Good afternoon, everyone. My name is Jim. I will be your conference operator today. At this time, I would like to welcome everyone to the Protara Therapeutics Lymphatic Malformations KOL Webinar. All lines have been placed on a mute and to prevent any background noise. Please note that all questions for the Q&A discussion at the end should be entered into the chat box in the bottom left of our screen. Now, for opening remarks and introductions, I am pleased to turn the floor to our host, Senior Vice President of Investor Relations, Justine O'Malley. Welcome.
Thank you, Jim. Good afternoon. Thank you all for joining us today for a review of Protara's lymphatic malformations program. Before we begin, I would like to remind you that during today's call, we will be making certain forward-looking statements. These statements represent our views as of today only should not be relied upon as representing our views as of any subsequent date. Actual results may differ from our forward-looking statements due to various factors, including those described in the Risk Factors section of our most recent annual report and subsequently filed quarterly reports that are on file with the SEC. Except as required by law, we disclaim any obligation to update these statements, even if our views change. I will now turn the call over to Jesse Shefferman, Co-founder, Director, and Chief Executive Officer.
Thank you, Justine, and thank you all for joining us this afternoon. Good afternoon from the World Congress of the International Society for the Study of Vascular Anomalies, or ISSVA. We are excited to provide an overview of our lymphatic malformations program today, including a recap of our recent FDA engagements and our plans to submit a BLA in the second half of 2027 for TARA-002 in lymphatic malformations. There is a significant unmet need in this rare disease. We believe that TARA-002 has the potential to be the first approved therapy for patients with macrocystic and macrodominant mixed lymphatic malformations. I am joined today by Dr. Jacqueline Zummo, Co-founder and Chief R&D Officer at Protara, who will walk us through an overview of TARA-002 as a potential treatment for LMs.
We're also privileged to have STARBORN-1 investigators Dr. Naiem Nassiri and Jesse G.A. Jones here to provide their perspective on the disease and how TARA-002 may fit into the treatment armamentarium. Dr. Nassiri is a board-certified vascular and endovascular surgeon leading The Vascular Care Group in Stamford, Connecticut, and is also an adjunct faculty member of the Yale School of Medicine and Yale New Haven Hospital. Dr. Jones is a board-certified interventional radiologist and an associate professor of medicine in the Department of Neurosurgery and Radiology at the University of Alabama at Birmingham. We're also joined by our Chief Commercial Officer, Bill Conkling, who will provide an overview of the LMs market and our views on commercialization. Finally, our CFO, Patrick Fabbio, will join us for the Q&A.
At the end of the call, we will answer questions submitted via the chat box on the lower left-hand corner of the screen. For those of you who are new to Protara, we are a clinical-stage biotechnology company developing transformative therapies for the treatment of cancer and rare diseases. Our lead asset is TARA-002, a genetically distinct strain of Streptococcus pyogenes that drives an immunologic identification and attack of cells that carry mutational burden. We are studying 002 in non-muscle invasive bladder cancer, or NMIBC, where we recently announced positive data at the American Urological Association conference last week. Today, however, we will focus on TARA-002 in LMs. In addition, we have a program in patients dependent on parenteral support where we are studying IV choline chloride, an investigational phospholipid substrate replacement therapy in an ongoing registrational phase III trial.
While the focus of today's call will be exclusively on LMs, we remain excited about all three of our pivotal programs and look forward to sharing additional milestones across the portfolio throughout the next 12 months. Now I'd like to talk about TARA-002, our investigational genetically distinct strain of Strep pyogenes that is fully inactivated while retaining its immune-stimulating properties. 002 is supported by an enormous amount of clinical data from its predecessor compound, OK-432, which is approved and marketed under the brand name Picibanil in Japan by Chugai Pharmaceuticals, where it has been the standard of care in lymphatic malformations for 30 years. TARA-002 builds on the efficacy and safety demonstrated by OK-432 in LMs over the years and is now in development by Protara using modern manufacturing techniques, which have led to potential improvements in the product's profile.
The clear unmet need and the potential for 002 as a treatment option in LMs is reflected in the multiple regulatory designations granted by the FDA, including Rare Pediatric Disease Designation, Orphan Drug Designation, Breakthrough Therapy and Fast Track designations, and 002 is eligible for a Priority Review Voucher or PRV upon approval. We expect to complete enrollment of our pivotal STARBORN-1 trial in LMs in the second half of this year and intend to submit a BLA based on these data in the second half of 2027. Looking ahead, 002 has potential use beyond LMs. There is extensive historical literature on the use of OK-432 in patients with multiple other maxillofacial cyst types.
Indeed, there is direct patient experience with TARA-002 in STARBORN-1 in two ranula patients, suggesting that this investigational therapeutic can treat other cyst types, providing strong supportive evidence for expanding the opportunity for 002. As we announced last week, we've had productive ongoing dialogue with the FDA on our LMs program. We received confirmation that the review of 002 in LMs has been moved from the Office of Vaccines Research and Review to the Office of Therapeutic Products, or OTP. OTP is a division that has significant experience in pediatric rare diseases. It is also the review division for 002 and NMIBC. The FDA has stated that they will evaluate the risk-benefit profile of 002 and LMs based on the results of STARBORN-1. They have not requested any changes to the sample size or the endpoints of the trial.
They have not requested an additional pivotal study and have confirmed that our non-clinical package is complete and that no additional reactogenicity or immunogenicity studies are required. We are pleased to have actionable feedback from the FDA on the path to registration for 002 and LMs and look forward to submitting a BLA in the second half of 2027. I will now turn the call over to Dr. Nassiri to talk about lymphatic malformations and the unmet need in this patient population.
