Developing a Novel Anti-Inflammatory for Patients with Severe Asthma

Severe asthma and chronic obstructive pulmonary disease (COPD) patients generally experience declining lung function for which traditional bronchodilators and steroids are no longer effective. There is significant work in the field to identify add-on therapies that can treat a broad range of respiratory patients, particularly those who do not respond to existing therapies. Robert Clarke, Ph.D., CEO of Kinaset Therapeutics, discusses the candidate that his company is advancing through early-phase clinical trials with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D.

David Alvaro (DA): What can you tell me about the limitations of the standard of care for patients with respiratory diseases?

Robert Clarke (RC): For both asthma and COPD, the standard of care is treatment with bronchodilators and steroids, and many patients are well served by those options. With disease progression, patients experience persistent symptoms and/or reduced lung function and are at risk of recurrent exacerbations that can lead to hospitalization and ultimately significant morbidity..

Eventually, standard of care therapy becomes less effective, and add-on anti-inflammatory therapies are then needed. There is a lot of effort today in developing such treatments to reduce exacerbation rates/hospitalizations, increase lung function, and improve quality of life.

DA: What different approaches are currently being developed across the industry to address the need for add-on therapies in long-term respiratory patients?

RC: Patients diagnosed with severe asthma have benefited from the introduction of parenteral monoclonal antibody therapies. However, such treatments, including Nucala/Fasenra (anti-IL-5) and Dupixent (anti-IL4Rα), are only effective in patients whose disease is dominated by eosinophilic inflammation. Consequently, up to 50% of this population, with non-eosinophilic mediated inflammation, have suffered from the limited availability of safe and effective treatment options. The recently approved parenteral anti-TSLP antibody (Tezspire) has been shown to provide benefit, such as reduced annualized exacerbation rates and lung function improvements, in all severe asthmatic patients regardless of the type of inflammation. In addition, TSLP is known to regulate the signaling of multiple pro-inflammatory cytokines/chemokines implicated in the pathogenesis of asthma, thereby providing evidence that broad anti-inflammatory activity can enable treatment of a much wider patient group.

Similar to TSLP, the JAK/STAT pathway has been implicated in the progression of multiple inflammatory respiratory disorders, including severe asthma. Consequently, there is an ongoing focus on the development of inhaled JAK inhibitors for the treatment of the entire severe asthmatic population.

More specifically, Kinaset is developing KN-002, which has shown to be a potent inhibitor of all JAK family isoforms (JAK1, JAK2, JAK3, and TYK2). Unlike the antibody therapies, KN-002 is delivered via the familiar and non-invasive inhalation route, which is not only preferred by patients but also represents an efficient means of delivering drug directly to the site of inflammation (i.e., the lung) while minimizing plasma exposure, thereby mitigating any potential systemic safety concern. Additionally, KN-002 is a small molecule and is anticipated to benefit from a significantly lower cost of goods, offering the potential for greater product pricing flexibility compared with biological alternatives.

In phase I development, Kinaset has benefited from the ability to leverage the clinical protocols used in earlier phase I studies for other inhaled JAKs to develop pharmacodynamic data and demonstrate safety and initial efficacy. When we move into phase II, which we hopefully will do on the basis of the phase I results, we could end up being the first to take an inhaled JAK inhibitor into advanced development.

DA: Can you tell me a little bit more about the origins of Kinaset Therapeutics and your pan-JAK asset?

RC: When the COVID-19 pandemic struck, I was in a transition phase and looking for a new project. I was considering a couple of options that weren’t really related to the respiratory space, but the pandemic really broadened the awareness of and led to renewed interest in respiratory therapies. I therefore decided to look for something in the respiratory space.

The history of the asset, KN-002, is interesting. It was initially identified and first produced by a small Spanish company looking to develop it as a treatment for rheumatoid arthritis (RA). The Spanish company halted development, due to a reprioritization of its development programs. At that point, aa British inhaled drug delivery company was scouting for novel anti-inflammatories to bring into their pipeline. Their scientists determined that KN-002 would be a good target for respiratory diseases and had the potential to be formulated as a dry powder for delivery via inhalation rather than as an oral or injectable product.

The UK company acquired a license, and researchers there did IND-enabling preclinical work, including tox screens, and also developed a formulation. In 2019, however, they changed its business model and became a contract development and manufacturing organization (CDMO), so it was looking to out-license all of its pipeline programs. I discovered that this respiratory asset was available and also happened to know one of the people at the company who was involved in the development of this particular candidate.

