TFF Pharmaceuticals: Innovating Pulmonary Drug Delivery with Nobel-Advised Thin Film Freezing Technology

Recently, the highly anticipated list of winners for the 2023 Nobel Prize in Physiology or Medicine was announced, with American scientists Katalin Karikó and Drew Weissman receiving the award. They were honored for their discoveries concerning nucleoside base modifications, which ultimately facilitated the successful development of mRNA vaccines against COVID-19.

The two scientists were not limited to breakthroughs in research achievements; they also made outstanding contributions to the translation of scientific findings and the practical application of technology. Katalin Karikó once served as Vice President and Senior Vice President at BioNTech, strongly driving the company’s mRNA vaccine development.

In 2006, Drew Weissman co-founded RNAX with Katalin Karikó. He also served as a scientific founder for the gene-editing star company Beam Therapeutics and the cell therapy company Capstan Therapeutics. Additionally, he has acted as a scientific advisor to multiple enterprises, including the biopharmaceutical company TFF Pharmaceuticals (TFFP).

TFF Pharmaceuticals was founded in 2018 and is currently headquartered in Austin, Texas, USA. The company specializes in the research and development of novel inhaled formulations for the treatment of pulmonary diseases, aiming to transform drug delivery methods by enabling direct targeting of medications to the site of action, thereby enhancing therapeutic efficacy and safety.

In 2019, TFF Pharmaceuticals successfully completed its initial public offering (IPO) on the NASDAQ in the United States. Through six rounds of financing following the IPO, it raised over $60 million, with investors including the U.S. National Institute of Allergy and Infectious Diseases, Leidos, and Liquid Venture Partners, LLC.

Drew Weissman is a member of the Scientific Advisory Board of TFF Pharmaceuticals. His involvement has advanced the development of TFF Pharmaceuticals’ R&D pipeline.

Many drugs fail to fully reach their therapeutic targets due to poor physicochemical properties, resulting in compromised bioavailability and subsequent adverse effects such as delayed onset of action and suboptimal efficacy.

Liquid and powder formulations are currently the most commonly used dosage forms. Liquid formulations are convenient to administer and can be taken orally or applied topically; however, they often exhibit a high degree of drug dispersion and are influenced by the dispersion medium, resulting in poor chemical stability and a tendency for the drug to degrade and lose efficacy. Furthermore, drugs with poor water solubility often require high-dose administration, which increases the risk of toxicity and side effects associated with liquid formulations.

In 2010, a study by Thorsteinn Loftsson and Marcus E. Brewster showed that, according to the Biopharmaceutics Classification System (BCS), approximately 40% of marketed drugs and about 90% of drugs in development consist of poorly soluble molecules¹. This means that nearly half of all drugs have poor water solubility. Meanwhile, some marketed drugs suffer from issues such as poor solubility, low permeability, rapid metabolism and elimination in vivo, and limited safety and tolerability.

Unlike liquid formulations, powder formulations offer superior stability, versatility, and portability. Furthermore, powders can enhance the aerosol characteristics for pulmonary drug delivery. Consequently, inhalation formulations have become a key research focus for many companies. Inhalation formulations consist of both the drug and the device; one or more active pharmaceutical ingredients are dissolved or dispersed in a suitable medium and delivered to the target site via a specialized administration device in the form of vapor or aerosol, thereby exerting local or systemic therapeutic effects.

To secure a foothold in the field of inhalation therapeutics, TFF Pharmaceuticals (TFFP) pioneered Thin Film Freezing (TFF) technology, focusing on dry powder inhalation formulations. This technology was initially developed by The University of Texas at Austin and later exclusively licensed to TFFP. Currently, TFF technology holds multiple patents in the United States and Europe.

TFF technology is a novel low-temperature technology that can change the delivery methods of small molecules, biologics, and combination drug therapies, allowing drugs to be "safely" delivered to different parts of the body, thereby improving drug efficacy and patient compliance, and reducing side effects.

TFF technology can transform drugs into brittle matrix particles characterized by low bulk density, high surface area, and an amorphous or nanocrystalline form. In this state, the drug maintains its structure, activity, and function, as well as thermal stability and aerosol properties. These brittle matrix particles can be further processed to produce inhalable dry powder formulations.

The development of inhalable dry powder formulations using TFF technology involves the following four steps:

1. Mixing. First, mix the drug with the dissolution formulation. The dissolution formulation includes agents that promote drug dispersion and excipients that facilitate drug delivery to the target site.

