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spk09: Greetings, ladies and gentlemen, and thank you for standing by. Welcome to the TFF Pharmaceuticals Third Quarter 2021 Results Conference Call. As a reminder, this conference call is being recorded. A question and answer session will follow the formal presentation. If anyone should require operator assistance, please press star zero on your telephone keypad. I would now like to introduce Corey Davis of LifeSci Advisors to begin the call.
spk08: Thank you, Operator. Hello, everyone, and welcome to the TFF Pharmaceuticals Third Quarter 2021 Financial and Business Results Conference Call. With me on the line today is Glenn Mattis, President and CEO of TFF, Kirk Coleman, Chief Financial Officer, Dr. Dale Christensen, TFF's Director of Clinical Development, and Dr. Bill Williams of the University of Texas at Austin. Chris Cano, TFF's Chief Operating Officer. Press release announcing our third quarter results is available on the TFF Pharmaceuticals website. Please take a moment to read the disclaimer about forward-looking statements in the release. Discerning's release and this teleconference both include forward-looking statements, and these forward-looking statements are subject to known and unknown risks and uncertainties that may cause actual results to differ materially from the statements made. Factors that could cause actual results to differ are described in the disclaimer and in our filings with the U.S. Securities and Exchange Commission, including the risk factors section 13. of our 2020 Annual Report on Form 10-K, filed with the SEC. And now, it's my pleasure to turn the call over to Mr. Glenn Mattis.
spk05: Good afternoon, and thank you for joining us today to review the company's third quarter operations and recent highlights. During this call, I will provide an update on our overall corporate progress. After my opening comments, I will ask Dr. Dale Christensen to update us on the outstanding progress we are making with our internal clinical programs. He will be followed by our CFO, Kirk Coleman, who will update financial results. Then Dr. Bill Williams will review the highlights of new data on thin film freezing generated in just the last quarter. And finally, our Chief Operating Officer and Vice President of Business Development, Chris Cano, will update the status of our partnering efforts. The third quarter was extremely productive with significant milestones in every area of the TFF business. These accomplishments are almost too many to discuss in a timely manner during this update. The positive outcomes have been accelerating throughout 2021 and continues to position TFF for positive value creation in the short, mid, and long-term periods. I'm going to begin by reviewing the significant milestones from our development of the internal pipeline. I'll provide a top line and Dr. Christensen will provide greater details. We concluded and reported results from both the Phase 1 and Phase 1B TFF inhaled voriconazole program. These data have confirmed safety and allowed us to select a dose to study in our upcoming pivotal Phase 2 program which we'll initiate by the end of this year. In addition, the results of the Phase 1B study gave us our first look at safety data in asthmatic patients. The data from both studies were quite positive and confirms our clinical strategy of pursuing an indication in patients with invasive pulmonary aspergillosis. We also concluded the Phase 1 study for TFS tacrolimus, And the results indicated that our inhaled product has an acceptable safety profile to achieve the appropriate balance of local and systemic concentrations for immunosuppression at the site of the lung transplant, while minimizing the risk of supertherapeutic exposure, well known to cause significant renal toxicity in patients. The outcome of this study allows us to initiate the pivotal phase two program shortly. Later in the call, Dr. Christensen will provide a more detailed overview of the data from both programs and inform you on our progress. We also achieved significant milestones in our two partner programs, which feature the novel antibody Augmenta 3387, co-developed with Augmenta BioWorks, and the antiviral niclosamide, who we partnered with Union Therapeutics. As a reminder, Augmenta 3387 is being formulated as a dry powder using TFF Pharmaceutical's proprietary thin-film freezing process to enable direct delivery to the lungs and remove the need of IV infusion that is required for delivery of current COVID-19 antibody therapies. In separate announcements, we described the high level of potency in animal testing. In these studies, Augmenta 3387 demonstrated the ability to reduce viral load in a dose-dependent manner after the animals have been fully inoculated. This is a unique finding, and in our view, Augmenta 3387 is fast emerging as one of the most promising new therapies for the treatment of COVID-19. Augmenta 3387 also demonstrated binding to the major COVID-19 variants, including Delta, Lambda, and Mu. Our inhaled niclosamide program has achieved a meaningful development milestone when we announced that TFS has received approval from Health Canada to begin a Phase I clinical trial of a dry powder version of niclosamide that will demonstrate safety data and allow for dose selection and subsequent clinical development of this potent antiviral agent. By way of additional background, niclosamide is included in the World Health Organization's list of essential medicines and has recently been shown to exhibit potent antiviral activity against SARS-CoV-2. The inhaled version of niclosamide will overcome the limited water solubility as well as low absorption in oral bioavailability. Using the TFS technology to develop a dry powder formulation of niclosamide that can be delivered directly to the site of viral replication within the lungs by inhalation, will be administered in the outpatient setting, providing an important treatment option for physicians. Again, Dale will provide greater details in just a few minutes. The significant progress we have made and will be making in the coming days and weeks moves all of our internal portfolio closer to monetization and meaningful revenue streams for TFF. Both the TFF for aconazole and TFF tacrolimus Phase II programs will be designed with an interim analysis of data. These data sets will be available mid-2022. Once we have the data, we'll begin a process to find a licensed partner to ultimately commercialize the assets. We've already received interest from pharmaceutical companies, and we'll use the interim data as the inflection point to pursue those partnerships. For Nyclosamide, the successful completion of the phase one study, in the early part of next year will be the inflection point for Union Therapeutics to trigger their option period. And for Augmenta 3387, we are committed to share funding of the development of the monoclonal antibody through phase one, at which time we will pursue a pharma partner to license the asset for further development and commercialization. So, TFF is rapidly reaching meaningful economic milestones for our internal portfolio. I also want to congratulate the TFF team for advancing all four of our development programs in a timely manner in the face of the global pandemic. As you know, COVID-19 has been a significant issue for clinical development in the industry, and TFF has been able to successfully navigate these issues and produce results with limited or no delay and on budget. Also on this call, Dr. Bill Williams will highlight important new data that he has generated during the quarter. Specifically, he will review new data demonstrating the applicability of thin-film freezing in creating successful formulations in biologics and complex molecules. These are the opportunities where thin-film freezing is highly differentiated from other methods for creating dry powders. It is important to note that these data were generated with materials provided by companies who are partnered with TFF. The results of these MTAs and statements of work with companies who we intend to partner with continues to expand the proof of the value of the technology and allows us to attract additional opportunities. It is also important to note that these observations and findings has enabled PFF to greatly expand our IP estate. We now have approximately 100 patents either granted or pending both in the U.S. and the rest of the world. Our academic and government collaborations are also proceeding very well. We have initiated the work with DARPA on formulating countermeasures and the development of novel vaccines at USAMRID is also progressing. We expect a second CRADA shortly, expanding the work we are doing in the