Greetings. Welcome to Rafael Holdings Phase III Top Line Results Conference Call. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. Please note this conference is being recorded. I will now turn the conference over to Barbara Ryan, Investor Relations. Thank you. You may begin.
Thank you, Sherry, and good morning to all of you joining us today. Earlier this morning, Rafael Holdings announced top-line results from the pivotal phase III TransportNPC study of Trappsol Cyclo in Niemann-Pick Disease Type C. Joining me today are Joshua Fine, our Chief Operating Officer, and Dr. Karen Mullen, our Chief Medical Officer. Before we begin, please note that today's call will include forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These include statements about the potential safety, efficacy, and clinical benefit of Trappsol Cyclo, the interpretation of the study data, our regulatory plans, including the timing of an NDA submission, and the potential for FDA acceptance or approval. These statements are based on our current beliefs, expectations, and are subject to risks and uncertainties that could cause actual results to differ materially.
These risks include those described under Risk Factors in our annual report on Form 10-K for its fiscal year ended July 31st, 2026, and our other filings with the SEC. The top-line data and the survival analysis remain subject to full analysis and FDA review. Forward-looking statements speak only as of today, and we undertake no obligation to update them. You can find today's press release containing today's data on the investor section of our website at rafaelholdings.com. I will now turn the call over to Joshua.
Thank you, Barbara. Hello, and good morning. Thank you for joining us as we announce this major milestone in our company and patients living with Niemann-Pick Disease Type C, or NPC. We spent the last 15 years focused on the pursuit of developing Trappsol Cyclo for the treatment of this rare, fatal, progressive genetic disorder. NPC is characterized by a defect in the NPC protein, affecting approximately 900 patients a year in the U.S. and 9,000 patients worldwide. The results presented this morning are a culmination of our rigorous dedication to the science and the patients who are in desperate need of effective therapeutic options. Trappsol Cyclo has been developed to treat both the systemic and neurological manifestations of NPC.
Across multiple clinical studies, we have shown encouraging results, bringing us to this morning's announcement reporting the top-line results from the TransportNPC study, a global double-blind, placebo-controlled phase III study in 94 patients with Niemann-Pick Disease Type C. We are extremely encouraged by these results, and this data gives us confidence to continue advancing Trappsol Cyclo. Based on our previously announced pre-NDA meeting with the FDA, we remain on track to submit our NDA for Trappsol Cyclo in the fourth quarter of 2026 and remain eligible for a priority review voucher or PRV. I'd like to thank all the patients, caregivers, patient community members, and the Cyclo Therapeutics and Rafael team members for their help and dedication throughout this process. At this time, I'd like to introduce our Chief Medical Officer, Dr. Karen Mullen, who will walk you through the data in more detail.
Good morning. This pivotal phase III double-blind, placebo-controlled study is the most comprehensive trial in NPC conducted to date, spanning 13 countries and 27 sites, comprising 94 patients randomized 2 :1 to receive Trappsol Cyclo, 2,000 mg /kg plus standard of care given intravenously every two weeks versus placebo plus standard of care for a total of 96 weeks. 63 patients were randomized to Trappsol Cyclo and 31 patients to placebo with an age range of 3 to 70 years, allowing the study to capture the broad spectrum of patients in this heterogeneous disease. The primary endpoint was changed from baseline in the four-domain NPC Clinical Severity Scale, known as 4D, at week 96. The 4D is comprised of four domains: swallow, ambulation, fine motor, and speech. A lower number indicates improvement and a higher worsening.
Improvement on the 4D scale is a negative value. The primary endpoint with the modified intent-to-treat analysis on the MMRM, this showed a mean treatment difference of -0.811 in favor of Trappsol Cyclo with a P value of 0.19. While this did not achieve statistical significance, it was directionally favorable towards Trappsol Cyclo and indicated a slowing of disease progression by 64% of the change of the 4D in 96 weeks. The study also included a pre-specified subgroup analysis of patients receiving background miglustat and/or leucine. For clarity, leucine in this study is a food supplement available in some European countries. This subgroup represented 83% of the study population, 78 patients out of the 94.
This subgroup, Trappsol Cyclo, showed a mean treatment difference of -1.105 reaching a statistical significant P value of 0.046, indicating a slowing of disease progression by 71% compared with placebo at 96 weeks. Moving to safety. Trappsol Cyclo was well-tolerated over the 96-week period, consistent with previous studies. The adverse events are largely consistent with the underlying disease. Most were mild to moderate, with a comparable proportion of patients in each group reporting treatment-emergent adverse events. 93.8% in Trappsol Cyclo versus 100% in the placebo group. Serious adverse events occurred more frequently with Trappsol Cyclo, 35.9%, compared to placebo, 16.7%. However, those that were considered treatment-related adverse events were reported in a similar proportion of each group, 3.1% Trappsol Cyclo versus 3.3% in placebo.