Good afternoon, everybody. It's a pleasure to be here. I am Naiem Nassiri. I'm a board-certified vascular and endovascular surgeon. I think it's important to understand my background. I'm a surgeon, but I also do all my own sort of interventional radiology or endovascular therapy when it comes to vascular malformations. That should provide a lot of good perspective regarding some of the recommendations that I'll be making. I've been treating vascular malformations for nearly 20 years. I am the founder or founding director of a world-renowned, internationally renowned destination center for treatment of vascular malformations, and that's TVCG CARES, which stands for the Center for Anomalies and Rare Entities International. I maintain very close academic ties with Yale University, where I was faculty for seven years.
I treat over 400 cases of vascular malformations annually, and I've been doing so for the last 15 years or so. Vascular malformations, in general, are essentially errors in the development of blood vessels, and it's a process that happens in utero. Depending on what sort of subtype of blood vessel, whether it's a vein or artery or combinations thereof or lymphatic channels, those configurations can manifest themselves in various forms. When we're talking about lymphatic malformations, these are channels inside our body that help carry fluid outside veins and arteries, simply stated.
When you have these rare disorders, they can wind up with these sort of abnormal clumps of lymphatic channels, that can lead to stagnation of flow of these fluids, and that can cause growth, irritation, and a variety of different symptomatologies, some of which can be life and limb-threatening and some of which can be, you know, relatively less impactful. Once diagnosed, treatment is almost always indicated regardless of the extent of symptomatology that you may have. While a symptom may be asymptomatic seemingly, treatment is always indicated because of the potential complications that can ensue as a result of the lymphatic malformation being left untreated. Broadly speaking, there are three broad subtypes. The vast majority of what we're talking about here today are macrocystic lymphatic malformations.
The analogy I like to use is that these are large balloon water balloons, right? They can grow, and there's constant accumulation of fluid or water within this water balloon. This water balloon is constantly growing, and it can chew through and erode into adjacent organs. The other subtype is microcystic lymphatic malformation. The analogy I like to use for that, you can think of them as these tiny little honeycombs. They have this thick, viscous, difficult-to-drain fluid inside of them. In the middle, in terms of prevalence, you have a combination thereof, and these are called mixed lymphatic malformations. We talk about current treatment paradigm, but I think it's very important for this audience to understand that there is no FDA-approved or agreed-upon treatment algorithm or subtype of medication that's used for treatment.
Everything that we're going to talk about has sort of grandfathered its way into the treatment algorithm. There is a desperate need from treatment algorithm approaches to come up with something on label that actually targets the very molecular pathway that causes these malformations in the first place. We'll talk more about these treatment options down the line. Won't go into too much detail about this, but suffice it to say that the mutations that cause these channels to become abnormal reside within what are called epithelial cells that line these channels, and these are cells that we would call endothelial cells if we were to talk about blood vessels or such as veins and arteries. Within lymphatic channels, these are termed epithelial cells.
Suffice it to say that when you have mutations inside these epithelial cells, and those mutations involve the classic PI3K/AKT/mTOR pathway, because of that abnormality, you can either regulate in a normal way or you can have it be abnormal, which is what happens when there's mutations, and you wind up with a lymphatic malformation. These happen very early on during the process of embryogenesis. These mutations are happening before the patient is born. Whether or not you see the lesion immediately at birth, that is irrelevant. The gross visibility of it has nothing to do whether or not that mutation actually exists. The natural history of lymphatic malformations, as I said, the vast majority of these lesions are within the head and neck, but they can be anywhere in the body, visible and non-visible.
Sometimes what you may see may only be the tip of the iceberg, and deeper inside, it's a much bigger and much more dangerous and much more problematic problem. These are not just cosmetically disfiguring lesions or a bubble in somebody's neck that one needs to worry about. Growth happens proportionally with the patient. There are two major environmental triggers for growth of vascular malformations in general. One is fluctuations in the hormonal milieu, which typically happens, classically speaking, during puberty, and the second one is during pregnancy for women. The other is trauma. That trauma, folks, includes surgical intervention. What is deemed a medical intervention can actually be an exacerbating factor. The person telling you this is a surgeon, okay. That's a very important, non-biased and highly accurate statement, clinically speaking.
The age of diagnosis is less relevant, but because the vast majority of these tend to happen fairly early on and become grossly manifest clinically, you tend to detect them fairly early on during childhood. By two years of age, the vast majority have sort of declared themselves depending on where the lesion is. You may have mixed components or deeper cysts, but, you know, you can have them within the peritoneal cavity. You can have it within musculoskeletal structures. You can have them within airway processes or adjacent to nerves. The location of where it is has a huge clinical impact on how you go about treating it and what the risks of that treatment are going to be. Next slide.
We talked a little bit about disease burden already in the pediatric patients. Let's just not forget that this is not just a pediatric entity. It can happen in adults as well. Obviously, these are adults who never had treatment when they were younger, which is a catastrophic process, but unfortunately happens quite often. Physical symptoms and complications. We talked about that water balloon analogy. Imagine that water balloon continuing to grow and then chewing through adjacent nerves, adjacent blood vessels, arteries, veins. You can now have what we call fluid levels, which we can detect. Sometimes you have a lymphatic malformation that's of a certain size, let's say the size of a tangerine, and all of a sudden it abruptly grows to the size of a grapefruit or a small watermelon. Why is that happening?
That's because there's abrupt bleeding into the structure, okay? You can now literally chew through any organ that's adjacent to this particular entity and can have potential catastrophic events. If that is within the airway, you now have airway compromise, the risk for sudden cardiac arrest, ventilatory compromise, difficulty swallowing or eating. It can compromise flow patterns to adjacent gastrointestinal structures. The list goes on and on. It is very important that once these lesions are detected, regardless of whether or not there is imminent threat or imminent symptoms, that one, be very proactive in terms of treatment, especially the macrocystic subtypes. We talked about the functional impairment.
We talked about the psychological and social quality of life, especially with macrocystic lymphatic malformations, and in particular, because of that water-filled balloon analogy I talked about, the cosmetic disfigurement of this for children who are going to be of child, or in school age, that is absolutely impactful and can be catastrophic for the psychological development of that child and their family, right? The family is affected as well. These are chronic in nature and progression. These continue to grow. This never stops. It's not like you're going to end 17, 18 years of age, and all of a sudden your lymphatic malformation is gonna stop growing. That obviously, that does not happen.
