for that program. Then, the potential to GO into a number of other therapeutic indications because this is a platform technology.
Great. Awesome. So now with all of the Phase 1 data sets that you have, could you just kind of recap those for us and where we are today, and what those data sets mean, particularly for each of those programs, but also what it means for-
Sure
- the platform, RaniPill?
Right. Right. So I think, maybe taking it program by program and then talking about it more broadly. So with RT-102, we showed 300% relative bioavailability to a subcutaneous injection. This is an outlier even for us. We've tested 15 molecules preclinically to date, and they've all been kind of on the order of the subcutaneous injection, except for teriparatide, repeat, RT-102. That is gonna be a daily administration, oral osteoanabolic, the first of its kind. Currently, whether you're talking about Forteo, the brand name for teriparatide, or Radius's Tymlos, abaloparatide, these have to be injected every single day because of their short half-life. We'll be able to make an oral in this, so that you don't have to...
Right now, patients are limited to drugs like Prolia, as a once every six-month anti-resorptive treatment, or Evenity, which you can only take for one year. That's the osteoanabolic from Amgen. That's the RT-102 program. So we've shown good bioavailability. We also did a seven-day repeat dose study, where we showed good tolerability, taking it every single day with that drug. With RT-111, we did a Phase 1 SAD study. This is our Stelara biosimilar from Celltrion, and we showed 84% relative bioavailability to a subcutaneous injection with a monoclonal antibody. That is, we call it 100 times better than any other oral biotherapeutic technology that's preceded us, and those were limited strictly to short peptides.
This is an antibody, obviously, 150,000 daltons, 150 kilodalton antibody, and we're getting pretty close to 100% equivalent. And you asked about the readout. I think that from all of these programs and the octreotide program we've done before, what they demonstrate is the safety and tolerability of the platform. If you look at subjects who've completed RaniPill studies, we've had a couple subjects who had some cramping pain, mild, and scored 1 or 2. One subject that was burping, which I did not know was an AE till we ran that study, and one subject that had 30 minutes of acid reflux. So it's been very tolerable. All the regimens have passed out in every one of the studies.
And then broadening it, if you look at our preclinical work, we've done 3,500 oral administrations in awake canines, a 60-day GLP study, where we looked at safety and tolerability, and, and that reads across all of our programs, and that could clean bill of health from it.
Great. It's such a fascinating idea of how to take medicines and make them oral.
Yeah.
Could you just, you know, maybe detail, like, how this works?
Absolutely.
I think maybe just that would help us set the stage for the rest of the conversation.
For sure. I should have probably mentioned that when I was giving the overview of the company. It's what we've developed is a swallowable auto-injector, and the reason this is so salient is because people have been trying to do this for 50 years, maybe even 100, if you go back to the discovery of insulin. The problem is that the gut evolved to break down biologic material, destroy it before it gets absorbed, and it's very good at doing so, so you don't absorb a virus through your gut, as an example. So before us, people took what we call chemistry-based approaches to this, where SNAC, Emisphere's SNAC, as an example, where you add permeation enhancers to try to get some drug to work. Even in those cases, you're talking about 0.5% bioavailability.
We looked at that and said, "There's no way to make this particular paradigm work." So what we did is we developed a swallowable auto-injector. Looks like a pill, you swallow it, it passes through. It has this entire coating that protects it in the acidic environment of the stomach. It passes through the stomach and gets to the upper jejunum portion of the small intestines, where the capsule dissolves. Inside of that capsule is a self-inflating balloon, and that balloon has Alka-Seltzer in it. The Alka-Seltzer reacts after the capsule dissolves, and the balloon inflates, aligns itself in the intestines based on its geometry, and inside of that balloon is a little micro syringe.
We have two versions of that micro syringe, a solid and a liquid, but basically both of them have a dissolving needle that penetrates the intestinal wall and either enrobes or encapsulates the drug in the solid form, or in the liquid form, the drug, just like a normal needle and syringe, the liquid comes straight through the needle, and then the needle dissolves thereafter. In the case of the solid drug, that's deposited inside of the needle, the needle dissolves in about 10 minutes, and then the liquid, it dissolves in 10 seconds.