vaccine area at USAMRID. Our collaboration with Dr. Ted Ross at the University of Georgia on universal flu, and Dr. Karthik Chandran at the Albert Einstein College of Medicine on VSV vaccines are now in the animal testing phase. And our work with Dr. Drew Weissman at the University of Pennsylvania is now in full swing, looking at the application of the thin-film freezing technology in mRNA vaccines and therapeutics. Dr. Weissman is the inventor of the current BioNTech Pfizer mRNA COVID vaccine. And we're honored to be working with Dr. Weitzman and believe this collaboration will result in important new products to prevent and treat viral infection. Dr. Weitzman provided this quote. The freeze-dried powder formulation by TFF has enormous potential to move the mRNA LNP vaccine platform to efficient worldwide use by allowing room temperature storage and the development of oral inhaled delivery. That's quite high praise from Dr. Weissman. I also want to thank our partner, Plus Products, for their work in optimizing the TFF formulation of cannabinoids and implementing thorough market testing. Plus has successfully completed a number of formulations which are being evaluated by potential consumers, leading to what we hope will be a successful commercial launch in the very near future. In relation to the status of our partnership business development activities, I continue to strongly believe with confidence they were on track to sign meaningful partnership licensing agreements. I'm aware that it is November 15th and we're entering into the final weeks of the year. The number of programs or MTAs continues to grow. Moreover, we are also seeing expansion of thin-film freezing application across a more diversified set of companies and drug candidates, mostly in the biologics arena. The work we are conducting with partners closest to finalizing transactions are focused on animal testing, the thin-film freezing formulations, stability work, and in some cases, production of GMP material. We are also discussing specific terms and agreements with a significant number of potential partners. In our discussions with these companies, we have agreed to the specific data that needs to be realized as the potential seminal milestone leading to a completed transaction. TFF works with great purpose to get these data produced and delivered to the partner for their assessments and analysis. At that point, we are at the mercy of the partner's timing to evaluate the data and provide feedback to TFF. There are situations we were asked to optimize the material, and the process continues. And TFF has been billing the partner for the additional work performed that has been outside of the original MTA and statement of work. It's certainly great news that many of our current partners with open MTAs and SOWs are large commercial-stage pharmaceutical companies. The pace of moving forward with these companies can be a challenge. The process has led to extended evaluations and, in some cases, are taking a bit longer than we expected. We do not have the ability to accelerate these discussions. We have communicated our strong desire to close these agreements by the end of this year and remain confident that this will happen. We strongly believe that we're on track. We will communicate and update the status of this work and ongoing negotiations. We have every reason to be confident that our numerous technology evaluation programs will result in meaningful collaborations and will drive near, mid, and long-term shareholder value. Later on the call, Chris Cano, our Chief Operating Officer and Head of Business Development, will provide more details on the total view of this effort and how the opportunities are progressing as well as expanding. I will now turn the call over to Dr. Dale Christensen, who will provide detail on our development efforts supporting our internal portfolio. Dale?
spk10: Thank you, Glenn, and good afternoon to everyone who has joined our update call today. The third quarter has been extremely busy for us, and we continue to make great progress in our internal clinical development programs. Last quarter, I provided an update on our Phase 1b study of voriconazole inhalation powder in asthma patients, where we found that the 40 milligram dose was well tolerated, and that we had escalated the dose and we're starting to enroll patients in the 80 milligram twice daily cohort. I am happy to announce that enrollment and dosing has been completed for the full study. Initial observational data following completion of the 80 milligram dose cohort shows that TFF4E is well tolerated in asthma patients and the 80 milligram dose has been selected as the proposed dose for our phase two study. We are now working on the closeout activities for this reactive airway study, and we'll be incorporating the findings from this study into our data package in preparation for the upcoming end of phase one meeting with the FDA, and continue to prepare for our phase two study. For our upcoming phase two trial, we have held scientific advice meetings with two regulatory agencies in Europe, in the key countries where we will be initiating this study. The feedback and advice we receive from these regulatory agencies is critical to moving forward with the Phase II study. In addition to the regulatory guidance we received, the data from the Phase Ib study in asthma patients will also be used to complete the protocol for our upcoming Phase II study in patients with invasive pulmonary aspergillosis. The study in asthma patients provides critical data for the physicians participating in this Phase II study on the use of concomitant medications, including inhaled steroids or bronchodilators, in their patients that will be included in the study. The development of the final protocol will facilitate completion of the CTA that will be filed by the end of the year, and upon approval, we will begin dosing IPA patients. In addition to the Voriconazole results, we completed a database walk in the phase one trial of our Crolimus inhalation powder. As a reminder, the goal for this program is to create an inhaled immunosuppressive therapy that can improve the survival of lung transplant patients while also sparing the patients as much of the systemic toxicity as possible. Crolimus has proven highly efficacious in the prevention of transplant rejection The lung transplant patients continue to lag behind other solid organ transplants with a median survival rate that is around five years shorter than heart, liver, or kidney transplant patients. This is because only a fraction of the tricholomus that gets into the blood reaches the lung, where it is required to inhibit the immune system from attacking the transplanted lung. As a result of this reduced delivery to the lung from the blood, Doctors have responded by prescribing higher dose levels of tacrolimus and raising the blood tacrolimus level so that sufficient levels can reach the lung to fight off the rejection. Unfortunately, when they raise the level of tacrolimus in the blood to get enough into the lung, it also increases toxicity in the kidneys due to the high blood levels. This paradox is a big factor in the lower median survival of lung transplant patients compared to other solid organ transplants. The paradox of getting enough tacrolimus in the lung to fight rejection, but keeping systemic levels low enough to spare the kidney from toxicity is exactly what the inhaled form of tacrolimus is designed to address. We flipped this paradigm and delivered the drug directly to the lungs. When tacrolimus is delivered to the lungs, The drug is deposited in the lung tissue and is then released at a slower rate into the blood. In animal models, we demonstrated that inhalation delivery results in lung tacrolimus levels that are three to four times higher than blood levels. This means that you can achieve high enough levels in the lungs to prevent rejection while at the same time keeping the blood levels low enough to avoid damaging the kidneys. This offers a new paradigm for lung transplant patients And there are physicians that cannot be achieved by oral delivery of the drug. In our phase one study, we dosed healthy normal subjects for a total of seven days. And the most common adverse effect in the study was hypomagnesemia. And there were not adverse events from the inhaled tacrolimus that were not previously described for the oral form of the drug, suggesting that inhalation is not associated with any unexpected toxicities. In the case of hypomagnesemia, this is a known toxicity of tacrolimus that results when blood levels are too high. With our full data set available, we can now confirm that mild hypomagnesemia occurred in patients with the highest