Let's not forget about the immense amount of impact on the healthcare, especially since currently everything is being done in a hospital setting, with extreme utility of cost and resources, ICU stays and all kinds of healthcare burden that's happening because we don't have a minimally invasive molecularly directed compound as of yet, not until just now. Next slide, please. I'm going to emphasize that there is no FDA approval. Regardless of what's said, everything that's sort of considered standard of care has sort of grandfathered its way into the treatment algorithm because we haven't had anything better to date. Because of the fact that there are these lesions affect all parts of the body, we have a vast array of specialists, both surgical, both interventional and non-interventional, who are treating these patients.
It's great to have a multidisciplinary approach. What winds up happening is when you're a hammer, everything is a nail. If you're a surgeon, then you're gonna wanna go and resect everything. Guess what? Surgery is not the right answer for all these lesions. If you're a dermatologist, you're gonna wanna think about some laser photocoagulation. If you're an interventional radiologist, you're gonna think about embolization or sclerotherapy. None of these things is really the way to go. If you are going to embolize, what compound are you gonna use? Are you gonna use an irritant of some sort to merely irritate the lesion? Are you gonna use a highly toxic compound that is going to burn everything along the way?
These are all considerations that have to be made that make it extremely impactful in terms of what are we using, how are we approaching, and what sort of compound we're using to do away with this lesion. Not necessarily to cure, but to eliminate it from becoming a nuisance or a life-threatening complication so that these patients can have a normal quality, duration of life and the ability to be able to go about and do what they need to do. In terms of the embolization and the endovascular interventional treatment of these lesions, I think it's very imperative to understand that these are two broad categories that we're using. Either we're using and everything that I'm gonna talk about, these are merely irritants. These are meant to literally just irritate the lesion, some more, some less.
Ethanol, folks may have heard of about ethanol as being perhaps the most effective compound that we have today. I use this analogy. I have termites in my house. I wanna get rid of these termites. I'm gonna get a blowtorch, I'm gonna burn the entire termite colony. Guess what? Along with the termites that I've destroyed, I have now destroyed my home. My home is now burned down to the ground. In the dogma of risk versus benefit ratio, which every astute surgeon, medical doctor needs to be mindful of, to me, that risk-benefit ratio doesn't quite tilt into favor of using something like ethanol. I actually have never used ethanol in my practice, and I stay away from it because in my opinion, the risks are just not justifiable.
Other compounds such as bleomycin, this is a chemotherapeutic drug that we're using because of its side effects, and we're hoping that 50%-60% efficacy will somehow be a durable approach. Let's not forget about the cumulative risk of pulmonary fibrosis and potential lethal complications that can happen with bleomycin as well. doxycycline is perhaps the compound that's been used most commonly. Folks, this is an antibiotic. What it happens to have as a by-product or a side effect of its antibiosis, it has anti-vascular endothelial growth factor to some extent, and it has some anti-matrix metalloproteinase activity. We're hoping that somehow the side effect profile of this antibiotic will have a durable impact directly on the disease that we're targeting. That's just not good enough. This has been what we've been doing for decades.
Obviously, there are efficacy limitations. There are risk and side effect, potentially lethal limitations, and there are anesthesia limitations. If you're using ethanol, you have to use general anesthesia because there's a huge risk of central pulmonary toxicity, sudden cardiac arrest, and death. You have to use what's called the Swan-Ganz catheter to measure pulmonary artery wedge pressures. Imagine the cost and the detrimental and potential complication associated with these invasive measures for treatment of something that can be an ambulatory treatment in a five, six, seven, eight-minute procedure. To me, again, the sheer risk of the what we are considering the standard of care right now does not tilt in favor of treatment. Surgical approaches. This is a surgeon speaking, and I wanna emphasize this.
I told you a little bit earlier before, two things that vascular malformations love in terms of growth. I call them fertilizer for them. One is hormonal fluctuations, which happens during puberty, pre-adolescence, and pregnancy. The other is trauma, whether that's wear and tear, against the joint space or if it's a surgical blade. A surgical blade is fertilizer for malformations. Not only that, when you're talking about surgically removing a water-filled balloon, inevitably there will be violations of the thin, mutated, abnormal epithelial lining of this water balloon. Guess what? If there is spillage, which inevitably in the vast majority of surgical cases there is, now you have a huge risk, greater than 50% risk of recurrence.
Now you have to go back in in a surgically scarred surgical field and try to re-resect and cause nerve damage and other adjacent organ damage to try to re-resect an area that should not have been treated by surgery in the first place. Here I am as a vascular surgeon telling you that surgery should not and is not an appropriate first-line treatment for macrocystic lymphatic malformations and for any vascular malformation to that effect. There is a huge increased risk of mortality and potential surgical complications by virtue of uncontrolled bleeding and by virtue of who's doing these operations. Next slide.
To summarize, and the sort of the end all be all to all the points that I tried to make is that there is an absolutely significant, I would go as far as saying desperate need for a more targeted, minimally invasive approach to treating lymphatic malformations, particularly the macrocystic subtype. We need an FDA-approved therapy that is on label, that provides a minimally invasive, direct targeted mechanism that undoes the very molecular pathway that led to the formation or the pathophysiology that led to the formation of that particular lesion. This needs to be targeted therapy, as I mentioned. We're trying to be much more sophisticated than what we have been thus far for decades.
We're not trying to merely irritate the lesion, folks, by introducing some sort of a detergent or some irritant compound, hoping that it'll be irritated enough so that it goes away for an extended period. We're trying to undo this molecular mutation pathway. It has to be minimally invasive and well-tolerated, not requiring expensive amount of resources and general anesthesia. It has to be repeated in an easily implementable manner and require minimal sedation. It has to be resource efficient, not only in terms of the compounds that are used, but in terms of the site of service. With that, I'll turn that over to the next speaker.
