PharmaShots Interview: TFF's Dr. Dale Christensen Shares Insight on the Thin Film Freezing Technology

In an interview with PharmaShots, Dr. Dale Christensen, Ph.D., Director of Clinical Development at TFF Pharmaceuticals shared his views on the preliminary data from the P-I trial of inhalable tacrolimus powder formulation for Lung Transplant & its TFF technology

Shots:

TFF has developed an inhalable tacrolimus powder formulation that can be delivered directly to the lung via an inhaler bypassing high systemic exposure
The preliminary data from the P-I trial demonstrated that inhaled tacrolimus powder achieves systemic therapeutic drug levels produced by TFF & showed the same plasma levels compared to oral forms in low doses
The company focuses on lung-directed therapeutics by using its expertise in respiratory medicine and has the ability to transform drugs into an inhalable dry powder formulation that results in efficient & targeted delivery

Tuba: What is Thin Film Freezing or the TFF technology platform?

Dale: Thin Film Freezing technology transforms drugs of all types small molecules, biologics, and combinations, including those with poor solubility into an engineered dry powder composition, that can be more than 95% active drug, for better efficacy, safety, and delivery.

The Thin Film Freezing process involves applying a liquid solution of the active pharmaceutical ingredient and excipients, substances other than the drug that help deliver the medication to your system, over a cooled stainless-steel drum. When the solution contacts the super cold surface, it ?ash freezes, resulting in a frozen thin film. Solvents are removed from the frozen thin film by lyophilization, a process that removes the frozen solvent by passing it directly into a gas, thus leaving behind a dried composition known as a 'Brittle Matrix Powder' These dry powder formulations are room-temperature stable and can be used to deliver the drug via several routes: pulmonary, intranasal, topical, ocular, and parenteral.

The Thin Film Freezing technology was licensed from The University of Texas at Austin, where it was developed by Robert (Bill) Williams, Ph.D., Professor and Division Head of the College of Pharmacy's Molecular Pharmaceutics and Drug Delivery Division and his research team. The technology was originally intended to improve the water solubility of poorly soluble compounds, but it was discovered to have important applications for inhalation delivery, particularly for delivering therapies directly to the lungs without the systemic toxicity frequently associated with oral delivery, while also improving therapy response time.

Tuba: How can Thin Film Freezing be applied to lung transplants? What are the advantages?

Dale: Our initial pipeline focus in lung-directed therapeutics leverages our profound expertise in respiratory medicine, and the ability of our platform to transform drugs into an inhalable dry powder formulation that results in efficient, targeted delivery.

Tacrolimus is currently only administered orally to prevent lung transplant rejection and is limited because only a low concentration makes it to the lung, where it is most needed. High doses of oral tacrolimus are administered to provide sufficient tacrolimus levels in the lungs for a therapeutic effect, and as a result, can cause systemic toxicity that often impacts the kidney.

To address this, TFF has developed an inhalable tacrolimus powder formulation that can be delivered directly to the lung via an inhaler, bypassing high systemic exposure and its associated adverse events while decreasing therapy response time for better efficacy. Direct delivery to the lung means less susceptibility for drug-drug interactions and may provide higher trough concentrations at lower total doses. This delivery method results in lower blood concentrations thus reducing adverse effects on the kidney, pancreas, and other organ systems.

Tuba: Discuss the P-I data of the inhalable formulation of tacrolimus.

Dale: We recently announced preliminary data from our Phase 1 clinical trial demonstrating that inhaled tacrolimus powder achieves systemic therapeutic drug levels. We have completed patient enrollment in our Phase 1 study evaluating inhalable tacrolimus for immunosuppression maintenance in lung transplant patients and anticipate additional safety data in Q3 2021.

The preliminary data show that inhaled tacrolimus produced by Thin Film Freezing is not associated with food effects, whereas oral administration decreases the rate and extent of absorption when taken with food. In the multiple ascending dose phase of the trial, data demonstrate that lower total doses of inhaled tacrolimus can achieve the same plasma levels compared to oral forms.