drug levels in the blood. In fact, three of the four subjects that developed hypomagnesemia showed blood tacrolimus levels above 15 nanograms per mil, which in clinical practice would have triggered a dose reduction when the blood levels reached this level. A physician treating a lung transplant patient would lower the prescribed dose if it ever went above a trough level of 15 nanograms per mil so that their blood level would return into the targeted range of 10 to 15 nanograms per mil. Since this is an expected sign of toxicity from Tocrolimus, these study subjects received oral supplementation with magnesium when mild hypomagnesemia was detected. All subjects continued dosing and completed the study with complete resolution of the mild hypomagnesemia during their enrollment period. However, as I stated previously, due to our direct to lung delivery providing a higher level of tacrolimus in the lung, as we move forward, we will be looking to achieve blood levels that are below 10 nanograms per mil. Since no subjects in the study with trough levels below 10 nanograms per mil experienced hypomagnesemia, We believe this is strongly suggested that we will be able to provide significant anti-rejection activity with lower toxicity than the oral form of the drug. In addition to demonstrating enhanced bioavailability, we also showed lower variability in blood levels across all the doses that are inhaled to colomus powder. This is important because it should allow for more precise dosing. We also demonstrated that a once-daily dose of our inhaled tacrolimus can achieve sufficient blood levels for systemic immunosuppression, but with reduced blood concentration spikes, which is typically seen with the administration of high-dose oral tacrolimus and is associated with toxicity. When subjects received inhaled tacrolimus dosing at 2.5 milligrams while fasting or within 30 minutes after a high-fat meal, there were no significant differences in systemic exposure, demonstrating that delivery by inhalation was not associated with food effects in this cohort of subjects. By contrast, the rate and extent of absorption of tacrolimus is significantly decreased when tacrolimus is administered orally when taken with food. and this effect is most pronounced after a high-fat meal. Thus, the once-daily dosing is also an advantage for patients, and when combined with the potential of eliminating food effects, this would mean that a patient would have fewer limitations on their daily activities while maintaining effective immunosuppression levels of tacrolimus. For this reason, we believe that there is potential for the inhaled form of tacrolimus to extend beyond lung transplant patients. We are currently preparing to initiate our Phase II study that is designed to validate our working hypothesis as described above, namely that we can reduce systemic exposures to Crolimus to levels that are safer for the kidney and other organs while maintaining sufficient levels in the lung to prevent rejection. To facilitate this study, we have identified our lead investigator and are preparing the protocol and other regulatory documents so that we can submit for approval to begin dosing lung transplant patients. This phase two study will be performed in lung transplant patients with stable graft function, but who are experiencing significant nephrotoxicity that is severe enough that their physician is planning to reduce their tachromus dose in order to spare their kidneys. As you can imagine, their physicians are concerned that by reducing the blood level of tacrolimus in order to protect the kidney, that the lower levels of tacrolimus in the lung may lead to rejection of the transplanted lung. However, our preclinical and phase one clinical data with the inhaled tacrolimus suggests that the physicians can reduce the systemic blood levels to protect the kidney and at the same time keep enough tacrolimus in the lung to prevent allograft rejection. We and the physicians who will be the key investigators in this study have high hopes that we will prove these benefits from the inhaled tacrolimus in this phase two study. Moving on to our niclosamide program, in the third quarter, we filed a CTA in Canada to begin dosing Healthy Normal volunteers with our inhaled niclosamide powder. The inhaled niclosamide is being developed for the treatment or prevention of COVID infections. A couple weeks ago, we announced that we had received a no objection letter from Health Canada and would be able to proceed with dosing. The site startup work has gone very smoothly, and at the time of this recording, we anticipate the dosing of the first subjects with niclosamide inhalation powder should be completed very soon. The anticipated first dosing in the study and efficient recruitment are encouraging, and we believe that we will complete dosing in early 2022. The niclosamide inhalation powder represents a highly promising approach for COVID and other associated respiratory viruses and, to our knowledge, will be the first dry powder antiviral to progress to clinical trials. Our future studies will position niclosamide for outpatient use so that patients diagnosed with COVID can pick up the drug from a pharmacy and administer it at home. Self-administration would make niclosamide inhalation powder competitive with at-home oral medications. but we also have reason to believe that the local delivery to the lung can provide an even greater benefit to patients. The excitement we carry into this program is based on completion of an in vivo efficacy study where we demonstrated that a low dose of 0.25 milligrams per kilogram dosing of niclosamide inhalation powder resulted in a seven-fold reduction in lung viral load in Syrian hamsters when the treatment with niclosamide was initiated a full 24 hours after inoculation with COVID coronavirus. The initiation of treatment 24 hours after coronavirus inoculation allowed the hamsters to have a very active infection before treatment was initiated. By contrast, molnupiravir showed a reduction in viral lung load in the same hamster model, but only when the drug was administered orally before COVID infections were established in the animals. Molnupiravir has gone on to demonstrate reduced hospitalization rates in COVID-infected humans and was recently granted approval in the UK. Our strong data showing the benefit in the hamster model in animals with more severe infections suggest that niclosamide powder could have a benefit to COVID patients that are either more ill when they initiate therapy or could provide an even greater reduction in the rate of hospitalization for these at-risk patients. It is also of note that in addition to COVID, mycosamide has demonstrated potent activity against the original SARS coronavirus, the MERS coronavirus, RSV, and influenza. This activity derives from targeting cellular processes in the respiratory epithelial cell that are required for viral replication. which indicates that in addition to COVID, our inhaled nicoosamide formulation could be used for other respiratory viral diseases where no suitable therapeutics exist. Finally, in the last quarter, we also announced that we had selected a lead monoclonal antibody, OG3387, as part of our collaboration agreement with Augmenta Bioworks. Importantly, we recently published data showing the dose-dependent reduction in lung viral load when OGG-3387 was delivered directly to the lungs of infected hamsters. These efficacy data in animals represents a critical step in the development of OGG-3387 because all antiviral drugs that proved beneficial in humans to date have demonstrated a viral load reduction in this model. This includes the antibody therapies that to date have proven to be the most effective drugs at reducing the rate of hospitalization for COVID patients. We are excited about the future possibilities for this antibody because stable dry powder created using the TFF process can easily be administered at home instead of requiring the patient to go to an infusion center to receive the antibody. This will be the first dry powder antibody delivered to the lung. Antibodies are well tolerated and an inhaled antibody can provide the efficacy of antibodies without the potential for systemic toxicities that come with the combined oral antiviral regimens. It can also be administered in locations that lack the infrastructure to deliver drugs by slow infusion. Furthermore, the dose reduction that can be achieved by direct pulmonary delivery means that more people can receive the drug for every manufacturing run, making this more economical than infusion. And with that update, I'd like to turn the call over to our Chief Financial Officer, Kirk Coleman, for a review of the financials. Kirk?