Thank you, Dr. Nassiri. We agree with you that an immune-activating targeted therapy like TARA-002 that drives immunologic attack of cells with mutational burden has the potential to shift the treatment paradigm in LMs. Now, moving on to the mechanism of action of TARA-002 in lymphatic malformations. Following aspiration of fluids from the lymphatic cyst, TARA-002 is administered directly into the cyst via injection to activate an immune response. TARA-002 activates TLR2 and NOD2 pattern recognition pathways. The innate and adaptive immune cells within the cyst are activated and produce a targeted immune cascade that eliminates the mutated cells in the epithelial lining of the cyst while sparing healthy tissue. Cytokines and chemokines, such as TNFα , interferon- gamma, IL-6, IL-10, and IL-12 are released. Neutrophils and macrophages are activated, and NK cells and T lymphocytes are rapidly recruited, which attack and destroy the mutated cells.
This increases epithelial permeability, which allows remodeling of vessels to support normal drainage, leading to the eventual deflation and structural collapse of the cyst. Pro-fibrotic cytokines promote this tissue remodeling and the formation of mature tissue to prevent recurrence. As observed in Japan, the Iowa data, and now our data, it promotes long-term resolution of the cyst. TARA-002 is a targeted approach that attacks mutated cells using the body's own immune system and promotes tissue remodeling to prevent recurrence. It has a strong safety and tolerability profile with minimal pain and discomfort for the pediatric patient. We believe this immune-mediated MOA conveys advantages to treating LMs with TARA-002, especially compared to off-label intracystic ablative agents.
We aligned with the FDA on our clinical program, including the design of STARBORN-1 trial, which is a pivotal phase II prospective baseline-controlled single-arm clinical trial, which is evaluating the safety and efficacy of TARA-002 for the treatment of macrocystic and mixed cystic LMs in 29 participants aged six months to less than 18 years. The trial has two stages. The first is an age de-escalation safety lead-in with three cohorts. The first cohort included children six to less than 18 years. The second included children two years to less than six years. The final, which we are actively enrolling, includes the youngest cohort of six months to less than two years. The second phase of the study includes the expansion cohort of patients across these ages. We are actively enrolling patients in the expansion cohort as well.
In the trial, patients receive up to four injections of TARA-002 spaced approximately six weeks apart. The primary endpoint of the trial is the proportion of participants with macrocystic and mixed cystic LMs who demonstrate clinical success, which is defined as having either a complete response, 90%-100% reduction from baseline in total LM volume, or a substantial response, 60% to less than 90% reduction in total LM volume. I'd like to walk you through the interim results from STARBORN-1 that we are presenting at the ISSVA World Congress. The analysis includes 16 patients as of the April 10, 2026 data cutoff. 83% of participants that completed treatment achieved clinical success. Of the participants who were assessed at the eight-week post-treatment time point, 100% of the evaluable participants achieved clinical success.
In 80% of these patients, clinical success was achieved with one or two doses of TARA-002. Looking at evaluable patients, it is clear that TARA-002 demonstrates a clinically meaningful response in macro-dominant disease. As is often the case in rare disease, differential diagnosis was made in two evaluable patients in the trial. These patients were initially diagnosed with macrocystic disease but subsequently confirmed to be ranula. Consistent with previous understanding of the MOA of TARA-002, one participant achieved a complete response and one participant achieved a substantial response. This speaks to the potential of 002 as a possible option for other types of maxillofacial cysts. Moving on to durability of effect of TARA-002. Of the seven participants who have reached the 32-week post-treatment assessment, all patients remain disease-free. The durable effect seen in these patients speaks to the robust effects of TARA-002.
This is medical photography from three patients treated with TARA-002. All of these patients achieved a complete response. As you can see from the photo, TARA-002's effect is prominent across varying sizes of macro-dominant cysts. The patient on the left had a 1.7 liter cyst at baseline. The patient on the right had a 28 mm cyst at baseline. As you can see, in both patients, the resolution of the cyst was dramatic and the skin remains healthy. Moving on to safety. The majority of adverse events were mild to moderate with no serious adverse events reported. The majority of AEs were grade 1 or 2, and the most common were swelling and fatigue, and most were transient and resolved within a few days.
I'll now turn it over to Dr. Jones to give a summary of his experience as an investigator in the trial.
Thank you, Jacqueline. I'm an interventional neuroradiologist and associate professor at the University of Alabama at Birmingham. I trained at UCLA in Los Angeles, where I learned to manage complex vascular anomalies in a multidisciplinary setting. I see about 50 vascular anomaly patients annually in my practice at Children's of Alabama, a large vascular anomalies clinic. The majority of these patients harbor macro or mixed cystic lymphatic malformation. Here's a summary of our results so far in STARBORN-1. As you can see, we've had remarkable safety and efficacy over the course of the trial thus far. When patients come to see me in the vascular anomalies clinic, which is a tertiary referral center, they're looking for an effective treatment. Lymphatic malformations, we can't always offer that. This represents a major unmet need. When Protara came to us with the clinical trial, we were enthused.
TARA-002 is a compound built upon a strong track record of OK-432 and has a vast experience in Asia, including Japan and Korea. It has been unavailable in the U.S. for decades. I'm excited about the prospect of bringing this key treatment back into our armamentarium. STARBORN-1 trial offers the unique opportunity to rigorously study sclerotherapy in a disease that has previously been steeped in anecdotes and case reports. The data will enable physicians like me to treat LMs with confidence, incorporating the principles of evidence-based medicine. I'd like to share with you a couple of my patients I'm especially proud of. The first is a three-year-old boy with a cystic lymphatic malformation of the paratracheal region of the neck, as evidenced by the arrow here.