... It's incredible.
It works. We've made thousands of these. Yeah, it is science fiction, but it, it's very, very real.
It's very real. Yeah, and so a question we get a lot, and, I think it's always a relevant one to revisit, is how, how consistent is this and how successful are the deployments, and what matters, right?
Yes.
Sometimes you don't see the 100% successful deployment rate, but we've talked about that-
Yeah.
It doesn't necessarily matter, but maybe you can help shed light on it.
Yeah. So I'll explain that, and I'll provide some context as well. So, through our most recent studies with the RaniPill GO at the, we call it our, d- version D device, we've had an average 90% success rate. So 90% of administrations, we pick up drug signal in the blood, and it's very binary. You either get the entirety of the dose or you don't. Now, you could say, is 90% good enough? With a SubQ, I know I'm getting it every single time, but this is where dose frequency comes into play. So, with Rybelsus, if you're familiar, this is oral semaglutide, Novo's product. They have a 67% success rate, and this is an approved product, and theirs has a bioavailability sub 1%.
Incredible variability, and what they describe as success is any serum concentration in the blood. You can go look at their- the Granh all paper, their Phase 1 paper. I think I sent it to you.
Yeah.
Right? To the, you know, where they explained all of this. That's an approved product because it's a long-acting drug, semaglutide lasts in your system for over a week. And so even if you miss a few doses, you can actually get better serum concentration than you do with an infrequent injection. So in the case of RT-111, even with our high capacity liquid delivery system, what we've modeled is you only have to take 3 pills per month to get better serum concentration, even with a 20% failure rate, not a 10%, as compared to a once every 3-month injection. So and then with our teriparatide program, even though that's once a day versus once a day, we're getting 300% relative bioavailability, which is why we were comfortable with that.
In our osteopenia rats preclinical PD studies, we showed faster and statistically significant bone growth in the same period that the SubQ did not. And we know the SubQ obviously works. It's an approved product, but it means that you can afford to miss a dose here or there, and you'll still get the same PD effect.
It's amazing. Okay, great. And, you've, you've done some business development in the past with Celltrion. So could you just talk us through that deal, where it stands today in terms of the RT-111, and what kind of Rani looks like with Celltrion and what it looks like without Celltrion in the future?
Sure. So just a little background here. Celltrion is a global biosimilars manufacturer. We get our ustekinumab biosimilar from them. We decided to go with them because they are getting their injectable version approved, and we can leverage off of their data package instead of going with a novel, where because of the route of administration, we're not a biosimilar, technically. We can now do a supplemental BLA or something similar off of their file. So that was the reason to partner. And we went out to get a supply agreement, which is what we have. We have a clinical and commercial supply agreement. They asked for a right of first negotiation to acquire the program after the Phase 1 data readout. To answer the next part of your question, we're in that period, and I can't say anything.
Okay.
But maybe what I can say is that irrespective of whether we do a deal with them or we go it alone, the path forward is gonna look very similar. We're gonna move this drug into our RaniPill High Capacity. So as I was saying, we can do 3 pills per month, only 36 pills per year. So we'll do an SAD study with that and then immediately go into a, a repeat dose in, in psoriatic patients, to, to show efficacy.
Okay. Okay. So looking forward a little bit in the year, I know you're looking to move RT-102 forward into Phase 2.
Mm-hmm.
And then you're saying that the path forward for RT-111 would look very similar with or without Celltrion. Do you have an idea of, since it, it doesn't really depend on, on them, what that looks like going forward, how soon we might see an update on that?
Right. I think we would expect data on the high capacity in 2025.
Okay.
That's what we're shooting for.
Okay.
Earlier would be better, but that'll, this is where it gets, there's a little bit more vagueness because of the partnership.