spk01: Thank you very much, Dale. For the three months ended September 30th, 2021, research and development expenses for the company were $6.3 million compared to $2.8 million for the same period in 2020. The increase in research and development expenses during 2021 was due to increased manufacturing costs, clinical and preclinical expenses related to niclosamide, TFF-Vory, TFF-TAC, and AUG-3387. along with the increases in payroll-related expenses and stock-based compensation. The increase in research and development expenses also includes our preliminary analysis and testing of dry powder formulations of several drugs and vaccines owned or licensed by third parties that we believe may lead to out-licensing of our TFF technology for the development of dry powder product candidates. General administrative expenses for three months into September 30th, 2021 were $2.4 million compared to 2.3 million in 2020. The company reported a net loss for the third quarter of 8.7 million compared to a net loss of 5.1 million in 2020. Weighted average common shares outstanding, basic and diluted for the three months ended September 30th, 2021 were 25,371,781 compared with 20,867,526 for the same period in 2020. As of September 30th, 2021, we had total assets of approximately 49.3 million and working capital of approximately 45.9 million. At the end of the third quarter, our liquidity included approximately 44.7 million of cash and cash equivalents. And with that, I'd like to turn the call over to Dr. Billy Williams, who will talk about some of the groundbreaking work we're doing using our thin film freezing platform, particularly with large molecule biologics and how our technology is unique in its ability to successfully transform these complex molecules into inhalable dry powder.
spk08: Bill?
spk07: Thank you, Kirk, and good afternoon, everyone. I am pleased to report that we have had a very productive quarter on many fronts for further expanding the thin-film freezing technology platform. Our laboratories have been engaged with many partners' validation projects where we test and confirm how a partner's compound will perform with the thin-film freezing technology to produce an engineered dry powder having the desired properties for its intended route of delivery, such as by inhalation to the lungs, installation in the nasal passageways, or injection after reconstitution. With regards to thin-film freezing, Our studies to date continue to confirm that because the process uses large millimeter-sized drops having a very low surface area to volume ratio, protein stability is preserved because it is not substantially exposed to the air-liquid interface. And this is compared to competing technologies like spray freeze drying that create very small micron-sized droplets generated through a high-pressure two-fluid nozzle that have a much larger surface area to volume ratio, which decreases the stability of protein at this expansive air-liquid interface. This is a significant advantage of thin-film freezing that we continue to leverage in our studies as I will discuss now. I would like to review a few of the programs that focus on application of thin-film freezing to biologics, specifically to monoclonal antibodies and vaccines that contain adjuvants. First, our work has focused on the formulation, stabilization, and delivery of monoclonal antibodies by a variety of routes of administration, including reconstitution for injection and inhalation. Specifically, in collaboration with Augmenta Bioworks, we applied the thin-film freezing technology to formulate and stabilize an inhalable powder of their monoclonal antibody AUG3387, which, as Dr. Christensen just stated, demonstrates a high affinity for the spike protein of the original viral strains that are responsible for COVID-19 and all variants tested to date. This work has resulted in the publication of our preprint paper titled AUG3387, A Human-Derived Monoclonal Antibody Neutralizes SARS-CoV-2 Variant and Reduces Viral Load from Therapeutic Treatment of Hamsters in Devo. In this collaborative preprint paper, co-authored with Augmenta Bioworks, Lovelace Research Institute, the University of California, Berkeley, and TFF Pharmaceuticals, we confirmed successful administration of an inhaled form of a TFF engineered dry powder containing AUG3387. We prepared a dry powder form of the monoclonal antibody by thin film freezing that exhibits excellent powder properties that could be used to deliver the monoclonal antibody directly to the lungs of COVID-infected patients using a dry powder inhaler device. We showed that delivery of a TFF-prepared AUG3387 dry powder into Syrian hamsters 24 hours after intranasal SARS-CoV-2 infection demonstrated a dose-dependent reduction in the lung viral load of the virus. thus supporting its use as an engineered dry powder to treat COVID-19 infection. The AUG3387 monoclonal antibody preprint will be submitted to a peer-reviewed journal very shortly. Furthering our applications of thin-film freezing to monoclonal antibodies, we also published the preprint paper titled Dry Powders for Inhalation Containing Monoclonal Antibodies Made by Thin-Film Freezing. In this second preprint paper, which has also been submitted to a journal for peer review, we report the use of thin-film freezing technology to produce dry powders for delivery of three monoclonal antibodies, including a nonspecific immunoglobulin G or IgG