Ready to go? Okay. Welcome back, everyone. I'm joined now by Dr. Tiago Reis Marques, who has been Chief Executive Officer of Pasithea Therapeutics since 2020. Tiago is a lecturer at the Institute of Psychiatry, Psychology and Neuroscience at King's College London, and a senior clinical fellow at Imperial College London, and practices psychiatry at the Maudsley.
Pasithea is developing PAS-004, an oral MEK inhibitor for neurofibromatosis type 1, or NF1. The company presents its first clinical data from the NF1 study at the European Neurofibromatosis Conference next month. Tiago, thank you for being here. Let's start with the disease. Walk us through the two manifestations that you're going after.
Thank you for the invite. It's a pleasure to be here. NF1 is a genetic disorder that arise from mutations into NF1 gene. NF1 gene codes a protein called neurofibromin. It affects approximately one in every 3,000 newborns, so there's approximately 150,000 patients in the U.S. suffering from NF1. In that disorder, that protein basically act as a negative regulator of the RAS, RAF, MEK, ERK pathway, the MAPK pathway.
When there's a mutation in that protein, this pathway is overactive. When it's overactive, because it's an important pathway in cell survival and proliferation, basically tumors arise, called neurofibromas. There's two different neurofibromas in neurofibromatosis type 1. The cutaneous neurofibroma that manifest as skin bumps, and then small lesions in the surface, in the skin, that can range from dozens to hundreds or thousands.
Plexiform neurofibromas that are tumors that arise from the deep nerves that we have in our body, and that's so-called plexiform neurofibromas.
Let's stay on the cutaneous neurofibromas, because that is the part of your program that might get overlooked. What is the patient burden? How large is the population, and what is available to them today?
It is a great question because this is definitely the most bothersome manifestation for a patient that suffers from NF1. As you can imagine, if you have hundreds of skin bumps all over your body, it impacts your quality of life, creates stigma. It can cause pain, itching, so it is definitely something that is a very bothersome manifestation. It affects over 99% of patients with NF1, and currently there is no drug approved for these disease manifestations.
They compound with time, so they arise around puberty. By the age of 20, you can have small lesions ranging from some dozens, and then as you get older, the number increase and the volume increase. Data from the large cohorts in the world show that over 80% of participants by the age of 50 have more than 100 lesions. The current treatment, it is absence.
There is no systemic, no FDA-approved treatment for this indication, but you can remove these lesions one by one through biopsy or laser. It ultimately leads to a small scar. There is definitely a large unmet need, and we aim to be the first systemic drug approved for this indication.
MEK inhibitors have never really been considered dermatology drugs, or in immunology and inflammation drugs. What is it about PAS-004 that changes that?
Yeah. We have seen a renaissance into use of MEK inhibitors, similar to what we have seen with JAK inhibitors. They started to be cancer drugs, and then they moved to other indications. The use of MEK inhibitors have expanded from their use in oncology into other indications. You see companies going after FAP, familial adenomatous polyposis, and other disorders, and we see the same with MEK inhibitors. It has been used in other indications.
The reason why it is not widely used is because of the safety liabilities of current MEK inhibitors. They lead to adverse events, and some of them really impact patient tolerability. We know that with existing MEK inhibitors, those that are approved for NF1, approximately over 90% of patients present with rash. 20% with grade three events, ocular tox, cardiotox, also around 20%. GI tox as diarrhea, over 50% of the patients.
We see discontinuations ranging from 15%-20%, dose reduction, dose interruption. While these drugs, and patients can tolerate these type of drugs in an oncology indication, you cannot tolerate these AEs in an indication that is more benign. When we develop our MEK inhibitor, we design it specifically for the chronic use in non-oncology indications. We've done that by creating the first macrocyclic MEK inhibitor.
These are molecules that have a rigid structure that confers them a very long half-life, and we also remove primary alcohols that avoid the presence of any active metabolites. Having a long half-life avoids the peaks and troughs of existing MEK inhibitors approved for NF1, where you need to take them twice a day. These drugs, at their Cmax, they're fully blocking the pathway, leading to potentially more side effects.
