Hello, everyone, and welcome to Oppenheimer's 36th Annual Life Science Conference. I'm Jay Olson, one of the biotech analysts here at Oppenheimer, and it's a pleasure to welcome you to our discussion with Pasithea Therapeutics. It's an honor to introduce Tiago Reis Marques, the CEO of Pasithea. Thank you so much, Tiago, for joining us here today. I'll turn it over to you.
Thank you so much, Jay. Thank you as well to the Oppenheimer team for invite us to be in this conference. It's really a pleasure to have the chance to introduce the company and our program. Having said this, and before starting the presentation, just asking everyone to pay attention to our company disclaimer as it contains some forward-looking information. As part of the disclaimer, also want to disclaim that I've been under the weather the past few days, apologize to everyone for my voice is still not totally recovered. Having said this, today I'm highlighting here on these slides why we consider Pasithea to be a very compelling story. I'm going to discuss today our lead program, PAZ004, the first macrocyclic MEK inhibitor to be advanced into clinical trials.
Due to its properties, I'm going to also show some data supporting a differentiated profile, particularly our safety PK and some early signs of monotherapy efficacy. I'm going to be covering also our main indication, that is the neurofibromas that are associated with a disease called neurofibromatosis type 1, in particular, discussing the plexiform neurofibroma as well as cutaneous neurofibroma. The large market opportunity that it constitutes. This is a very large TAM. Currently, MEK inhibitors in NF1 are only, and we only have data for one MEK inhibitor in pediatric population with worldwide sales of approximately half a billion dollars annually, we consider that the TAM is much larger. When we consider the opportunity in cutaneous, it can be a very interesting opportunity. Although all our focus is in our, PAZ004 program, we also have other programs, particularly one in schizophrenia, PAZ001.
As I mentioned, currently, all our attention and capital is devoted to advance PAZ004. We currently have two clinical trials ongoing, a dose-escalation trial in advanced cancer, and we hope to report data at ASCO, an update on the trial, and also a phase I-B study in the NF1 population, and we're going to report data on the second half of this year. Now I'm going to discuss PAZ004, next generation MEK inhibitor. Giving a brief overview of what MEK inhibitors do. MEK inhibitors targets one of the proteins in the MAPK pathway. That is a very important pathway for cell-survival and proliferation. It's constituted by a chain of proteins, the RAS, RAF, MEK, and ERK, that when abnormally activated, lead to the formation and progression of tumors. These mutations in this MAPK pathway have been described in many different types of cancers.
Also there's been mutations in RASopathies. In NF1, there's a mutation in the NF1 gene that encodes for a protein, neurofibromin, that is a negative regulator of RAS. When this protein is not functioning, the MAPK pathway is hyperactivated. A MEK inhibitor block MEK, inhibit MEK and block the phosphorylation of ERK. As mentioned initially, currently in NF1 alone, we have data from one of the MEK inhibitors. There are currently two MEK inhibitors approved for the treatment of plexiform neurofibromas in NF1, both approved very recently for pediatric and adult population. Until very recently, there was only selumetinib approved for the pediatric population and doing annually approximately $500 million in sales. Talking about NF1, that is a genetic disorder with a complex phenotypic presentation. In NF1, patients can develop neurofibromas that are non-malignant tumors derived from the Schwann cells.
Some of these tumors are present around and grow around the large nerves in our body, these are called the plexiform neurofibroma. They are present since birth. They grow at a slow rate of 2%-3% a year, at some point, as you can see here in the image, they will either cause deformities, or they will compress structures, or because they wrap around the nerve, they'll lead to motor dysfunction or sensory dysfunction. Until the approval of MEK inhibitors, the only available treatment was surgery. As you can imagine, doing a surgery of a tumor that grows around a nerve is very complex, very difficult to remove without causing serious side effects. These plexiform neurofibromas also have a malignant potential. Not all patients with NF1 develop plexiform neurofibroma.
NF1 is a genetic disorder that affects one in every 3,000 newborns, meaning that there are currently around 115,000 patients in the U.S. alone living with NF1. Around 30%-50% develop plexiform neurofibroma. Let's say around 50,000 patients in the U.S. alone. For these indications, there are two MEK inhibitors approved: selumetinib, marketed by AstraZeneca, and mirdametinib that has been developed by SpringWorks, now, since its acquisition by Merck KGaA, is sold by this company. 100% of patients develop cutaneous neurofibroma. They are also neurofibromas, they arise from the nerve terminals that we have all over our body, they show up as skin bumps. They typically grow in numbers. They can even grow to thousands, as you can see here in the image.
Some patients have only some dozens, of course, these cause a huge impact in the patient quality of life. They can also cause pain, pruritus, and irritation. There is no approved treatment for this indication. Let's focus on the current treatment landscape with two drugs approved. Both selumetinib and mirdametinib are drugs that are dosed twice a day. They have a short half-life. They typically tend to take seven to eight months to generate a response. What is really evident, and here we bring in in-label data, is their suboptimal profile, leading to many patients discontinuing or having dose reductions or interruptions. If you look to the safety profile, you're going to see that patients present with many adverse events, particularly rash, that can as high as 80%-90%.