He also was affected by cystic fibrosis, which is a genetic condition affecting primarily the lung, resulting in frequent upper respiratory tract infections, which exacerbated lymphatic malformation, leading to multiple episodes of respiratory distress, including intubation. I and my partners treated this patient multiple times, as you can see here, with a large variety of existing sclerotherapy options. These include medications such as doxycycline, Sotradecol, and eventually ethanol. As you've heard earlier, when physicians reach for ethanol, you know we've reached the end of the road in terms of sclerosing agents. Unfortunately, none of these agents proved successful, and the lymphatic malformation recurred yet again. Luckily for this patient, Protara was willing to engage in expanded access use of TARA-002 in this young boy.
With the help of their administrative staff and our IRB, we were able to secure this drug and treat this patient outside the confines of the STARBORN trial. He underwent one session of sclerotherapy with TARA-002. 4 mls of fluid were aspirated, and 4 mls of the treatment agent were injected per STARBORN protocol. Following just one treatment, he had a remarkable response. At follow-up two months later, there was no visible evidence of a residual malformation. We performed an ultrasound in the clinic setting. While there no other residual was seen, the boy was squirming about a bit, as most kids do. Regardless, his result was so powerful there was no need for any additional treatment. He has suffered no adverse events and has been discharged from our care.
The second case I'd like to share with you is a girl, a seven-year-old female, with a large cystic malformation about her chin. She also was treated multiple times with the presumed diagnosis of a lymphatic malformation. Over the course of her treatment, which included fluid analysis in the laboratory setting, her diagnosis changed, as described previously, from that of a lymphatic malformation to a ranula, which is the growth of the submandibular gland that secretes a viscous fluid. She, like the other boy, underwent multiple treatments of the usual agents that we have available to us. doxycycline, Sotradecol, ethanol. All of these were ineffective. The lymphatic malformation recurred. At this point, she was fortunate enough to be in the window of the STARBORN-1 trial and was enrolled. Over the course of four treatments of TARA-002, her malformation decreased, as you can see here in the table.
At the end of the fourth treatment, she underwent an MRI, which we'll show here. As you can see, her malformation has drastically reduced in size to the point where it is barely palpable and not visible on external examination. The patient and her family were quite pleased with this result. At this point, we stopped further treatment. This ranula, I think, shows how not just lymphatic malformations, but other cystic head and neck lesions, in this case a ranula, may be amenable to TARA-002. I look forward to continuing enrolling patients in STARBORN-1, but also exploring the expanded use of TARA-002 for other indications in the future. I'd be happy to take questions at the end of this presentation. Thank you.
Thank you, Dr. Jones, for sharing your perspective and experience treating patients with TARA-002. We share your excitement. The pictures you shared are clinical evidence of TARA-002's effectiveness, but they also make us think about how patients and caregivers must feel as they deal with the challenges of living with or caring for a child, knowing that there are no FDA-approved treatments for macrocystic lymphatic malformations. TARA-002 has the potential to become the first and only FDA-approved treatment for patients with macrocystic lymphatic malformations, which makes an exciting time for us at Protara. Our target indication for TARA-002 is macrocystic and mixed cystic lymphatic malformations. Based upon our market research, public research completed by other industry players, and published literature on lymphatic malformations, approximately 1,500 patients are diagnosed with lymphatic malformations each year, and there are up to 80,000 patients currently living with lymphatic malformations.
We believe that 20,000 of those patients have macrocystic or mixed cystic disease and are seeking treatment. This makes it an attractive total addressable market opportunity in which we believe is greater than $1 billion. 90% of patients with LMs are diagnosed in the community at birth or at an early age. Macrocystic lymphatic malformations, by definition, are larger cysts and, as a result, are more often referred to a tertiary center, typically an academic medical center with a children's hospital or vascular anomaly center. Two primary treatment options for patients with macrocystic component up to their LM are surgery and sclerotherapy. These centers often utilize a multidisciplinary team to evaluate and treat patients. Our research suggests that multidisciplinary teams at vascular anomaly centers are increasingly preferring sclerotherapy over surgery and other treatment options. We believe that this trend will continue.
As Dr. Nassiri pointed out, and our market research confirms, patients face a significant burden in managing their lymphatic malformations. Macrocystic LMs and their treatments can cause pain, fatigue, anxiety, sleeplessness, and social isolation, while repeated interventions can cause emotional and financial distress. Today's treatment paradigm for lymphatic malformations has its challenges. There are currently no FDA-approved therapies for macrocystic lymphatic malformations. The patient burden and high recurrence rates associated with surgery are well documented. The reported safety and efficacy of currently utilized sclerosants varies widely because of a lack of consensus dosing and administration guidelines, and a lack of well-controlled studies. This typically results in significant variance in patient outcomes and risks based upon provider preference and experience.
There is a significant opportunity to improve upon patient outcomes and patient treatment experience when compared to other options by using TARA-002 because it is a targeted therapy that leverages a patient's immune system to eliminate the cyst and restore normal tissue function. The data presented to date on TARA-002 compares favorably to currently available treatment options. TARA-002 demonstrated 100% clinical success in evaluable patients to date, and no patient experienced recurrence at 32 weeks. We believe that current TARA-002 clinical profile to date will enable it to garner Orphan Drug pricing. The most important reasons to note for this are the disease incidence, the product's high clinical success rate, the durability of response observed with limited numbers of doses, and TARA-002 treatment being administered in the ambulatory setting. To date, the majority of patients treated with TARA-002 experienced clinical success with one or two doses.
As the potential first approved treatment for macrocystic lymphatic malformations, we are excited to bring a new treatment option that can help standardize the way in which macrocystic lymphatic malformation patients are treated. As we prepare for a potential launch of TARA-002, we anticipate a focused commercial launch that targets its efforts on vascular anomaly centers, their referral networks, and key patient support networks. We see that up to 80% of lymphatic malformation sclerotherapy claims come from a limited number of centers. We are confident that we can achieve commercial success with a relatively modest-sized commercial organization, and we are excited to begin the commercial infrastructure build as we eye a BLA filing in 2H 2027. I would like to turn the call back over to our CEO, Jesse Shefferman.