Single ascending dose evaluation in four cohorts of healthy subjects in a Phase 1 trial provided clinical evidence that inhaled tacrolimus produced by Thin Film Freezing was safe. The drug was well tolerated with no reports of clinically significant drug-associated adverse events, and a single dose provides substantial systemic blood levels that approach those associated with effective immunosuppression in heart, lung, kidney, and liver transplant patients.

Tuba: What are the advantages of TFF technology?

Dale: Thin Film Freezing technology addresses many drug delivery limitations. The technology can be used to improve water solubility and absorption an important drug delivery limitation. Poorly water-soluble drugs comprise approximately one-third of the WHO Essential Drugs List and an estimated 40 percent of all New Chemical Entities. The Thin Film Freezing technology can be used to provide engineered powders with excellent physical properties that facilitate dry powder aerosol administration. The technology can also be used to stabilize biologics, including vaccines, thus making them more commercially viable.

This technology can be used to produce high-potency powders that require minimal inactive ingredients, a benefit to drug development. The Thin Film Freezing platform also has the potential to prevent molecular damage due to temperature, air or water degradation, or damage from shear stress. The TFF process can be used to generate particles with improved solubility that can increase absorption and can produce materials in high yields and is scalable.

Additionally, TFF technology can successfully prepare dry powders of proteins and protein-containing products such as vaccines while maintaining their structure and functional activity, with good aerosol performance properties, and improved thermostability for potential ultra-cold chain-free storage. While other powder formulation techniques require the use of additional substances to improve the solubility of the protein, TFF technology does not rely upon a proprietary or exotic ingredient to increase solubility.

TFF technology has limitless applications across a broad range of molecules, including biologics, with partnership opportunities to create technology-enriched products for better patient outcomes.

Tuba: How will this technology support the stability and safety of future flu vaccines?

Dale: The TFF technology converts a vaccine and other biological products, which are traditionally delivered in liquid form, into powder. The powder state is typically more stable than the liquid state so flu vaccines would be able to be stored at temperatures that would support more widespread distribution and use of vaccines around the world. The safety of drugs formulated using the TFF technology has been tested in early clinical trials that were designed to test the safety of these drugs. These trials proved that the TFF technology can produce safe drugs, and we believe that we can improve vaccines by producing powders that can be delivered worldwide without ultra-cold chain storage requirements.

Furthermore, we are investigating the delivery of vaccines as a dry powder directly to the mucosal surface in the lung and nose. Delivery of vaccines to mucosal surfaces could lead to the development of both the traditional IgG response and an IgA response. The IgA response produces a mucosal antibody that can provide enhanced protection at mucosal surfaces, like the lungs, to neutralize pathogens more rapidly at the site of exposure.

Tuba: Do you think TFF technology could help overcome the logistical issues of current vaccines? How?

Dale: Peptides, proteins, and other biologics, including vaccines, are rapidly growing areas of the biopharma industry, but logistical challenges including the need for ultra-cold chain storage can limit distribution, especially in developing countries and rural America. We see an increasing need for alternative ways of delivering vaccines and other therapies to overcome roadblocks like cold chain storage and distribution a need underscored during the COVID-19 vaccine rollout.

Our Thin Film Freezing technology allows us to develop dry powder formulations that are stable at room temperature even for an extended period and dont require an extreme cold chain. We are continuing to pursue solutions to address COVID-19 and other infectious diseases as a near-term goal through our work with:

UNION Therapeutics to develop a dry powder formulation of niclosamide, an oral therapy that has exhibited potent antiviral activity against SARS-CoV-2
Augmenta Bioworks to develop a monoclonal antibody therapy which has demonstrated binding and neutralization of the SARS-CoV-2 variants including the Delta variant in vitro
University of Georgias Center for Vaccines and Immunology, led by Ted Ross, Ph.D., Professor of Infectious Diseases, to develop universal influenza vaccines for pulmonary delivery

In addition to the above partnerships, we also work with several pharma companies, academic institutions, and the government on applying Thin Film Freezing technology to COVID-19 vaccines and other infections. We are focused on partnering to enable the use of this technology in potential second-and third-generation COVID vaccines. In addition, we believe that Thin Film Freezing will also be applied to many other specific vaccines and platforms.