antibody, the specific antibody called anti-program cell death protein or anti-PD1 monoclonal antibody, and anti-tissue necrosis factor alpha or anti-TNF alpha monoclonal antibody. We confirmed that thin-film freezing is suitable for converting the liquid form of these monoclonal antibodies into stable dry powders having excellent properties for inhalation to the lungs. The thin-film freeze-dried anti-PD-1 monoclonal antibody powder is chemically and physically stable when stored at room temperature for up to 10 weeks, indicating that monoclonal antibodies converted from a less stable liquid form to the more stable dry powder form by thin film freezing may not need such cold chain storage. This work on stabilizing and delivery of monoclonal antibodies has contributed to our robust intellectual property portfolio. Next, our efforts have also focused on applying the thin-film freezing technology to different hard-to-formulate and stabilized nano-emulsion-based adjuvants like MF59 and Ativax, which are used to spare doses of different vaccine antigens while boosting a strong immune response. The problem with nano-emulsion-based adjuvants is that they require storage at 2 to 8 degrees centigrade and must not be frozen because unintentional exposure to freezing temperatures can lead to significant damage to the vaccines. We have published the preprint paper titled Formulation of Vaccines Containing MF59 or Ativax by Thin Film Freeze Drying in collaboration with Professor Ted Loss's laboratory at the Center for Vaccines and Immunology at the University of Georgia. MF59 is Novartis' proprietary vaccine adjuvant based on a squalene, oil, and citrate buffer nanoemulsion stabilized with two non-ionic surfactants. Maintaining its specific formulation, composition, and physical properties are critical for MF59 to exert an adjuvant effect. So why is MF59 important for us to study? MF59 is important to study within film freezing technology because it is a commonly used adjuvant in seasonal and pandemic influenza vaccines, including being used in Auden's and influenza A H5N1 monovalent vaccine and in Fluad quadrivalent, an influenza vaccine against influenza virus subtypes A and B. because it enhances the immunogenicity and efficacy of these vaccines. There are many more MF59 adjuvanted vaccines against various other infections currently in clinical trials. Because MF59 adjuvant is not available for commercial purchase, we studied the adjuvant Ativax, which is a preclinical grade nano emulsion vaccine adjuvant with the same composition as MF59. So, in other words, Ativax is a surrogate for MF59 in our studies. As previously mentioned, these clinically important adjuvants are formulated in liquid form as a liquid nanoemulsion. This liquid nanoemulsion contains nanometer-sized oil droplets measuring about 160 nanometers in diameter within a continuous liquid aqueous phase. Liquid emulsions in general, and particularly nanoemulsions, are not physically stable if exposed to freezing temperatures, and they can phase separate. Or in other words, the nanometer-sized oil droplets will coalesce into larger droplets or into a single oil phase, causing the adjuvant to lose its ability to boost the immune response induced by the antigen. In our preprint paper, we applied thin-film freezing technology to vaccines containing MF59 or Ativax as an adjuvant. For example, we applied thin-film freezing to the Fluad quadrivalent influenza virus vaccine that contains MF59, and we applied the thin-film freezing technology to mono-, bi-, and trivalent influenza virus vaccine candidates containing H1, and or H3 recombinant hemagglutinin proteins and Atavax. The results clearly demonstrate that for all MF59 and Atavax adjuvanted vaccines we tested, the thin-film freezing technology successfully converted the liquid form to a more stable dry powder form. For example, the thin-film freeze-dried vaccine powders were not sensitive to repeated freezing and thawing. in contrast to the liquid vaccines. And the chemical integrity and hemagglutination activity of the hemagglutin antigens remained intact when the dry powders were stored at 40 degrees centigrade for up to six weeks, whereas storing the same vaccine in liquid form at 40 degrees centigrade for six weeks led to significant antigen degradation and a reduction of hemagglutination activity. Importantly, we confirmed that using monovalent, bivalent, and trivalent recombinant hemagglutin proteins against H1 and or H3 influenza viruses adjuvanted with Ativax, the thin-film freezing process did not significantly affect the immunogenicity of the antigens in a mouse model, thus pointing to the potential development of a universal dry powder flu vaccine, which may enable their storage, or stockpiling at room temperature. This preprint will be submitted for peer review shortly. And this work has further contributed to our robust intellectual property portfolio. In closing, I thank TFF Pharmaceuticals for their continued support of our technology validation and research studies at the University of Texas at Austin. I acknowledge my colleague, Professor Zhenrong Kui, for his significant contributions to these very important advancements in the Thin Film Freezing platform. Now, I'd like to hand it over to Mr. Chris Cano, Chief Operating Officer and Vice President of Business Development, to update you on TFF Pharmaceuticals' business development activities. Chris?