Thank you, Bill. The progress and strategy described today represents an important evolution of our LMs program toward registration and, ultimately, meeting a significant unmet medical need. As we look beyond our pivotal study in LMs, we are excited to potentially expand TARA-002's reach to additional congenital and acquired cystic masses where OK-432 has demonstrated efficacy. There is substantial literature describing the effectiveness and safety of OK-432 in multiple additional types of maxillofacial cysts. The success we observed in the ranula patients who achieved clinical success with one or two doses hints at further opportunities to expand 002's reach. In addition to ranula, the most cited non-LM cyst treated with OK-432, we've been looking at thyroglossal duct cysts as a further potential area to explore the use of 002. This is based on OK-432's historical utilization and efficacy profile in these maxillofacial cyst types.
Taken together, the raw epidemiology of ranula and thyroglossal duct cysts represents a significant market expansion opportunity, and we look forward to sharing more about this as we solidify the opportunity in LMs and move closer to filing. To summarize, we are very pleased with these initial data and TARA-002's potential to address a significant unmet need in macro and mixed cystic patients. With no FDA-approved therapies, existing off-label treatments presenting unfavorable side effects, and surgery oftentimes leading to recurrence, there is a significant therapeutic white space in LMs. We believe that TARA-002 has the potential to fill this gap as a de-risked, safe, and efficacious treatment with its data to date reflecting and potentially improving on the safety and efficacy profile of OK-432 in Japan and in multiple investigator-led studies around the world over the last 30 years.
Looking ahead, we anticipate STARBORN-1 to be fully enrolled by the end of 2026. We intend to submit a BLA to the FDA based on the results of STARBORN-1 in the second half of 2027. I would like to thank all of the patients, families, investigators, advocates, and Protara employees who have helped move this important trial forward. Justine will now take Q&A from the chat box. Justine?
Thanks, Jesse
First question we have is can you provide some additional context on TARA-002's durability seen in the data that you presented today.
Yeah. Jacqueline will take that one.
From a durability perspective, what we've seen is that all patients who have reached that time point have maintained their durability. It's consistent with what we know from OK-432 in terms of, you know, duration. We even know from OK-432 that the duration is even longer. In those studies, we had followed out to nine years with durable responses.
Great. Thank you. This question is for Dr. Jones. Given the data that you have seen from TARA-002, if it were to be approved, what percentage of your patients would you use TARA-002 in? Would you use it ahead of some of the existing sclerotherapies that are used off-label today?
When I first started enrolling in STARBORN-1, I was a little concerned because some of the patients who were coming to me had failed multiple treatments previously, and I didn't want to enroll a patient and have them fail and make the trial look bad. To my surprise, the drug's been very effective, even in patients who they've failed other therapies. For that reason, it's actually become my go-to treatment, and I would enroll everyone that I could in it.
What improvements have you made to the manufacturing of TARA-002 compared to OK-432?
You know, we have made modern manufacturing improvements. You know, when the drug was approved in Japan, several decades ago, the way that these drugs were controlled and released and just how they were actually formulated, very different than the way that we do it today. We modernized it in a way that gave us much more control, which then allows us to have a much more predictable safety and efficacy profile.
As we think about potential positioning for TARA-002 versus sclerosing and surgery, is there anything else you think physicians treating LMs would want to see in order to replace sclerosing?
I'll actually ask Doctors Jones and Nassiri to answer that question.
I think, by virtue of the current MOU, I do not see a barrier to this compound becoming the go-to therapeutic mechanism. Not only mechanism of action is directly targeted at the disease process, and we're not just relying on its side effect profile to have some sort of, you know, cross my finger effect to an unpredictable extent. The side effect profile is nowhere near what it is that we're using. I mean, if you think about it, if you're using an irritant, that irritant is going to not only irritate the lesion but irritate everything else along with it. You use STS, you're gonna have hemoglobinuria, you have this high risk for non-target embolization. You have a risk of potentially putting the eye out of the operator. You have tons of potential issues, ulcerations, et cetera.
By virtue of a very favorable side effect profile with a non-toxic medication that is meant to put into place an autogenous body-mediated immunogenic response that undoes the formation of the malformation is, as Dr. Jones mentioned earlier, and as would be the case for me as well, this would be the go-to mechanism for treatment of malformations. I don't think anybody would look into any other more dangerous, less efficacious compound.
One follow-up question. What is the relative size of an LM versus other cystic malformations?
It can be quite a range. As you saw from some of the clinical photography, there was one lesion over a liter, and others measured in milliliters. It's quite a range. Regardless, they can all be treated, as you saw. I think that the size of the lesion is not really, at least for this agent. Other agents, such as ethanol, there's a toxicity, and the same with bleomycin. We've not encountered that with TARA-002.
Think about maybe some of these other malformations, thyroglossal duct cysts. Do they tend to be more homogeneous in size? I think that was the other piece of the question.
They tend to be more unilocular. You don't get a mixed microcystic granuloma, for instance.
Can you talk about the practical implications of the move from TARA-002 from the Vaccine Division to OTP and what the impacts of that could be?
Well, look, I think, they are mostly speculative at this point, right? I can sort of share our lived experience. I think the first is just, you know, the nature of OTP. OTP is where CAR Ts and gene therapies and sort of viral vectored treatments, you know, that's where all these sorts of drugs go within the FDA. Again, this is speculation, it would seem as though that is a review division, A, that is facile with small data sets that are pediatric in nature, that are employing targeted therapies where there's sort of a known mechanistic addressing of a, usually a genetically mediated disease or a cancer. There's just that piece, right? Again, it's just our speculation.
You know, I'm sure there are, you know, stories of drugs that have gone to OTP and failed as many as there are that have gone and won. I think you gotta take that with a grain of salt. What I can tell you anecdotally is that since we have been in that division, and it sort of coincided with our being awarded Breakthrough Therapy Designation, the dialogue is active, and it is less sort of adherent to sort of type B, type C meeting with briefing package, you know, formal meeting over an hour, and then you get your meeting minutes back. It's much more of a, of a give and take and a back and forth with the review team.