Ultimately, Kinaset was formed by me and two members of the original KN-002 development team t. Because KN-002 was a clinic-ready asset when we in-licensed it, we were able to raise $40 million in Series A funding from Atlas Ventures and 5AM, along with GimV Fund of Belgium, to support taking the asset through phase I and phase II proof-of-concept studies.

At the moment, Kinaset is essentially a virtual company with the original three co-founders as the only current employees developing KN-002. All of the R&D and production work is conducted through partnerships with contract research organizations (CROs) and CDMOs.

DA: I see that the product is a dry powder formulation. Why was that the most sensible dosage form?

RC: For the severe asthma population, a dry powder formulation is what is needed from a commercial perspective. The majority of severe asthma patients use dry powder inhalers (DPIs), and from our market research we know there is a high patient/physician preference for this form, even over other inhaled dosage forms. We did consider delivery via a nebulizer. We know that Theravance, for instance, is developing a Pan-JAK for the treatment of COVID-19 in a nebulized form, but that type of delivery is most appropriate for hospitalized, non-ambulatory patients with more severe conditions.

Severe asthmatics who are ambulatory, however, will definitely prefer a dry powder inhaler that is easy to use, and right now all of our safety/CMC data support the dry powder formulations. It is also the delivery form that we know best, which has practical advantages.

In addition, delivery into the airway and lungs via a dry powder inhaler allows for direct treatment of the area of the body affected by the disease. Furthermore, with our formulation technology, we can control the particle size and the particle size distribution to help ensure minimal systemic exposure by keeping as much of the dose as possible in the airway..

DA: How does your own background in respiratory science support you in your role as CEO of this nearly virtual company?

RC: I’m a scientist first. I’m driven by science, and I want to leverage my scientific background to help patients. Within the company, we don’t currently have a Chief Scientific Officer, but with my background in developing respiratory therapeutics and then aerosol science, coupled with the almost 30 years of experience our chief development officer Frazer Morgan has working in inhaled products for respiratory disease, we are able to provide the scientific insights we need. We are also able to have in-depth, collaborative discussions with our scientific advisors, and that is working really well so far.

While the other side of my job is dedicated to fundraising and managing a board. I still have a lot of time to spend thinking about the science, which is great. It’s obviously something that I love. So, it works as a good fit for me.

DA: What can you tell me about the phase I trial that began in 2021?

RC: The study was started in the summer of 2021, and it is a four-part trial. The first part involved healthy volunteers and was a single-ascending dose trial to establish safety in healthy people. Part two of the study involved steroid-naïve asthmatic patients, or patients who have not progressed to the point where they need steroids as part of their treatment regimens. Patients receive four ascending doses over a 10-day period as a means for further evaluating the safety and tolerability of KN-002, but also providing a first glimpse of its pharmacodynamics (PD). We are hoping to see a reduction in the amount of fractional exhaled nitric oxide (FeNO), which is an indicator of reduction of inflammation of the airway epithelium. At the end of part two, we will hopefully have identified the best doses to use in our future phase II trial. We expect to read out the data in the first half of 2022.

Following that, we will advance into parts three and four of this phase I study, which will run in parallel. Part three will involve a more severe patient population — stable moderate-to-severe asthmatics with both phenotypes, but with the same dosing regimen and end point. Part four will be unique to our JAK program, because it will involve COPD patients. We are not aware of any other studies with JAK inhibitors in COPD patients. In this study, we will obtain some PD and pharmacokinetic (PK) data in that patient population and will be looking at certain biomarkers and other indicators of reduced inflammation. Those latter two parts will read out in the second half of 2022.

DA: How much of a challenge has it been to plan and execute clinical studies for respiratory patients during the pandemic?

RC: It has been quite fortuitous that we are running our trial at a single site in the UK — the Medicines Evaluation Unit (MEU) in Manchester. This 36-bed unit conducts many early-stage asthma and COPD clinical trials and is perfectly sized for what we’re trying to get done. Remarkably, there has been no slowdown whatsoever during the pandemic. Patients saw that participation provided an easy way to stay safe from COVID-19 for the two-week duration of the trial. As a result, we’ve managed to maintain our timelines and haven’t had any significant slowdowns relative to the pandemic affecting clinical enrollment.

DA: Beyond asthma and COPD, do you plan to target other indications?

RC: Right now, reading out our phase I study is important. Once we have that data, we may consider looking at KN-002 as a treatment for COVID-19, given that it unfortunately seems it will eventually become an endemic disease along the lines of seasonal influenza and that there will be a need for therapeutics to treat patients with more severe cases. We are thinking about potential grants and other ways that we might be able to financially support that type of project.