spk02: Thanks, Bill, and good afternoon, everyone. Thank you for joining us today. The TFF business development team is focused on three key areas of growth for the company. These three key areas are, one, growing the TFF pipeline and our internal development programs, two, our pharma partnering efforts, and three, our government and academic contracting efforts. We continue to make tremendous progress in each of these key areas. For today's call, I will be focusing on our lead collaboration efforts with both our pharma partners and our academic collaborators. TFF continues to be very active in the mRNA space. The number of mRNA projects has significantly increased since our last earnings call, and we are in discussions with other companies to discuss additional mRNA projects. We are working with pharma partners to formulate their proprietary mRNA into a dry powder. For some partners, we are formulating a dry powder for inhalation, delivering the dry powder mRNA deep into the lungs to treat respiratory ailments. For other partners, we are formulating their proprietary mRNA vaccines into a dry powder to form a more stable vaccine that overcomes cold chain storage challenges. The TFF dry powder quickly reconstitutes for injection on site. We have many mRNA projects to discuss. Here are a few examples. First, we'll discuss a vaccine project where we successfully formulated our partner's proprietary mRNA. The TFF dry powder showed very good particle size. polydisparity index, or PDI, and had a very high encapsulation efficiency rate, greater than 95%. We have subsequently sent samples to our partner to run an accelerated stability study, and this study is ongoing. We are also preparing additional samples to send to our partner to run a transfection study. With successful formulation testing completed, and what we expect to be positive in vitro testing and stability testing. Based upon this well-defined path forward, TFF has initiated meaningful licensing discussions with our partner. Another leading mRNA project at TFF is with a top 10 big pharma company, where we are formulating their proprietary mRNA for delivery to the lungs. This project continues to gain momentum as our formulation work is close to completion, and we will be shipping samples to our partner for transvection testing. This partnership continues to grow. Based on the performance and success of the TFF technology on this mRNA project, we are now formulating our partner's monoclonal antibodies, or MAPs, for inhalation, and we are also generating a TFF dry powder for our partner's pressurized meter dose inhalers, or PMDI. The many applications of the TFF technology to different complex biologics is a real game changer. This one project has now turned into three different projects across the portfolio of a big pharma company. They're a leader in the respiratory space. This is an outcome that we are seeing repeat itself often, building on the success of the initial engagement. TFF has many other nucleic acid projects underway, including formulating siRNA, oligonucleotides, plasma DNA, and other RNA molecules into our TFF dry powder. These programs predominantly focus on delivery of the nucleic acid formulated as a dry powder for delivery directly to the lung to treat different respiratory diseases. For our most advanced nucleic acid project, a plasmid DNA, for delivery to the lungs, we successfully formulated our partner's proprietary plasmid DNA. The TFF dry powder showed very good aerosol properties, including very good particle size and lung deposition. Our partner recently shared with us very positive in vitro testing data. where the TFF dry powder performed just as well as the liquid version in knockdown testing in transfected cells. We are currently in discussions with our partner to finalize the protocol for animal testing for our TFF dry powder. TFF has initiated licensing discussions with our partner, and these discussions are ongoing. TFF continues to be very active in the monoclonal antibody space, formulating either MABs or FABs. As in the case with our mRNA portfolio, our number of MAB projects has also increased, and we continue to discuss new projects with companies. As mentioned previously, by both Dale and Bill, we have made very good progress with our partner, Augmenta Bioworks, and we continue to build our expertise in formulating antibodies, utilizing our innovative dry powder technology for delivery of these therapeutics directly to the lung. The TFF dry powder technology is differentiated from other dry powder technologies when it comes to formulating peptides, proteins, and phages. We are currently working with a number of different companies formulating their proprietary peptides, proteins, and phages into our dry powder for delivery to the lung to treat respiratory ailments. The number of TFF vaccine projects continues to grow as well. In our most advanced vaccine project, we successfully formulated our partner's phase three vaccine into our TFF dry powder. The TFF dry powder showed very good particle size and potency. We have recently sent samples to our partner to run an accelerated stability study. The study is ongoing. We also sent additional samples to our partner to run additional potency testing in order to complete the formulation optimization testing. We are looking to engage in licensing discussions at the next time point during the stability study, which is expected to be in about the next two weeks. Next, as an example of the broad application of our thin-film freezing technology, we are working with the partner to develop an oral delivery to improve bioavailability and absorption in the GI. We have successfully formulated our partner's proprietary compound, and the TFF dry powder showed very good dissolution and solubility properties. We finalized the protocol for animal testing of our TFF dry powder, and this study is scheduled to start later this month. TFF has initiated licensing discussions with our partner. TFF's goal is to enter into licensing agreements with each of our pharma partners. These transactions would contain a license to our TFF technology in exchange for an upfront payment, development milestones, commercial milestones, and trailing royalties. A few partners have requested if TFF would enter into a milestone-based licensing agreement where the upfront payment would be paid upon successful animal testing, and or successful stability testing results. These requests are under consideration as each negotiation is unique, but the underlying premise in negotiating these licensing arrangements is to secure and maximize the full value of the TFF technology for the company and its stakeholders. As mentioned on our last call, we have completed the negotiation of a new CRADA with USAMRID. This agreement has been approved by both parties. It is sitting on the commander's desk awaiting signature. Once signed, we are ready to ship our TFF dry powder materials in order to start our animal efficacy study. We continue to make very good progress with our academic partnerships. As Bill previously mentioned, in collaboration with the University of Georgia, We filed a publication a few weeks back on the TFF technology formulating certain adjuvants. These were adjuvants utilized in our mouse immunogenicity study. Also with our partners at UGA, we are expecting to have initial results from our efficacy study in ferrets by month end. This study is being funded by CIVIX, the Collaborative Influenza Vaccine Innovation Center. With the Albert Einstein College of Medicine, we are now moving our VSV program into animal studies while performing stability testing. And with Dr. Drew Weissman at the University of Pennsylvania, we are beginning our initial mRNA formulation work, and we have finalized our protocols for animal testing, which we expect to start later this month. As Glenn stated previously, Dr. Weissman is very supportive of the TFF technology being part of future mRNA formulation work. In summary, the TFF BD team has been making tremendous progress in our partnering efforts. We continue to grow the number of collaborations with pharma partners and with our academic collaborators as we continue to expand the application of our thin-film freezing technology. In closing, I would like to thank our partners at the University of Texas at Austin. With the continuing efforts and support of Dr. Bill Williams and his research team, we continue to expand the applications of the thin-film freezing technology into new and innovative areas of drug delivery. The TFFBD team is focused on closing meaningful licensing transactions by the end of the year. We are very well positioned to meet this objective. and we continue to foster future growth opportunities for both our technology and our company. Thank you for your time today. Enjoy your evening. I will now hand it back over to Glenn.
spk05: Thank you to all the TFF leaders who presented on this call, and congratulations on the progress and success. I trust that we've been able to communicate the outstanding progress TFF is making across all facets of our business. Our hybrid business model of creating shareholder value with our internal portfolio and business development is on track to realize the potential of the company. I do apologize for the length of this call, but we had so much information to share with you, we decided to put it all in here for your consideration, and we'll certainly leave time for questions at the end of this call. Thank you for sticking with us. The TFF board and management fully recognizes that the past few months have been a challenging period for small-cap biotech companies, and shares of TFF Pharmaceuticals have not been immune from this trend. In my view, TFF has not received the recognition for the many significant accomplishments in the business as well as the near-term value creation opportunities. I want to reassure our investors that TFF Pharma remains steadfast and confident and the progress we were making to build value for our shareholders. Over time, we believe both the healthcare-focused institutional and retail investor base based most of their decisions upon the strength of clinical data generated from well-controlled trials in areas of high unmet medical need. We therefore believe that ongoing success with our internal portfolio products will realize that in addition to TFF being a technology platform company, We're also an innovation-driven developer, proprietary therapeutics addressing areas of high medical need. And we expect that more investors will understand TFS dynamic business model and reward us for the progress that we've made and will continue to make both in our proprietary and current and future partner programs. The opportunities for value creation in both the portfolio and partnership arenas are remarkable and growing every week. We look forward to sharing our progress again with you next quarter. As always, we appreciate the support of our investors and partners. Again, thank you for listening. We'll certainly spend a lot of time answering all your questions. And with that, I will turn the call back to the operator and open up the line.