Tuba: How is a Computationally Optimized Broadly Reactive Antigen (COBRA) approach being applied in the search for a universal flu vaccine?

Dale: The COBRA approach for developing broadly reactive vaccines utilizes multiple rounds of layered consensus building and sequence data from flu surveillance databases to generate influenza vaccine hemagglutinin (HA) immunogens. COBRA HA antigens are capable of eliciting potent, broadly reactive HA-specific antibody responses that can protect against both seasonal and pandemic influenza strains that have undergone genetic drift. The TFF process allows protein vaccines to be more stable and longer-lasting than their liquid counterparts. Our partners at the University of Georgia, led by Dr. Ted Ross, tested the immunogenicity and efficacy of universal TFF HA vaccines and found that effectiveness was retained following the Thin Film Freezing process.

Tuba: How are researchers at the Albert Einstein College of Medicine developing recombinant vesicular stomatitis virus (VSV) vaccines to address SARS-CoV-2?

Dale: We are collaborating with Dr. Kartik Chandran from the Department of Microbiology & Immunology at Albert Einstein College of Medicine to develop a Thin Film Freezing formulation of SARS-CoV-2 specific rVSV to treat COVID-19. They are applying the Thin Film Freezing technology to multiple potential rVSV candidates, having generated more than 60 rVSVs bearing spikes from many virus families to date. rVSVs have allowed the rapid identification and down-selection of therapeutic monoclonal antibodies. Preclinical results show rVSV-SARS2 protects hamsters from SARS-CoV-2 challenge via multiple routes. The next step is to determine if fragile membrane-enveloped VSV particles survive freezing.

Tuba: How can one investigate high biocontainment (BSL-3 and BSL-4) viral pathogens safely and efficiently?

Dale: We exploit the modular nature of viral entry apparatus to genetically and functionally transplant it onto an innocuous virus, vesicular stomatitis virus (VSV).

Tuba: What motivates you to develop dry powder formulations of tacrolimus and vaccines for infectious diseases?

Dale: Today, many drugs intended for lung conditions are only administered orally due to properties that make them ill-suited for direct delivery to the lungs. Administration by the oral route typically results in only about 10% of the drug reaching the lungs, and these drugs may cause unwanted and even deadly side effects when dosed to achieve therapeutic lung levels. We believe that our Thin Film Freezing platform for the first time will allow many of these medications to be formulated into the convenient, direct-to-lung dry powder inhaler format providing delivery of the drug directly to the target site.

Our technology is potentially game-changing with broad applicability to transforming drugs into dry powder formulations that can be delivered via multiple routes. We believe it has high-value opportunities and is partnering with academic, pharma, and government agencies to advance programs across our pipeline.

Dr. Christensen is a Director of Clinical Development at TFF Pharmaceuticals. He has received his B.S. in Chemistry from Utah State University, and a Ph.D. in Organic Chemistry from the University of Utah & was an NIH Postdoctoral Fellow at Texas A&M University. He has published many papers and is an inventor on numerous patents and patent applications in drug discovery.

Image Source: UT Southwestern Medical Center

About Author: Dr. Christensen is a Director of Clinical Development at TFF Pharmaceuticals. He has received his B.S. in Chemistry from Utah State University, and a Ph.D. in Organic Chemistry from the University of Utah & was an NIH Postdoctoral Fellow at Texas A&M University. He has published many papers and is an inventor on numerous patents and patent applications in drug discovery.