While we, with a very long half-life, we have a 60 hours half-life, we can titrate the pathway. In disorders outside of oncology, such as NF1, you don't need a full pathway inhibition to achieve efficacy. You can have efficacy with around 50%-60% pathway inhibition in plexiform neurofibroma, and even around 25%-50% in cutaneous neurofibroma. What we aim with our drug is to have the ability to partially block the pathway, achieving efficacy, and at the same time, reducing the safety liability of these drugs.
Let's talk about your upcoming presentation at the European Neurofibromatosis Conference. I know you might not be able to tell us everything, but you have data from 18 patients across roughly 70 lesions, covering both manifestations. What should people be watching for? What would you consider a successful outcome?
Just giving you a brief overview of our current trial. We are now in the dose escalation part of our phase Ib trial in NF1. We're testing different doses across six dose cohorts from 4- 24 mg. We're measuring, in these patients with NF1, we're measuring the size of the plexiform neurofibroma through MRIs, and also the size of the cutaneous neurofibroma that we're measuring with digital calipers.
Answering your question, what is a successful outcome? To see an opportunity for the cutaneous neurofibroma opportunity, we see as a successful outcome because we are the first ones developing a drug for this indication. We see efficacy is paramount. Can you show efficacy, a significant reduction in volume of cutaneous neurofibroma, and significantly reduce the size of the lesions that we're measuring? As you mentioned, we're measuring over 70 lesions across 18 patients.
For the plexiform neurofibroma, it's a different story because, of course, we are going to report efficacy, but this is initial findings. Both selumetinib and mirdametinib that are approved in NF1 plexiform neurofibroma, the average time to respond is around seven to eight months. You need a long time for these patients to demonstrate a response. We are in a dose escalation trial.
We started with 4 mg, and then we enroll successive cohorts as the SRCs allow us to proceed. We have patients in the lowest dose cohorts with over a year on treatment, but at the highest dose cohorts, patients are just on trial for four to six months. What we're going to show in PN is trajectory of change, mainly, if the tumors are reducing in volume. If we show that's already a successful outcome in PN.
Then you need to pair this with safety, with tolerability. Can our drug be tolerable in these non-oncology settings such as NF1? Looking to those reductions, those interruptions, those discontinuations, frequency of AEs, severity presence of the less frequent but more impactful and meaningful AEs such as cardiotox, ocular tox. You'll be able to look to this data compared to safety liabilities of existing MEKs, and then, of course, look to efficacy in both indications.
We are running out of time. I'm going to try to squeeze two more quick questions in. One thing that I thought that was fascinating when I spoke to you on the phone previously, you said that the two manifestations indications go through two completely different paths of regulation at the FDA. Explain that, what that means, and how that changes the way you run this program.
Yeah, it's very interesting because these are neurofibromas. They are exactly the same, but one manifests into skin and the other one manifests into deep nerves, but they're basically the same, but regulated by two different divisions. The Division of Oncology regulates the opportunity in plexiform neurofibroma, and typically for the two approved MEK inhibitors, the approval path is through a Phase II registrational trial versus historical controls. That's the path of mirdametinib and versus a placebo in the case of selumetinib.
For cutaneous neurofibroma, we are trailing the path, so we expect a large phase II where we're going to look because it's a Division of Dermatology, we're looking to reduction in volume of the cutaneous neurofibroma. But typically, we need also to pair it with a PRO or an IGA tool. Then the approval through a single phase III registrational trial.
Perfect. That alarm, that reminded me we have to move on. What should the audience be expecting to see from you over the next 12 months?
Definitely our data now in the European Neurofibromatosis Conference, the initial data. Later, the selection of our doses for the expansion phase for the Part B of our study around Q1 or Q2 of next year. Also, if we are successful in getting an IND with the Division of Dermatology to test our drug in a phase II trial in cutaneous neurofibroma.
Perfect. Tiago, thank you.
Thank you so much.