spk09: Thank you. We will now be conducting a question and answer session. If you would like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 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. One moment, please, while we poll for your questions. Our first questions come from the line of Jonathan Ashcroft with Roth Capital Partners. Please proceed with your questions.
spk12: Thank you. Good evening, guys, and congrats on the progress. My first question is for Kirk. Can you help us with the R&D expense trends for 4Q21 and next year, given how it's bounced around quite a bit this year so far?
spk01: Jonathan, I'd be happy to. Leading into this previous quarter, we had a higher amount than normal because of the increased manufacturing for the three clinical trials that are kicking off here in this fourth quarter. I would expect the fourth quarter to remain at around the same levels previously, and then as the clinical trials begin to mature, then that will tail off at that point in next year, after Q1 next year.
spk12: So you're saying that fourth quarter looks lighter, like half of what it was this quarter, in the third quarter?
spk01: I wouldn't say that it would be lighter, but it will start to trend off in the next year for sure. There's going to be three trials going to be running concurrently at the same time.
spk12: Understood, understood. Thank you. That was clear. Can someone please give me an update on the status of the Greenlight Biosciences vaccine collaboration?
spk02: Sure. Thanks, Jonathan. So with Greenlight, we continue to make very good progress. We have received their mRNA. We have formulated their mRNA. We have sent them back samples. And there's testing underway right now at Greenlight. So we are actually continuing discussions and continuing our collaboration. That's about all I can disclose at this time, but we're making very good progress with Greenlight, and we're very excited about our collaboration with Greenlight.
spk12: Thank you. That was fun. Succinct is always appreciated. Can you update us on any noteworthy recent additions to your patent estate? You mentioned the number, about 120, but any ones that are standouts?
spk05: Yeah, so our strategy has been pretty focused on wherever we have new data in a specific technical area or therapeutic compound area, we file very, very broad patents. So, for example, in the areas of mRNA, SRNA, wherever we've made really great progress, especially in the field of biologics, we file pretty broad patents there. And in anything that we've recently developed, learned around method of use and process. In working with those materials, we also have focused, Jonathan, quite a bit on expanding beyond our domestic patent portfolio and expanding those patents across the rest of the world.
spk12: Okay, Glenn. Thank you, guys.
spk05: Thanks, Jonathan.
spk09: Our next questions come from the line of Myank Mamtani with B Reilly Securities. Please proceed with your questions.
spk03: Hey, team. Good afternoon. This is Soho Tasmian from Myank. Thanks for the really comprehensive update. A couple of questions from us. First off, as it relates to niclosamide and the augmented program, can you talk about how you're seeing the value of those programs given, you know, the recent developments from Merck and Pfizer in the antiviral space? Sure.
spk06: Dale, can I ask you to give perspective on that, please?
spk10: Yes. Thank you. And so in terms of, I'll address niclosamide first and foremost, or first in this. And essentially the value for niclosamide as well as the Augmenta is that while Pfizer has been very effective, it also has some PK issues. And so it has to be administered with ritonavir to make it last long enough. And so there are some systemic toxicities that can develop through that two drug combination. So it is, it's not quite as clean as a single drug. The other thing is, and this applies to all the competition for both, you know, the Merck compound, the Pfizer results, is that while they are promising, they are systemically delivered and they, you have to have higher levels. And so there is the possibility of systemic toxicity, whereas We're delivering the drug right directly to the site of infection. We intend to get there early. And if you compare, as I mentioned previously, if you compare the Merck compound to our animal results, we showed that we could infect more or we could treat effectively more severely infected animals. And so we think that there is an opportunity for better efficacy there. And so certainly we don't think that just those results are going to eliminate a market or create problems. The other thing with the niclosamide is that there is a broad spectrum activity. So it has been documented to already work with kill RSV as well as influenza. So the niclosamide product can be a pan-respiratory viral therapeutic in the future.
spk03: Great, thank you. And then as it relates to some of your business development activities, maybe we can start with kind of how do you expect any ongoing discussions or activities, to the best you're able to disclose, to play into anything getting done by the end of the year? And then on a more long-term basis, could you provide a little more color on sort of the size and plans for the interim analysis and the TFF TAC program, and what sort of patient exposure from a sample size or duration perspective might qualify you for sort of a meaningful biopharma transaction?
spk05: Yeah, I'll start with the BD. So, you know, as Chris described, we have a number of partnerships that are wrapping up some data analyses this month. We have term sheets that already assume that we've gotten to the finish line on the work and diligence is being performed. So, look, I'm well aware that it's November 15th and, you know, we are doing everything we can and the partners understand our desire to get to the finish line by the end of the year, and we're hopeful that that will happen. It takes two to get the signatures on the agreement, but all things being equal and getting cooperation from those partners, we still are saying that we think there's a likelihood, reasonably high likelihood, or Chris said confident, that we have the ability to close two meaningful transactions by the end of the year. We have so many things in the funnel that we remain confident that that will be the outcome by the end of the calendar year. As to the TAC program, I'll again turn that over to Dale.
spk10: Sorry, could you please restate the question on TAC?
spk03: Yeah, absolutely. Just wondering kind of the size of the Phase II study, including, you know, the number of patients at the interim analysis you're planning, and what level of patient exposure, sample size, or duration do you think will qualify for sort of a meaningful biopharma transaction at that point?