For other indications in the respiratory space with this specific compound, there are considerations. People have thought about JAKs for idiopathic pulmonary fibrosis (IPF) and pulmonary hypertension (PH), but at Kinaset we’re considering in-licensing other assets that might pair up well with KN-002. I think we would be very much focused on something that is a respiratory target. It doesn’t necessarily have to be inhaled, but it most likely will be, given our expertise in this space. Ultimately, we are looking to potentially build a pipeline that will establish Kinaset as a next-generation respiratory therapeutics company.

DA: Assuming that you have great success in the clinical trials with KN-002, what is your plan for commercialization and beyond?

RC: With the $40 million in funding that we raised to get us through the phase II studies, we are in a very nice position. We have had a number of conversations with different people and have generated quite a bit of interest in the phase Ib data that we will soon be reading out. When we start the phase II proof-of-concept study for KN-002, we will need to think about whether to partner with/sell the asset to a larger pharma company or commercialize it in-house. Members of our team have experience with both. If we choose to take it to phase III internally, we will then have to consider whether to do that as a publicly or privately financed company and how we build a pipeline that fits well with KN-002. It is certainly exciting to think of the future.

DA: You mentioned that as a virtual company you rely on CROs and CDMOs. Can you tell me a little bit about those partnerships and the role they play in supporting a virtual company like Kinaset?

RC: We have benefited from the fact that the UK company that originally licensed KN-002, which developed the initial formulation and conducted the preclinical work, has become a CDMO. So, we were able to leverage their infrastructure and experience with the product and the process. That has made things extremely efficient for us. On the clinical side, we work with MEU, an organization that all three cofounders have previously run clinical trials with, so that has also been extremely effective.

I will also add that the device is a capsule-based inhaler that is commercially available from the Italian company Plastiape. Developing devices is complex, and there are a lot of potential regulatory and scientific trip hazards there. Using an off-the-shelf and inexpensive device that has previously been approved has helped streamline our time to the clinic.

We do expect, though, that if we consider a partnership with a big pharma company at phase II, it is likely that that pharma partner would select one of its own devices to marry with our KN-002 formulation. That drug–device combination product would then go through phase III and, eventually, commercialization. We are prepared for such a development because we already know that our formulation works not only with capsule-based devices, but also with blister-based devices — another type of dry powder inhaler.

DA: You mentioned the possibility in the longer term of potentially in-licensing other molecules that might be good fits with KN-002. What are you thinking about along those lines?

RC: I can’t disclose any mechanisms of action, but we are looking at a number of potential new chemical entities that could be interesting and potentially effective treatments in respiratory diseases, including asthma and other indications. There are other rare diseases in the respiratory space that have a lot of unmet need, such as PAH and IPF, as well as acute respiratory distress syndrome (ARDS), in light of COVID-19. Lung cancer is another huge opportunity as we think about what could be done to help patients in need. Kinaset’s advisory board and investors are very supportive about considering such opportunities if any of these possibilities emerges as a great potential product, so due diligence work is being conducted in the first half of 2022.

DA: Is there anything else you’d like to share about the core team and the advisory board and the importance of each to Kinaset’s success?

RC: As I mentioned, the core team comprises three people with a lot of experience and very complementary skill sets. I have a science background and have been a CEO before, so I bring that combination of experience. Our Chief Business Officer Roger Heerman has worked at small to large pharma companies and is very skilled in conducting deals and thinking about deal structures, as well as thinking about how to analyze and identify opportunities of the right scale and value. Our Chief Development Officer Frazer Morgan has decades of experiences and deep knowledge or respiratory therapeutics. He was responsible for the program at the UK company and now leads all of our CMC and clinical/nonclinical efforts as we advance KN-002. That’s a great set of complementary skills to have.

Beyond the core team, we have a clinical advisory board of leaders in severe asthma, which ensures that we are getting the right advice. We also have a number of clinical consultants that help with clinical protocol development and regulatory filings and will also provide support in the analysis of the clinical data once it comes in. A set of CMC consultants provide other needed support. With the emergence and acceptance of online meetings, we’ve been able to really leverage all of the expertise of the people we need.

Robert Clarke, Ph.D

Robert Clarke, Ph.D., is Co-founder and CEO of Kinaset Therapeutics. He previously served as CEO at Pulmatrix Inc. (NASDAQ:PULM), a clinical-stage respiratory drug delivery company. During his tenure, Pulmatrix listed a successful IPO and raised over $140 million to support the company’s development programs. Dr. Clarke holds Board seats at several institutions including EnBiotix, Johns Hopkins University and Boston University College of Engineering. Dr. Clarke earned his Ph.D. in physiology at Johns Hopkins University and completed his post-doctoral training in respiratory biology at Brigham and Women’s Hospital and Harvard University.