For hearing, the majority of the hearing-related treatment-emergent adverse events were mild to moderate, 15.6% in the Trappsol Cyclo group versus 13.3% in the placebo group, and this included all ear-related adverse events. Importantly, only one treatment-related event was severe, with the patient requiring bilateral hearing aids in the Trappsol Cyclo group. No adverse events led to death. One participant in the Trappsol Cyclo group had an adverse event that led to early withdrawal from the study. As previously presented, an open label pediatric substudy of this phase III study was conducted. This enrolled 10 patients under the age of three in this highly progressive infantile form of NPC. Of the patients who reached 96 weeks, 71% showed an improvement or stabilization on the Clinical Global Impression of Change, and 29% of the patients showed deterioration. The safety profile was considered well-tolerated. 27 reported serious adverse events, none considered related to study drug.
Separate from the phase III study, an overall survival analysis comparing patients with infantile-onset NPC treated with Trappsol Cyclo across the clinical development program was compared against matched external controls from the International Niemann-Pick Disease Registry. The primary analysis was associated with an 85% reduction in the risk of mortality, a hazard ratio of 0.154, and a P value of 0.044. This comprised 41 patients treated with Trappsol Cyclo and 93 matched controls from the registry. In a secondary analysis, to broaden the registry cohort with an additional matched external control from published natural history studies, Trappsol Cyclo was associated with a 94% reduction in the risk of mortality. Hazard ratio 0.057, P value 0.008. This analysis had a total of 133 matched external controls. The consistency and magnitude of these survival associations, we believe, provide additional supportive evidence of the potential clinical benefit of Trappsol Cyclo in patients living with infantile-onset NPC.
The totality of these data provides a compelling rationale to continue advancing Trappsol Cyclo for patients living with NPC. As a reminder, the top-line data, complete data set, and overall survival analysis remain subject to a full analysis and FDA regulatory review. Finally, we are deeply grateful to the patients, caregivers, and clinical investigators whose participation was critical to completing this study. I'll hand back to Josh.
Thank you, Karen. In summary, the company remains on track to submit our NDA for Trappsol Cyclo to the FDA in the fourth quarter of 2026. Over the coming weeks, our priorities are completing the full analysis of the TransportNPC data set, preparing the NDA submission, then focusing on commercial readiness. Before we close, I would like to thank everyone who joined our call today and all of our stakeholders for your continued support on working with us to bring this much-needed therapy to the NPC community. With that, operator, please open the line for questions.
Thank you. We will now be conducting a question and answer session. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. Our first question is from Sumant Kulkarni with Canaccord Genuity. Please proceed.
Good morning. Thanks for taking our questions. We have a few. Given this data set, during your pre-NDA meeting, did the FDA provide any feedback about acceptability of the totality of data in your upcoming NDA submission?
Hey, Sumant. Thank you for joining the call today. I will take this first and then pass to Karen. Based on the outcomes of the pre-NDA meeting, I think what we got was an alignment on our submission strategy and a basic understanding of what the total data package was going to look like, with the expectation that based on the interim, which we published, that our P value wasn't achieved. Anything further than that, I am not able to provide, unfortunately. But we feel comfortable with the fact that we believe we are aligned with the FDA and have confidence that we can get this drug to these patients.
Got it. Thanks for that detail. Given there are a couple of products already approved in the U.S. for NPC and there is one pending for infantile onset, how do you think the data set here would be viewed against that backdrop, I guess?
Morning, Sumant. Great to have you join us this morning. This is a devastating disease, and it's great to have options for these patients, and we know that they may well be used in combination. Obviously, there's no head-to-head studies. We are confident about our data, our totality of our data. Importantly, there's a real unmet need in the infantile form, the early infantile form, which is highly aggressive. Also not just treating the neurological symptoms, but also treating the visceral symptoms as well, where, as Josh had said, the development of Trappsol Cyclo is actually also for the visceral and neurological symptoms. I think that if all our drugs are approved, it's great to have options for the community out there.
All right. Last one before I hop back into the queue. Were there any sub-domains of the scale that the product was most relevant in?
Great question. Of the four sub-domains, there was a favorable direction to Trappsol Cyclo. The main one being swallowing, which we know that that is probably one of the most important domains with regard to morbidity and mortality. We're seeing improvements across the board on the domains.
Thank you.
Sumant, you may follow up with any further questions, or if anybody else has a question, it is star one on your telephone keypad if you would like to ask a question. We will just pause for a brief moment to see if there's any more questions. Okay, we do have a follow-up from Sumant. Please go ahead, sir.
Thanks for the follow-up. So in the event that regulators require additional data, what types of data might be able to be generated? And could you balance that against the company's financial and operational capability to do so?
Sorry, Sumant, you broke up a little. I heard the end of the question.
Sure. So if regulators require any additional data, what form or what types of data could you already have or need to generate, I guess?
Yeah, we've got a large totality of data across the 15 years of development. As Josh said, we had good alignment at our pre-NDA meeting about the road map for our submission, which we're well on track for. If there is any additional analysis of data required by the FDA, we would absolutely be working with them to ensure that we would submit that in a timely manner to be able to bring this to patients. That matters.
Got it. Thank you.
There are no further questions at this time. I would like to turn the call back over to Joshua for closing remarks.
I'd like to thank everyone for their time today in joining this call and for their continued support of Rafael Holdings and Cyclo Therapeutics. We look forward to speaking with you all in the future.
Thank you. This will conclude today's conference. You may disconnect at this time, and thank you for your participation.