Abliva’s 2023 Year-End report focuses on the successful enrolment in December for Wave 1 of the phase II ‘FALCON’ study with lead candidate KL1333. Other key milestones include initiating dosing and receiving Fast Track Designation for the programme. BioStock contacted Abliva’s CEO Ellen Donnelly to learn more about the most impactful milestones achieved during the quarter and the recently announced rights issue that aims to support ongoing activities and provide additional runway.

In December 2022, Abliva announced the start of the global, potentially registrational phase II FALCON study with the lead candidate KL1333. KL1333 is being evaluated for the treatment of mitochondrial DNA (mtDNA)-related primary mitochondrial diseases in adult patients suffering from debilitating fatigue and muscle weakness.

The disease disturbs cellular energy conversion and causes severe symptoms such as stroke-like episodes, muscle weakness, and heart failure, but patients report that it is the impact on the quality of life, caused by the overwhelming fatigue and muscle weakness, that is most disruptive to their life. Primary mitochondrial disease has a profound effect on patients as it not only lowers the quality of life, but it also causes reduced mobility and can be fatal.

There are no approved therapies for the treatment of systemic mitochondrial disease, and the competitive landscape is limited, providing opportunities for KL1333. The company states that the potential annual sales for the candidate could be over USD 1 billion.

Progress within the FALCON programme

Q4 2023 was a quarter of significant progress for the FALCON study. Achieving the enrolment target for Wave 1 of the study was a key milestone, further demonstrating the high unmet medical need in primary mitochondrial disease. KL1333 dosing in Wave 1 patients has commenced and data collection is now underway for the interim analysis expected in mid-2024.

Reneo’s failure may set the stage for KL1333

In the interim report, Abliva’s CEO Ellen Donnelly discussed the impact that Reneo Pharmaceutical’s negative results from December might have on Abliva’s programme. Donnelly concluded that the negative readout from Reneo’s pivotal STRIDE study evaluating their drug candidate, mavodelpar, in primary mitochondrial myopathies, presents an opportunity for Abliva. The mechanisms of action of the two drugs and the clinical programmes were very different, and thus the negative outcome of their study is neither predictive of success nor failure with the FALCON study.

A potentially lucrative deal with Owl Therapeutics

In November last year, Abliva announced a licensing and collaboration deal with US-based Owl Therapeutics for the development of NeuroSTAT in Traumatic Brain Injury. The deal includes potential milestone payments of USD 43.65 million. NeuroSTAT has received orphan drug designation in both the US and Europe. In addition, the drug has both Fast Track status and IND approval to start clinical studies in the US. BioStock did an interview with Ellen Donnelly where she discusses the deal. Read it here.

Rights issue to finance the final stage of the FALCON study

Last week, Abliva resolved a fully guaranteed rights issue of SEK 46 million and a directed issue of convertible bonds of SEK 42 million to prepare for the final stage of the FALCON study. The proceeds from both are intended to further support KL1333 (clinical, non-clinical and manufacturing) and provide additional runway for the company.

Comments from the CEO

BioStock talked to Ellen Donnelly to get her thoughts in the latest development and to find out more about Abliva’s goals for 2024.

First and foremost, having released the Q4 report, how would you summarise 2023?

– I think 2023 was an extremely productive and successful year. The primary focus for the team during 2023 was obviously on execution of the FALCON study – from activating sites across the globe to focusing on patient recruitment – and the team delivered all of our communicated milestones, dramatically decreasing the risk in the study. In parallel, the team was working to increase value across the portfolio, announcing NeuroSTAT deal with Owl Therapeutics, enhancing the NV354 programme with a new patent and orphan drug designations in the US and EU, and gaining approval of Fast Track designation for KL1333.

Can you discuss the importance of the milestones reached thus far in the KL1333 programme and the FALCON study?