2. Freeze-drying. The drug mixture is placed in a low-temperature drum and frozen. Subsequently, the drug formulation transforms into brittle matrix particles that are highly porous, have a large surface area, and exhibit low density.

3. Drying. Sublimate the frozen solvent from the brittle matrix particles to remove it. Finally, pure drug particles can be obtained.

4. Fine processing. The drug particles are further processed to ultimately obtain a dry powder formulation for direct inhalation.

Throughout this process, TFF technology does not introduce heat, shear stress (internal forces), or other forces that could degrade the active pharmaceutical ingredients; instead, it reformulates the drug mixture into a dry powder formulation that is easy to store and stable.

Data published on the TFF Pharmaceuticals website indicates that TFF technology can convert poorly water-soluble drugs into inhalable dry powder formulations comprising over 95% active pharmaceutical ingredient. Furthermore, clinical data from TFF Pharmaceuticals demonstrate that the aerodynamic properties of brittle matrix particles enable approximately 75% of the drug dose to deposit in the target organ. This allows for precise dosing tailored to patient needs, thereby reducing toxic side effects associated with excessive doses. Ultimately, the pharmacokinetic profile and safety of the drug are enhanced.

In addition, TFF technology will transform the transportation and storage of pharmaceuticals. Currently, most drugs require cold-chain transport to maintain their potency, resulting in exorbitantly high transportation and storage costs. By contrast, TFF technology can convert large molecules, small molecules, vaccines, and other therapeutics into dry powder formulations, ensuring that drug potency and structural integrity remain stable at room temperature. Consequently, this will reduce storage and transportation costs and further expand the market reach of these pharmaceutical products.

With the support of TFF’s technology, TFFP has currently developed two primary pipelines: TFF VORI and TFF TAC.

TFF VORI is a next-generation inhaled dry powder formulation of voriconazole under development by TFF Pharmaceuticals, designed for the treatment of pulmonary fungal infections such as invasive pulmonary aspergillosis (IPA).

Voriconazole is a first-line treatment for invasive pulmonary aspergillosis (IPA). However, intravenous or oral administration of voriconazole can cause severe adverse effects in patients, such as visual disturbances, hepatitis, and acute liver failure, which may even lead to death. Therefore, strict control of its dosage is required.

Unlike traditional IPA administration, patients can administer TFF VORI using a dry powder inhaler, which delivers the drug directly to the site of pulmonary infection. During treatment, TFF VORI is administered in small doses per actuation and does not disseminate to other parts of the body, resulting in high bioavailability. Consequently, TFF VORI reduces the risk of systemic dissemination of voriconazole and its associated drug interactions.

Data from the Phase I clinical trial of TFF VOR conducted by TFF Pharmaceuticals indicate that patients who inhaled a 40 mg dose of TFF VOR directly into the lungs twice daily, administered via nebulization of an intravenous solution, achieved clearance of IPA infection after seven days of continuous treatment, with no adverse effects observed.

On July 31 this year, TFF Pharmaceuticals and Uniphar Durbin Ireland Limited, a pharmaceutical and healthcare technology services provider, announced the launch of an Expanded Access Program (EAP). Patients with idiopathic pulmonary arterial hypertension (IPA) in the United States, Australia, the United Kingdom, Canada, and select European countries will also gain access to TFF-VORI treatment. Currently, TFF-VORI is undergoing evaluation in Phase 2 clinical trials.

TFF TAC is a tacrolimus dry powder inhalation formulation under development by TFFP, indicated for immunosuppressive therapy and rejection prophylaxis in lung transplant recipients. Tacrolimus is currently a commonly used immunosuppressant in solid organ transplantation. However, as a potent agent, its long-term use can lead to adverse effects and increase the risk of renal complications and reduced resistance to infection. Therefore, “achieving high efficacy with low-dose tacrolimus” has become an urgent unmet need.

TFF Pharmaceuticals has improved its tacrolimus formulation for administration via a dry powder inhaler. Its developed TFF TAC can be delivered directly to the patients’ lungs. Clinical data show that TFF TAC achieves higher lung deposition compared with oral tacrolimus. This means that lower doses of tacrolimus can yield greater efficacy, thereby reducing the risk of systemic exposure and adverse effects.