Gotcha. Okay, sounds good. Then back to RT-102, the Phase 2-
Mm-hmm.
-that you're planning for, could you talk about the gating factors to getting that up and running, and is that likely a mid-2024 or a late 2024 then?
Yeah. So that program is generally ready to go. The only gating item here is whether we wanna spend the money to run that study in the US or to do it OUS, ex-US. And a study outside of the US would cost significantly more. So the US study is 2.5 times the cost to us, so that is obviously not a gating item, but a consideration. And if we were to. But the benefit is then we would have a full IND, and I think that's de-risking for us and for investors. So this is something that we're just going through on balance, figuring out which way we wanna go, and then we can get that study done.
Okay, great. And then, so the RaniPill HC, the high capacity, you mentioned briefly about that. Could you just talk about the shift towards that, how the company looks with both the RaniPill and the RaniPill HC, RaniPill GO and RaniPill HC-
Mm-hmm.
-going forward?
Yeah.
And it's likely to be ready at the end of the year. Could you just talk about how you're thinking about what to move into the high capacity first?
Yeah, great question. So the RT-111 is the first one.
Okay.
That one's pretty clear because we get this advantage of moving from QD, where you'd have to make 365 pills per patient per year, to 36.
Mm-hmm.
So it's more convenient for the patient, it's better leverage on our manufacturing for us, and we can even still do QD in the beginning for the induction phase to get to higher serum concentrations. So you can only do that with the HC, and so that one's very clear, but that's the one that we would move forward. We've already put out, alongside the clinical data, the preclinical HC data. We put that out earlier this year. And I think going forward, you're going to see the bulk, if not all, of the programs on the HC. Because one of the things we've learned over the course of the past, you know, 12 or 18 months of developing it, is it has a number of advantages. Capacity is the obvious one.
Just for folks, I maybe didn't mention this, the GO has a capacity limitation of about 3 milligrams per pill, and the HC is limited to 200 microliters. So depending on the concentration of the formulation, that could be 20 mg, 40 mg, you know, anywhere in between. The other advantage is CMC. We don't have to reformulate, so we can take the drug from a partner and just put it directly into the RaniPill HC. Whereas with the GO, we have to lyophilize, we have to put in excipients to make it microtablet capable, and that takes months of development work, right? So we eliminate all of that at the front end, so we can get in faster and we can deliver more with the RaniPill.
Interesting. Okay. And so we have a lot of data for go so far in the clinic.
Mm.
Can you talk about how the differences between the programs-
Yeah
... and the pill, the HC versus GO, and how we can leverage that data we already have to say, RaniPill HC, we have a lot of de-risking ahead of that as well.
Yes. I'm glad you asked that question, because these are not two completely different animals. Because you could think about the dosing capacity and say, "Well, it must be completely different." It really isn't. If I had a RaniPill HC and a RaniPill GO on this table, you would not be able to tell the difference.
Yeah.
The capsule size is the same, the coating is the same, the capsule shell is the same, the balloon is the same, the reaction system, that Alka-Seltzer reaction is the same, the amount of reactants are the same. The only thing, even the syringe profile, the dimensions are the same. All of the differences in the mechanism inside of that's microsyringe. In the case of the GO, we have this needle, dissolvable needle, that where there's a micro solid microtablet drug inside of it, and that gets deposited in the tissue. In the case of the HC, the needle doesn't break off. It stays attached to the syringe, and the entire syringe is filled with liquid. So instead of just using the innards of the needle as your capacity, you get the whole microsyringe, like in a normal saline syringe mechanism.
And that's how we're able to get more, more capacity. But what the takeaway is, it actually leverages an incredible amount of the work, the decade of work that went into the RaniPill GO. So in our preclinical work, first, we were able to stand this up in a year, and do oral administrations in canines. In preclinical studies, it's actually performing as well already as the GO.