– The three major milestones achieved in the FALCON study (study initiation, screening completed, Wave 1 recruitment finished) are all important for different reasons. The initiation of a global study in a rare disease is always a challenge, preceded by years of planning and discussions with regulators, ethics boards, hospitals, and sites, and thus we were thrilled to get the study started and quickly expand the footprint across six countries and 18 sites. Once the study is underway, the next risk comes in the identification of patients, as it is very difficult to predict whether the patients you are seeking will be easy to find and willing to participate in clinical research. For this reason, we were extremely happy to see the high level of interest in the study with over 90 patients identified for potential inclusion in the study. Not only did this give us confidence in our ability to recruit the full study, but it also helped support the prevalence of the disease and the potential USD 1 Billion-plus commercial opportunity. Finally, the communication of all Wave 1 patients fully recruited in December was an important milestone as we have now closed the first phase of the programme and will shift our focus to data collection, cleaning and interim readout in the middle of 2024.

How does Abliva plan to address the unmet medical need in primary mitochondrial disease with the KL1333 programme?

– The FALCON study evaluates adult patients (with genetically confirmed mitochondrial DNA mutations) who suffer from extreme fatigue and myopathy. Data from the MitoCohort registry study, the UMDF/FDA Patient Focused Drug Discovery meeting, and peer-reviewed research suggest that not only are these the most burdensome symptoms for patients, but they are also very common, occurring in 70-80 per cent of patients with primary mitochondrial disease. We are evaluating both fatigue and myopathy in the ongoing study, so if both are positive, we would expect to receive approval to treat patients with this profile. Once the drug is approved, we will commercialise KL1333 while working, in parallel, to expand the indication by running additional clinical studies.

In light of Reneo Pharmaceutical’s setback, how do you perceive the competitive landscape and opportunities for KL1333?

– The landscape of therapies being developed for diseases of mitochondrial origin can be divided into two groups – those which get into the brain and target the neurological issues of the disease and those which impact the periphery, including myopathy. KL1333, Reneo’s mavodelpar, and Astella’s bocidelpar target the mitochondria outside of the brain, whereas the drugs like Abliva’s NV354, PTC’s vatiquinone, Khondrion’s sonlicromanol, and Tisento’s zagociguat are all expected to have neurological effects. The failure of mavodelpar, a PPARdelta agonist and the most advanced programme in this area, removed a major competitor from the area, and the lack of efficacy of this drug brings additional questions to the second most advanced program, the Astellas program, as they also have a PPARdelta modulator. With regards to the drugs targeting the brain, this field is less advanced with clinical data limited to small, often open-label, studies in epilepsies, cognition or cerebral blood flow, meaning that all are a few years (or more) away from registrational data. This is all good news for KL1333 as this drug now has the potential to be the first to market, providing a huge opportunity for Abliva and patients with mitochondrial disease. And in this area, like others, there is room for many different drugs, and thus we expect continued growth of the market with the approval of other therapies and the use of multiple treatments for mito patients.

Finally, you are looking to raise a total of 88 MSEK through a rights issue and a directed issue of convertible bonds. Why did you settle for this solution?

– In June 2022 we did a financing round comprised of a directed share issue of SEK 150 million and a rights issue of SEK50M. This financing enabled Wave 1 of the ongoing FALCON study and provided with 24 months of runway. With many of the risks of study start-up of a rare disease trial behind us, we made the decision to raise additional capital now to ensure that we can prepare for Wave 2 of the study while conducting key activities in parallel that will support KL1333 marketing approval after a positive study readout. In addition, we wanted to ensure that we have sufficient runway after the interim readout to allow time for robust discussions with investors and potential partners. The financing was structured as it is, with a preferential rights issue of SEK 46 million and a convertible of SEK 42 million (both dependent upon a favourable EGM vote in March), to both allow our current shareholders to participate in the issue and retain their share in the company, whilst also providing an additional infusion of de-risked capital with a positive, non-futile, readout of the interim analysis. We are thankful to be supported by a strong group of institutional investors and retail shareholders who are as passionate and confident as we are about the potential for KL1333 as a new medicine for patients with primary mitochondrial disease.

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