Then I would say, obviously, there is a practicality to the fact that both of our programs are now, you know, kind of being reviewed under the same roof. We know that when OTP would give us feedback, let's say on clin pharm or on CMC, the vaccines division had to be formally updated by the OTP division and vice versa. So I think those are, again, just our perspective. It's a better move.
Look, I mean, it's not all You know, there is some getting up to speed that OTP has to do, and I think that you have to ask yourself, does that sort of, you know, sort of a get, you know, kind of a learning curve and an upward slope as the OTP reviewers take on this program? You know, yeah, I think it would be disingenuous to say that there wasn't some type of learning curve. What I can tell you is, you know, we get our minutes back really quickly. We get responses back well within sort of the allotted timeframe. Under Breakthrough, if you send an email to the PM, you know, they're obligated to respond within 20 days. They have never taken 20 days to get back to us.
I think, you know, that's sort of the, the totality. On the whole, it has to be a positive. There is a learning curve piece. We haven't seen that, you know, drive significant delay, but it's there.
This morning we saw Relay Therapeutics data announced. Can you tell us if you see that as a competitive threat? We know that there were some LM patients treated in this dataset. What is your view on their data?
Well, I think what I'd like to do is I'd like to just state that, you know, the systemic and topical approaches utilizing agents that are active along PI3K/AKT/mTOR pathway, this is not new. You know, we've seen the utilization of rapamycin and the like in this setting and looking at our two positions here. That's not a new approach. What we know is that those tend to not be effective in macrocystic disease. You know, what we do understand, and this is increasingly being borne out by data, is that they are somewhat effective given the sort of the investigator-rated assessment of response in microcystic disease. Listen, any development that helps kids that suffer from this disease, whether it's micro or macro, we're we champion that.
We don't see what Relay is doing or what Palvella is doing as competitive to where we are. That's really a microcystic story, and we're really the only ones out there right now in the macrocystic place. Again, you can look at the literature to see that, you know, topicals don't necessarily work with these architectures, and systemics don't seem to address them in the way that 002 does, which is, as you've heard today, offering sort of, you know, functional cures for patients. Again, great for the field, but not a concern.
What are some of the learnings from the Japan experience in LMs with OK-432? How different is the market and the potential receptivity compared to the U.S.?
What I can tell you about the Japanese experience is that it's obviously more longitudinal than what we've put together in STARBORN-1, it generally, I think, is directionally the same. We are reconciling the fact that as our dataset grows and the number of cases requiring, you know, two or fewer doses is seemingly more the norm than less, whereas our understanding of the experience in Japan with OK-432 is that generally, you know, about half those patients require kind of two to three doses, and the majority require all four. I would say that that's sort of just observational at the moment, and that is leading us to ask ourselves and the other piece I would say is, you know, you've got this really substantial safety database that continues to exist in the Japanese approval dossier.
You know, the side effect profile that exists for OK-432 seems to be slightly more intense than what we've observed with TARA-002. I think the numbers are still small, but we've seen enough now to kinda ask ourselves, is there something about TARA-002? Is there something about the modernization of the manufacturing process that is conveying potentially enhanced safety and efficacy? I think it's a question and not one that we'll plant a flag on at the moment. As the dataset evolves, we'll continue to watch that.
Related to enrollment of the STARBORN-1 trial, can you give an update on how enrollment is going? We know that in the earlier stages of the trial enrollment, can you elaborate on how things are going now?
Sure. I'll start by saying there's a lot of enthusiasm across our sites, and we are bringing on new sites just based on interest in the trial. The pediatric vulnerable population, it's always slow and steady in the beginning. You generate data, it gives more confidence to investigators. Dr. Jones said, he was a little skeptical about putting patients in. You generate data and you show a safety and efficacy profile like this, I think that, you know, both investigators in the room will agree that now it's easier to say, "Okay. Yes, I wanna put a patient into the trial." Our age de-escalation cohorts were definitely challenging. We started with a population, that was, you know, six to 17 years old.
That's a difficult set of patients to bring into a trial. You're 16 years old, you've been living with it, your urgency to treat is low. Took us a while to get through that, now that we're through it, you know, I think our sweet spot is definitely in the two to, like, 10-year-old range. That's where we're seeing the majority of patients coming in. You know, I think we're on track to enroll the study by the end of the year.
I think also, just to jump in, I'm gonna ask Dr. Jones to kind of, you know, weigh in on this. You know, our imaging modality that the FDA required of us is MRI. You know, whether it's a six-month-old, you know, or a three-year-old, I think anyone with kids probably would agree. I mean, I have kids. They're certainly not that age anymore. You know, MRI is not an insignificant thing, and I, and I found it interesting in Dr. Jones's case study that for the child with the cystic fibrosis co-diagnosis, the ultrasonography was utilized. I, and I'm imagining that in a real-world application, it's probably ultrasound that is driving a lot of this, right?
The MRI piece just introduces, I think, a scientific experiment-based variable that in the real world I don't think is really the way imaging is utilized.
We're doing a clinical trial here, and I'm not rushing. The company may be more pressed than the investigators. You know, I really am excited to see high-quality data come out because that's what's been lacking for 40 years, and they are requiring a lot. The FDA is requiring a lot, and MRI is part of that. The upside is I think it's gonna show without a doubt that this is a very effective and safe treatment. As the trial's gone on, some physicians that come up to me almost it's like kind of like a FOMO. They wanna get involved too. I had one physician in Mount Sinai ask for a referral to come on out, if she can get in the trial.
I think it's kind of picking up steam in the sense that the news is out there now that this trial is going on, and the results are good. I think if anything, it's just gonna continue to enroll faster.
Another question for Dr. Jones. Why do you think the patients that you treated responded to TARA-002 when they failed so many other therapies?