Previously, TFF successfully completed single and multiple ascending dose studies in four cohorts of healthy subjects during its Phase I clinical trial. Clinical data from this phase demonstrated that TFF TAC was well tolerated, with no clinically relevant drug-related adverse events observed. Furthermore, low doses of TFF TAC (0.5–1.0 mg) achieved systemic blood concentrations sufficient to effectively suppress immune responses.

Its superior efficacy led to the FDA granting orphan drug designation to TFF TAC in June 2020 for the prevention of lung allograft rejection. Currently, TFF TAC has entered Phase II clinical trials.

In addition to advancing the development of its two pipelines, TFFP has entered into strategic collaborations with pharmaceutical companies, research institutions, government agencies, and CDMOs.

In March 2022, TFF Pharmaceuticals and Catalent entered into a collaboration. Under the agreement, TFF Pharmaceuticals will provide its Thin Film Freezing (TFF) technology to Catalent to facilitate the production of biologic dry powder formulations for inhalation administration, enabling partner companies to access enhanced drug delivery options.

Meanwhile, TFF Pharmaceuticals has entered into a global co-development partnership with Augmenta Bioworks, an immunotherapy R&D company, for the COVID-19 monoclonal antibody therapy AUG-3387. TFF Pharmaceuticals will utilize its TFF technology to formulate AUG-3387 as a dry powder inhalable formulation, enabling direct delivery of the therapeutic agent to patients’ lungs.

Furthermore, in May of this year, TFF Pharmaceuticals entered into a Cooperative Research and Development Agreement (CRADA) with the U.S. National Institute of Environmental Health Sciences (NIEHS). The two parties will collaborate to develop a hyaluronic acid dry powder formulation (TFF-HMW-HA formulation) for the prevention and treatment of respiratory diseases.

TFFP has also entered into a partnership with Leidos, an IT provider in the broader health sector. Under the U.S. Defense Advanced Research Projects Agency’s (DARPA) Personalized Protection Biologics (PPB) program, TFFP will develop next-generation protective biologic systems for military and healthcare personnel, enhancing their protection against chemical and biological (CB) threats.

Inhaled respiratory formulations are the preferred dosage forms for controlling and treating asthma and chronic obstructive pulmonary disease (COPD). In 2020, the Center for Drug Evaluation of the National Medical Products Administration issued the “Guiding Principles for Bioequivalence Studies of Generic Orally Inhaled Products,” formally implementing review policies for generic inhaled formulations in China. With the introduction of these policies and growing patient demand, the inhaled formulation industry is poised to enter an era of accelerated domestic substitution.

However, from the perspective of the competitive landscape of China’s inhaled formulation industry, foreign enterprises have long held a dominant position, limiting the growth space for domestic pharmaceutical companies. According to the report “Special Report on Inhaled Formulations: High Technical Barriers Are About to Be Broken, A Blue Ocean Awaits” published by GF Securities and Hang Seng Bank, foreign companies accounted for 80% of China’s inhaled formulation market in 2018, with international giants such as AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline monopolizing the domestic market for inhaled formulation drugs.

Currently, the major companies in China engaged in the research and development of inhalation formulations include Chia Tai Tianqing, Joincare Pharmaceutical, and Hengrui Medicine. Among them, Chia Tai Tianqing’s respiratory portfolio mainly consists of five products, including Tianqing Sule (tiotropium bromide powder for inhalation, already marketed) and formoterol fumarate powder for inhalation. Joincare Pharmaceutical currently has more than twenty respiratory products in its pipeline, with compound ipratropium bromide solution and levalbuterol inhalation solution having been launched as the first generic versions in China. Hengrui Medicine focuses on an “innovation + generics” strategy in the field of respiratory medications; it boasts a rich pipeline and currently has five drugs under development, including salmeterol/fluticasone powder for inhalation and indacaterol maleate powder for inhalation. Chinese domestic enterprises are continuously stepping up their efforts to break through the monopoly surrounding inhalation formulations.

However, it is evident that the current R&D pipelines of Chinese enterprises are predominantly composed of generic drugs, and the field of inhalation formulations still requires the entry of more companies with strong innovation capabilities. To break through technical R&D barriers and dismantle the monopoly held by foreign pharmaceutical companies, domestic drug manufacturers still have a long and arduous journey ahead.

References:

1. Kalepu S, Nekkanti V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm Sin B. 2015 Sep;5(5):442-53. doi: 10.1016/j.apsb.2015.07.003. Epub 2015 Aug 24. PMID: 26579474; PMCID: PMC4629443.