Oh, wow! Okay. So there's so many different applications, of course, for the RaniPill technology in general. Some things we've thought about are GLP-1, which we can get to in a bit, and then RT-105, which you put it on pause-
Yeah
... at some point. But just, I guess, to start there, with the oral adalimumab program, such a big opportunity ahead-
Yes.
What needs to happen for that to come back online? And is that something that, you know, do you have any update on how you're thinking about that in the portfolio?
Well, yeah, that's, that's an easy one. That would be an HC program. We love it, too. It's money. We just need to raise a little bit more money. We paused that strictly out of financial considerations.
Okay.
I think if anything, the need has been demonstrated or is even more acute, given that the biosimilars have not performed well, because all they can compete on is price.
Right.
and now you're seeing them go even, not just biosimilars, but generic biosimilars, where they're unbranding and then getting sold through third-party payers, and that might be the only way, and they're really going to have to create a price to make that happen. Having a once-a-week pill would differentiate any product-
Right
... and in particular, this one. Now, you mentioned GLP-1. We put out data last year with an obesity program, preclinical asset. This is a triagonist, GLP-1, GIP, glucagon. And we showed, and I'll give you the context after, the same weight loss in canines at the exact same dose, this is a critical point, as the SubQ. Same triglyceride and same other, you know, biomarker reductions were the same, regardless of whether it was SubQ or our route. When you look at the orals in the incretin space, if you followed this at all, you have the small molecules that by and large have tolerability issues. They, if you look at danuglipron, the Pfizer program, it had a 34% discontinuation rate in its early study.
It went even higher, and they had to terminate. That's because of the short half-life of the drug. You have these intraday peaks and troughs and a very high discontinuation rate to go with it. Then with the peptides, as we were talking about it, so oral semaglutide, oral amycretin, Viking's oral, they have to use hundreds of mg of drug every week instead of single digit, you know, 2.4 mg for semaglutide at the highest dose, which is a cost of goods issue and a supply chain issue. In our case, we think that we can put together a very differentiated program, when we find the right partner and the right asset, whether that could be a once a week pill or even less.
Okay.
With the same dose as the injector.
Okay. How do you think about that with so much going on, and obviously, you have to choose, you know, as we were just talking about with adalimumab, you have to choose what you're going for. How does that fit into the overall plan for Rani in terms of prioritization?
I think this is an obviously a big market, everyone's aware of it, and we have something that's very potentially very differentiated. So I think it would jump to the top of the list if you had something that fit well to it.
Okay.
I think we have to solve that part of it. We have to find the right kind of asset. We haven't done that yet, but I think it would be an important program for us.
Okay. Okay, fair. And then with so much going on and so many different trials that you could run, and the data, the different trials you are running, there's obviously some read-through to each program based on the singleness of the RaniPill and the RaniPill HC. How can you leverage that data for each of those particular respective programs? If it can speed up development at all, is that a possibility?
So every drug is going to be treated independently by the regulators, right? So you're going to have to do terminal efficacy studies, you know, Phase 3 with most programs, because of the route of administration change. The benefit we get from this being a true platform is that all of the preclinical and non-clinical work we do, the V&V work, you know, stability of the device, et cetera, et cetera, that will all go into a Drug Master File that will be referenceable by all our programs, right? So those are the things that we can leverage from program to program, but ultimately, each program is its own independent entity.
Okay. Okay. And with just a minute left, I would love to talk about the upcoming year for Rani and what you think that you'd like to highlight that maybe we didn't get to today.
I think we covered a lot. I think this is going to be... The next year is going to be the story of the RaniPill HC. We're going to be bringing that into the clinic, maybe bringing it into the clinic multiple times. There's obviously a Phase 2 planned as well. So, continue, I think we've done a good job of, you know, incrementally de-risking the platform itself through the life of the company and continuing to do that now with bigger data sets and now getting some efficacy data as well. So those are the things that we want to try to accomplish in the next 12 months.
Great. I'm looking forward to hearing more.
We're excited to make it happen.
Thanks so much, Talat.