spk10: Okay. Thank you. So the study as designed – is one that will really set the stage for the phase three. This is a case where we've already gotten feedback from the FDA that a phase three efficacy study demonstrating efficacy would be required. And so the phase two, we're targeting 20 to 25 patients and we are planning on treating for a duration of 28 days where the patients coming in will be on oral medication but already experiencing significant kidney toxicity. And so their physicians are ready to reduce their blood levels of tacrolimus to protect the kidney. And so the idea is Since they're already planned for reduction, they are going to go on to the inhaled therapy with the plan being a lower systemic level would be coupled with a higher maintaining the lung tissue level to prevent rejection. And so they will get bronchoscopy at the start, bronchoscopy at the end, and we can compare the lung levels to the blood levels from oral and then inhaled. And then from the bronchoscopies, we'll also be able to look at biomarkers that are predictive of rejection. And so we'll be able to document that in that study. That will give us the information we need to move on into phase three. So it's about... you know, 20 to 24 patients total and 10 patients will be treated before. And as you can imagine, we're doing this open label because the physicians need to know exactly what the patients are getting in this case. And all the endpoints are very objective.
spk03: Excellent. Thanks a lot. I'll jump back in the queue. Congratulations on all the progress and appreciate you taking our questions. Thank you.
spk09: Thank you. Our next questions come from the line of Michael Oakenwich with Maxim Group. Please proceed with your questions.
spk04: Hey, guys. Thanks for taking the questions. So, I wanted to ask something that relating to the particle size for the proteins you discussed being on the millimeter scale as opposed to the micron scale to provide greater stability. Could you talk about how the thin film freezing platform allows you to maintain proper aerodynamic properties while having that lower service area to volume ratio for the stability?
spk06: Can I ask Dr. Williams to answer that question?
spk07: Yes, certainly. That's a great question. So actually what I was talking about is we get asked often to compare thin film freezing to spray freeze drying. And we have studies ongoing and have had, you know, we've got several papers published on this. And what I was speaking of is the difference between the droplet size that is applied to actually freeze the thin film freezing technology. The droplets are in the millimeter size are quite large, which means there's just not a lot of surface area to, for the protein to diffuse to very low surface area to volume ratio. On the other hand, the liquid droplets for spray freeze drying are in the micron size. So they're very small. And so there's a very high, like, you know, 6,000 times as high, literally, surface area to volume ratio. So that's what I was speaking to, not necessarily to the aerodynamic particle size. Our powder does produce very high aerosolizable powder levels. for the different products that we've been talking about for the proteins. So hopefully that answers your question.
spk04: Yes, it does. Thank you. And then I'd also like to touch on, you mentioned a bit before, you were talking about applying TFF to both PD-1s and TNF-alphas. These are some of the most successful drug classes of all time. So is this something you're looking at, targeting for a new drug for inhalation for lung localized disease, considering the significant toxicity and off-target effects of these drug classes? Or is this more just a proof of concept to show the power and broad applicability of the TFF platform?
spk07: Yeah, great question. And we're doing it for the latter. We are using those as, you know, models that we can learn from. and try to, you know, be able to anticipate every different physical chemical property of different antibodies, different proteins. And so we are using it as a model, not necessarily as something that we are developing internally as a product.
spk04: All right. Thank you very much. And then just one more, and I'll hop back in the queue. So I know... There was previously some discussion as to whether the upcoming Phase IIs could be registration-enabling. It seems like for TAC, now we're looking at a Phase III. How should we be thinking of the path forward for VORI, and what should we look at for the potential timelines to approval?
spk05: Yes, we've always said, actually, Michael, that we were going to need some Phase III data for TAC and lung transplants, so we're hoping that the work we're doing in the phase two program will minimize the amount of patients that we're looking to recruit for the phase three. And again, it won't distract us from starting the process of finding a partner for TecoLimus. And you know, the way we look at the VOI program is that the FDA is never gonna tell you yes or no. It depends on the data. And that's the position we're taking. It's gonna depend on the data. And we're getting input from the rapporteurs in Europe, as well as we're going to get some data information from the FDA about the VORI protocol before we finally start it. So I'll use the same answer that the FDA will give. It depends on the data. And, again, we're hopeful that that will allow us to get into the queue for approval. I believe the trial will end about mid-year to third quarter 2020. next year. Adele, am I correct on that?
spk06: You're correct, Glenn.
spk05: So then normal, either accelerated or normal review at that point. All right. Thank you very much. Thanks, Michael.
spk09: Thank you. Our next questions come from the line of Richard Deutsch with National Securities. Please proceed with your questions.
spk11: Yes, thank you for taking my call and getting me along the way for my PhD presentation today. This is for Dr. Williams. You mentioned that one of the monoclonal antibodies you were working with had stability at, I think I recall, 10 weeks. Was that the limit that it was able to maintain stability or is it still open for ongoing
spk07: stability longer than that and I have one other follow-up yeah so Richard that is still ongoing that was 10 weeks of 40 degrees centigrade which is extremely harsh conditions and we still do have that that that particular antibodies we're still studying it on stability so it can extend quite a bit longer thank you and the other question is can patients on ventilators
spk11: ultimately be expected to be able to use your powder inhalation.
spk07: Dale, I'm going to let you answer that.
spk10: Okay. Thanks, Bill. So currently there is no existing device that is approved by the FDA as, you know, with a device approval to deliver dry powders through a endotracheal tube. So, you know, our intent clinically is to actually treat the patients early before they get to the hospital and before they get intubated so that we're treating them before they would get to that point. Okay. Thank you.
spk05: Okay. With that, I don't see any other questions in the queue. Actually, I do have two pieces of news that came in while we were having this call. Number one, I want to report that we did actually dose the first patient in the glycosamide phase one trial today. So that's a headline. That trial should conclude recruitment and be done very early part of 2022. And we are going to have the second TFF Science Day on the 13th of December. We'll announce the time. I believe right now it's scheduled for 1.30 p.m. Eastern time. with Chris Amick, who is the CEO of Agmenta, and Dr. Carson Schwartz, who will talk about our Voraconazole program. So with that, I would like to thank all of you for participating in this call. Again, I apologize for the length, but we had an awful lot to communicate. I want to wish you all health and a great holiday season. And as you know, I'm always accessible for follow-up. Thank you and good evening.
spk09: This does conclude today's teleconference. We appreciate your participation. You may disconnect your lines at this time. Have a great day.
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