As, as has talked about previously from the previous presentation with my colleague, you know, the other therapies are all similar in the sense that they try to irritate, or destroy the lesion through a mechanism of either desiccation, like dehydrating it or denaturing it. TARA-002 works differently. It, it incites a targeted inflammatory response. I really think the mechanism of action being unique is what differentiated the treatment response. Do you have any comment on that?
I agree. I think, like I said, everything we're using thus far is, as I said before, has grandfathered its way into the treatment algorithm. We are relying on the side effects of the medication which has not been regularly studied and that the sort of dosage and the effect efficacy thereof has not been regularly repeated. We're just hoping that it irritates it enough to an extent that is adequate and not risky enough, which as we've seen is not often the case at all.
With the accelerated approval pathway and submission under Breakthrough Designation, what do you expect could be the range of ages where TARA-002 could be used?
Yeah. We're pretty confident that it'll be the whole range of ages that we've enrolled in the study. I think, again, given the Breakthrough Therapy Designation. look, I think we will continue to enroll macrocystic dominant mixed patients. There, I think it's our obligation to sort of articulate how a macro dominant mixed lesion is sort of, in some respects, I'm looking at our two positions here, sort of the macro element of that mixed lesion is sort of quote unquote, "Your index lesion." Right. It's what you will treat first in that mixed environment.
Again, if you look at the data that we're generating in the STARBORN-1 study in mixed patients, and, you know, to the extent that we are able to refer back, you know, in a, in a general way to the experience of OK-432, that gives us some opportunity to if, for instance, the majority of the patients we treat are gonna wind up being just macrocystic patients only. I think there will be enough education of the review team to understand that mixed lesion is really sort of an index lesion of a macrocystic lesion. I will refer that to you guys.
I think this, it's critical to understand the response rate to the macrocystic, because let's not forget that we're not talking about a different genetic mutation now. It just so happens that the end product of that mutation happens to be in a microcystic environment versus a macrocystic. What happens with the macrocystic, by definition of the channel that's formed, it winds up accumulating more fluid. The genetic basis and the molecular basis and the mutation is essentially the same. I could see a scenario where as the experience with the macrocystics and the mixed lesions grows, we could pivot into the microcystic environment and understand the inflammatory and the immune-mediated response that is generated in the, in the macros and the mix, and apply that down the line to the, to the microcystic lymphatic malformations as well.
As I said before, again, this is not a bash on surgery, it's just that combination therapy still will have a role, and it's just that, you know, maybe the solution is for surgery to only be present after you have adequately caused that inflammatory reaction and replaced the mutated lesion with now a fibrotic residue, then that fibrotic residue is appropriately surgically resected.
I think if the question inferred sort of, you know, combinatorial approaches of 002 with either topical agents in that, you know, mTOR pathway or systemic, it's not in our current strategy, given the effect size that we have seen in the macrocystic setting and the macro dominant mixed setting. Look, I think as we have often said in our NMIBC program, until you are achieving 100% response of all active disease in the patients that we're lucky enough to treat, then, you know, the world will evolve. If combo emerges as sort of, a viable and economic means of addressing the mixed cystic lesions, then, you know, our objective is to treat patients that need the therapies that we hope to provide.
Right. What proportions of prevalent patients over the course of their lifetime might be eligible for or seek?
As Dr. Nassiri said earlier, these are macrocyst. They are in need of treatment. We believe that the incident population is actively treated. The prevalent population, as Dr. Nassiri said also, you know, there's events that spike the need for treatment, whether it's puberty, pregnancy, that those pop up. You know, I would say that each of them, we believe if we look in a timeframe of five years, they're active in treatment. It's just whether sclerotherapy or surgery would be in that. They're seeing physicians, so they're choosing to stay active in the pool, and that's how we measured it. We measured it off claims. They're actively seeing physicians.
We would anticipate that they would, you know, if they're actively having their pain, they're suffering for symptoms as they're going back to physicians, that, if treatment isn't immediate, it will be within a year or two.
Yeah, I think just to reiterate, these are not data that the prevalence estimate that we put up today of about 20,000 patients, from, you know, broadly speaking, 80,000 that have sought treatment, those are claims-based, meaning those patients are actively seeing a physician and, you know, under a diagnostic code of a lymphatic malformation. Whether they're seeking intervention, there may be a lot of reasons. Either there's treatment fatigue, there may be, you know, maybe they went through that ethanol phase and there's sort of at the moment nothing quite available for them. That is different than a patient that has sort of gone back into their community and is no longer actively seeking treatment based on the fact that that data comes from claims.
A patient, you know, is seeing a physician, under a claim for lymphatic malformations. Again, I think many of them, they're prevalent because they're not seeking intervention.
All right. Okay. Macrocystic and mixed cystic LMs, what degree of volume reduction usually translates to symptom improvement? How does this relate to the definition of the STARBORN-1 trial? Complete response of 90%-100% reduction in cyst size or substantial response to treatment?
Yeah. Dr. Jones here. Just kind of looking back at some images I showed from my presentation with that ranula patient, I would say at about 60%-70% volume reduction, you're seeing significant clinical improvement to the point where many patients may find that adequate and not desire further treatment. This is not a cancer. We're not aiming for a complete radiographic response. The radiographic response, as Jesse mentioned earlier, is a little skewed 'cause we're in a trial. Typically, I'll do a sclerotherapy. The patient will come back and see me in four to six weeks. I'll look at them. I'll examine them. I'll ask them, "How do you feel?" If they feel like they're adequately treated and on examination, there's minimal palpable residual, I do an ultrasound in the clinic and there's minimal fluid there, we're done.
Got it. Okay, thank you. Those are all the questions we'll take today.
Excellent. Again, we wanna thank everybody for joining us this afternoon. A huge thank you to Doctors Nassiri and Jones. Again, thank you to the families, the patients, the providers that have contributed to the STARBORN-1 study, and especially to the Protara employees that have been working tirelessly to keep this study going and off the ground. With that, we'll say good evening, and thank you again for your attention today.
Ladies and gentlemen, this does conclude today's session, and we thank you all for your participation. You may now disconnect your lines and have a good day.