GI tox, also somewhere around 50%-60%, GI tox with nausea, vomiting, and diarrhea. CK increase, typically asymptomatic, around 50% of the patients. Ocular and cardio tox, around 20% of the patients. This is, of course, what is on label. If we look to the severity of these AEs, we know that around 20% of patients develop grade 3s. We also know that somewhere between, and this is data from the clinical trials, the phase II clinical trials, registrational trials that led to approval, that approximately 20% of the patients end up discontinuing the drug over the first two years of treatments. Definitely there's a huge room to improve in the safety profile of a MEK inhibitor. This is what we're trying to achieve with PAS-004. Our drug fit the sweet spot between efficacy, safety, and also a differentiated PK profile.
I'm going to show you in the subsequent slides data that supports this claim. First, let's talk about how PAS-004 differentiates from other drugs. PAS-004 is the first macrocyclic drug, you can see this ring-like structure that confirm the macrocyclic structure versus cyclic structures of other MEK inhibitors. Because of the conformational rigidity of these molecules, of macrocyclic structure molecules, they're typically highly selective with a reduced off-target effects. They're also molecules that typically have a very long half-life. Also improve oral bioavailability. When designing PAS-004, we also took a very attention to removal of metabolic unstable groups such as primary alcohols that other MEK inhibitors present. This allow us to reduce the potential for having any active metabolites that are present with other MEK inhibitors. Now, talking about conceptually what we think is our biggest differentiator versus existing MEK inhibitors.
The two approved MEK inhibitors for NF1, they have very short half-life. As mentioned before, between AstraZeneca and mirdametinib, their half-life is between six to seven and a half hours. With this short half-life, what typically occurs is that the drug is immediately absorbed, reach a very high Cmax, then the drug concentrations drop and drop below a therapeutic level. This pulsatile pattern happens every 12 hours. It's impossible to titrate the pathway with drugs with such a short half-life. On contrary, with a very long half-life, such as the one we've seen with PAS-004, it allow us to, once steady state levels are achieved, to keep a constant inhibition with, Cmax to Cmin ratio below, in the case of PAS-004, below two, with a drug even at C-trough being above the therapeutic level and with Cmax below what we consider a toxic level.
The ability to titrate the pathway is very relevant for an indication such as NF1. Currently, before presenting our human data, we have as previously mentioned, two ongoing clinical trials. This is our phase I/IB clinical trial in NF1, it consists of a part A, modified 3+3 dose escalation design and a part B of dose expansion. In this part A, we're testing four different dose regimes for eight, 12, and 18 milligrams, we're going to select two doses for a dose expansion. Patients in part A are followed approximately for at least six months, but a patient will continue on treatment even after this six months, so we're going to have data on both the plexiform neurofibroma and on the cutaneous neurofibroma volume by year-end.
After in 2027, we're going to select two doses for a dose expansion, and we're going to select the recommended phase II dose for a registrational trial. We're currently conducting this trial in five different centers, one in U.S., two in Australia, and two in South Korea. Our dose escalation trial in advanced cancer patients with mutations in the MAPK pathway is a 3+3 study design, and we're testing our drug in the capsule formulation in 8 different cohorts. We have now data in all cohorts. We have completed the 8 cohorts. The main objective of this trial is to evaluate the safety as well as the PK/PD and some preliminary anti-cancer activity. Now let's look to the human data.
On the left screen, you're going to see an overlap between our PK profile at the 37 mg capsule dose and the mirdametinib published trial at the approved drug for NF1, 4 mg BID. As you can see by the mirdametinib profile, the ratio between Cmax to Cmin is approximately 10, similar to selumetinib. While PAS-004 show a very flat PK profile, if you look to the data on the table below, I want everyone to pay attention not only to our Cmax, but particularly to our Cmin. Our Cmin is much significantly higher than the C-trough or Cmin of mirdametinib and selumetinib. At these dose levels, the drug is still above the IC50, still an effective and therapeutic dose. With this profile, we managed to keepTo pathway that continuously inhibits with a ratio between Cmax and Cmin below 2, actually around 1.5.
Our drug PAS-004 is less potent than mirdametinib, but more potent than selumetinib. Here is the overlap between PAS-004 at 37 mg and approved dose of NF1. Another thing to pay attention is with this very flat PK, what we can achieve is very high exposures. I will highlight the exposures because exposure matter as they correlate with treatment response in NF1. At the 37 mg dose, we're achieving exposures that are almost as high as the exposures of selumetinib. Here are some more data of our PK at multiple dose cohorts. As you can see, a very flat PK dose proportionality. With selumetinib, and this is data published by AstraZeneca, you see the pulsatile PK profile and also the existence of N-desmethylselumetinib that is an active metabolite that can, of course, impact on the PK and on the safety of this drug.
At the highest dose tested, we model these doses to be at or above the IC90. We are bringing again attention to exposure. This is data published by mirdametinib, where they explore relationships between treatment response in NF1 and their PK data. What they've seen is that there is a positive relationship between treatment response and exposure. Every patient that responded with NF1, they have an AUC at from 0 to 12 hours higher than 600 ng. If you multiply this by two, that's approximately 1,200. At the 37 mg capsule, we're getting an exposure that is very high and both with capsules and also with tablets. Again, what matters in NF1 is not how high your Cmax goes, but really how high your exposure is.
