There is a significant need for new technologies that enhance the solubility and hence the bioavailability of poorly soluble small molecule drugs. At the same time, parenteral drugs, including vaccines and biologics, pose logistical challenges stemming from the need for storage and handling at low (and often ultra-low) temperatures. To address both of these challenges, TFF Pharmaceuticals has developed a process called Thin Film Freezing (TFF), which produces drugs that are highly soluble and stable in a powder form, for a variety of applications, including delivery to the lung. TFF Pharmaceuticals CEO Glenn Mattes discussed the company and its technology with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D.

David Alvaro (DA): Glenn, can you begin by discussing the increasing solubility challenges of small and large molecule drugs, particularly those targeting the lung, and the opportunity you saw for a new technology to overcome them?

Glenn Mattes (GM): Thin Film Freezing (TFF) addresses a multitude of needs. When I talk about the technology, I often describe it as being ubiquitous, in that it can really help formulate all types of drugs, be they large or small molecule. Most drugs are fairly insoluble in water, an issue that is only growing in significance. As a result, they have to be dosed at a fairly significant level to achieve a therapeutic outcome, and thus there is usually a bit of a compromise around the risk–benefit ratio of efficacy versus safety.

That’s the basic premise. Additionally, some products can’t be formulated at all; if you can convert those chemical compounds into a dry powder, it provides an opportunity to give these drugs directly to the lung, for example. At TFF Pharmaceuticals, we can also develop formulations that can be administered through the nose. We’re even working with the U.S. Department of Defense to formulate different countermeasures for warriors that can be given topically or through the eye.

DA: Can you explain how Thin Film Freezing works and the real advantages that it confers over alternative technologies?

GM: The magic of TFF is that we flash-freeze the chemical compound that we’re working on. Through that flash freezing, we are able to get the compound into the solution. Flash-freezing is able to capture the molecule in a highly active state, so whatever we’re producing is a highly concentrated product. The process allows us to then lyophilize the drug, which gets it into a powder that can be administered to the patient as a powder through the lung, or it can be reconstituted — as in the case of a vaccine — by liquifying it and administering it via injection. But what is critical is that the flash-freezing, without any impact of the environment, be it heat, water, or stress, gives you a very, very pure compound that opens up all sorts of opportunities for reformulation or basic formulation of large and small molecules.

DA: Can you tell me about TFF Pharmaceuticals’ business strategy and how you’re pursuing and developing TFF for internal drug development, as well as external partnerships?

GM: We have a hybrid business model in that we are developing products internally, some of which are basic reformulations utilizing the 505(b)(2) regulatory pathway. Our first lead compound is a TFF version of voriconazole, which is an antifungal. We’re developing that as an inhaled version for the treatment of invasive pulmonary aspergillosis (IPA).

The second compound we’re developing is a TFF version of tacrolimus, which is an immunosuppressive drug that’s given to prevent the rejection of organs after transplant. We’re developing it specifically as a treatment to prevent rejection after lung transplants.

For both of those programs, we’re aiming for them to be at least as effective as the existing compound, but we believe that they will actually be more effective when delivered to the lung and will offer much better adverse event profiles. We’re also doing reformulation work with partners. One is on a product called niclosamide that we’re formulating as both an oral and an inhaled version for COVID-19. The last internal program we’re doing is a series of monoclonal antibodies in partnership with Augmenta Bioworks, the first of which is also a COVID-19 therapeutic.

The second part of our business strategy is to work with pharma partners, academia, and the government. We have over 45 partnerships in place where we exchange material and perform feasibility, in vitro, and in vivo testing. We believe that we’ll be able to include two important transactions a year, with upfront milestones and royalties — hopefully more. We’re currently working with 10 of the top 20 Big Pharma companies on some of their assets.

DA: For the candidates in your internal pipeline, can you expand on where they are in clinical development and what you expect over the shorter term?

GM: For TFF voriconazole, we recently announced the full readout of safety and pharmacokinetic data from the phase Ib study (NCT #04576325) in asthma patients, who are particularly vulnerable to IPA. We are pleased that TFF voriconazole is well tolerated in asthma patients, and data show no drug–drug interactions with bronchodilators, which many of these patients use for their asthma medications. This data supports inclusion of a broader patient population — patients prescribed a bronchodilator and those with hyperreactive airway disease comorbidities — in our planned phase II trial in IPA patients in 2022.

For TFF tacrolimus, results from our phase I study indicate an acceptable safety profile to achieve the appropriate balance of local and systemic concentrations for immunosuppression at the site of lung transplant while not exposing other organs to supra-therapeutic plasma levels that are well known to cause renal damage, and we expect to initiate phase II shortly. We are a clinical-stage company, and we’re making GMP material.

We recently enrolled and dosed the first patient in the phase I trial for niclosamide in Canada, and previous preclinical results showed that TFF niclosamide is able to reduce COVID-19 viral load in vivo, offering both direct delivery to the site of infection in the lung and more convenient outpatient administration compared with the IV administered approved antibody COVID-19 treatments. By the way, our collaboration with Augmenta Bioworks to develop an inhalable monoclonal antibody has been shown to be effective against major variants of COVID-19 in in vitro testing, and we plan to study the omicron variant as well. We recently published positive in vivo data showing that the dry powder formulation of COVID-19 antibody AUG-3387 neutralizes SARS-CoV-2 infection and reduces viral load in a well-accepted preclinical model. We’re excited about the potential of that program and look forward to advancing to clinical testing.

DA: Beyond what you’ve shared about the near term, what can you tell me about what the future holds for TFF and how broad you see the applications and opportunities for the platform?

GM: I mentioned earlier that we see this as not only an effective technology but one that can be ubiquitous. This is actually the first time that it’s been shown that you can develop biologics as powders. One potential example I can give you involves what we’re now seeing with the COVID-19 vaccines. As you know, these are mRNA-based vaccines, so they are very dependent on cold-chain distribution and cold-chain storage. About two-thirds of the costs of these vaccines are tied up in these cold-chain distribution and storage issues. By applying TFF to these vaccines, you can eliminate the need for ultra-cold chain by taking a liquid-based vaccine and creating a powder, which can be used as the vaccine, or it can be reconstituted and would be beneficial for both the developed world and the developing world.

We’re not just working in the COVID-19 space. We’re working on universal flu, VSV-based vaccines, the mRNA space, and the sRNA space. We’re working with different types of monoclonal antibodies, including the programs I mentioned earlier with the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). We really have a huge range of opportunities; the applications and opportunities for this technology are really limitless. Unlike your classic biotech company, where you have one or two shots on goal, the business plan for TFF really sees no end in sight. We can continue to build value for the company and for our shareholders.