This supports the fact that with a very long half-life and very large AUC, we might see also treatment response at these dose levels. We have efficacy data. Far we only present in our advanced cancer study. Monotherapy with MEK inhibitors in advanced cancer is limited, but we know and so far we have 22 efficacy available patients. We know that certain mutations in the MAPK pathway are more sensitive to monotherapy MEK inhibitor. In advanced cancer, typically, MEK inhibitors are paired with a BRAF inhibitor. When we specifically look to patients with BRAF mutations such as V600E mutations, what we see is approximately 70% of patients achieve a stable disease. A disease control rate of 70%. Patients that remain on trial for many cycles with multiple stable disease scans along the way. Let's look to our AE profile.
This is the AE profile at different dose cohorts. We haven't yet disclosed the safety profile of our cohort 8 45 milligram capsules. What we're seeing here is data up to cohort 7 during the DLT periods. What you'll see is that we have GI tox such as vomiting, nausea, and diarrhea in less than 20% of the patients. Also, single-digit number in rash and fatigue and CK increase also in a limited number of patients. Of course, this is a dose-escalation trial. Some of the patients into initial cohorts were dosed at doses that are subtherapeutic, so we need to take this data when we compare to existing on-label safety profile of AEs.
Far, even at the highest dose cohort tested, we're seeing a significantly improved safety profile. When we look to mirdametinib advanced cancer studies, we're comparing our advanced cancer study with mirdametinib advanced cancer study, where they go from one milligram to 30 milligram BID at their approved dose for NF1 is the four milligram, as you can see here on green. When you look to the safety profile at even the lower dose of two milligram or one milligram, you're going to see that 50% of patients present with diarrhea, 75% with nausea. We already into those dose-escalation studies of other meds, we are seeing AEs even at the lowest dose tested.
This supports the fact that what I've shown you before is not only the fact that we're dosing low, is due to the fact that we're not getting to very high Cmax, completely blocking the pathway and leading to safety profile. This is our program timelines. As we're continuing our phase I study in solid tumors, we're going to provide an update on the safety PK and efficacy at ASCO this year. For the adult NF1 patients, we're going to present data on the Part A of the study by the second half of this year. We're also planning and start working into moving our drug into the pediatric population, with the ultimate goal to start a registrational trial, both in adult and pediatric patient population by 2028.
Just highlighting that what we're going to show in the second half of this year is not only data in plexiform neurofibroma, but also in the cutaneous neurofibroma, where currently there is no drug approved. We're also assessing other potential opportunities in the space, particularly looking to other RASopathies such as Noonan syndrome, and we have an investigator-led trial that is about to start in ALS. Finally, focusing on our intellectual property. We have currently composition of matter patent issue until September 2032 with an extension to 2037. We file in January 2024, a new composition of matter based on the identification of a crystalline form, and we anticipate that this will provide patent protection until 2045. We also have Orphan exclusivity for NF1 and we're pursuing multiple patent extension strategies.
In November of last year, we complete a financing with a very strong group of investors. We raised $60 million. We have disclosed by year-end approximately cash balance of $60 million. That will allow us to run our company until at least the first half of 2028. Currently, we have approximately 88 million shares outstanding. Having said this, I hope that everyone consider Pasithea a compelling investment opportunity. Of course, we'll be free and available to discuss any of this data with everyone. Thank you so much for your attention.
Thank you, Tiago. I don't know if maybe we have time for one or two questions or so. Maybe starting with, could you comment on the brain penetration ability for 004? Do you think that brain penetrance is important for treating NF1?
Not for treating NF1. Actually, mirdametinib is very brain penetrant. They suffer from ocular toxicity. That's why in NF1, the drug mirdametinib is dosed three weeks on, one week off. We haven't yet assessed the brain penetration of PAS-004. We are very excited with the opportunity to test PAS-004 in ALS patients because we're going to be assessing the PAS-004 concentrations into CSF.
Okay, great. Well, we look forward to that. Maybe if you could comment briefly on the tolerability profile for 004. Looks like it has very favorable therapeutic index so far. With regards to tolerability, will you be collecting any patient-centric measures like quality of life?
In NF1, yes. We're collecting that. Not in the advanced cancer study. What we can comment is really we haven't seen any grade 3 AE. We haven't seen any dose discontinuation. All patients remain on trial. We haven't seen any DLT. Of course, we have the convenience of our drug being dosed once a day. We still haven't conducted food effect studies, so our drug is still taken fasted. We know that once taken with foods, MEK inhibitors can flatten the PK profile and lead even to a better safety profile. All of this, all of the existing data suggests that PAS-004 is a very tolerable drug. Of course, as more data emerge, we'll be hoping to continue to see the same profile.
Okay, perfect. We'll wrap things up there. Thank you so much, Tiago, for joining us here today and bringing us up to speed on all the impressive work you're doing at Pasithea.
Thank you so much.
Our pleasure. Thanks everyone for joining us.