Addex Therapeutics - H1 2024

Transcript

Operator (participant)

Good day, and thank you for standing by. Welcome to the Addex Therapeutics Half Year 2024 Financial Results and Corporate Update conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be the question and answer session. To ask a question during the session, you need to press star one one on your telephone keypad. You will then hear an automated message advising that your hand is raised. To withdraw your question, please press star one one again. To ask a question via the webcast, please access the Ask the Question tab. Dear participants, due to the technical issues today, please use the Download button to download the presentation from the download menu and follow it. Thank you so much. And now I would like to hand over the conference to your speaker today, Tim Dyer. Please go ahead.

Tim Dyer (Board Director and CEO)

Hello, everyone. I would like to thank you all for standing by and attending our Half Year 2024 Financial Results conference call. I'm here with Mikhali Kalinichev, our Head of Translational Science, who will be providing an update on our R&D programs I draw your attention to the press release and the financial statements issued earlier today, which are available on our website. Unfortunately, there has been a technical issue with loading the presentation to the webcast system, so please use the download button in order to download the presentation. We will be indicating slide numbers so that you will be able to follow, hopefully. So on to slide three, the disclaimer slide. I also draw your attention to our disclaimers. We will be making certain forward-looking statements that are based on the knowledge we have today.

I will start this conference call by giving a quick overview of our recent activities and achievements before reviewing them on our pipeline. I will then hand over to Mikhail, who will review in more detail some of our clinical and preclinical programs. I will then speak about the recent launch of Neurosterix before reviewing our half-year 2024 financial results. Following that, we will open the call for Q&A. So moving to slide four, highlights. We launched Neurosterix with a Series A of $63 million, led by Perceptive Advisors. This is an innovative financing transaction that provides us with the resources needed to advance our preclinical portfolio without diluting our shareholders' interest in our clinical-stage assets and partners programs.

As part of the transaction, we received CHF 5 million and a 20% equity interest in Neurosterix, securing the balance sheet and retaining significant upside in the programs for our shareholders. I will speak more about this innovative financing transaction later in the presentation. We have made excellent progress in our GABAB PAM program, and our partner, Indivior, has selected a compound for development in substance use disorders and will now take over operational responsibility for development. As a reminder, under the terms of the agreement, Addex is eligible for payments of up to $330 million on successful achievement of pre-specified regulatory, clinical, and commercial milestones, as well as tiered royalties on the level of net sales from high single digits up to low double digits.

Under the terms of the agreement, we have exercised our right to select an independent compound to advance our own GABA-B PAM program for the treatment of chronic cough. We have some exciting data in cough with our lead compound, which Mikhail will be sharing with you later in our presentation. Janssen Pharmaceuticals discontinued development of ADX71149 in epilepsy. Our partnership remains ongoing, while the full data set from the phase II study as an adjunctive epilepsy treatment is analyzed. Now, moving on to slide five, the pipeline slide. Now for a quick review of our pipeline. As mentioned, our partner, Indivior, has selected a GABAB PAM drug candidate for development in substance use disorders and expects to start IND-enabling studies in the H1 of 2025.

We are advancing an independent GABAB PAM program for chronic cough and expect to start IND-enabling studies in 2025, subject to securing financing. We continue to believe in dipraglurant and are executing our plans to reposition the development for brain injury recovery. Neurosterix has made excellent progress in advancing its pipeline, including starting IND-enabling studies with its M4 PAM program. Now, I will hand over to Mikhail, who will give you some more details about our exciting portfolio.

Mikhail Kalinichev (Head of Translational Science)

Thanks, Tim. Hello, everyone. I will start by speaking about dipraglurant in our plans for development in brain injury recovery. Following termination of the development of dipraglurant in PD lead, we embarked on a detailed evaluation of a number of potential indications of interest for future development. We have completed this exercise and have identified brain injury recovery as an interesting indication for the future development. We believe the differentiated profile of dipraglurant makes it particularly suitable for enhancing the impact of rehabilitation in traumatic brain injury and stroke patients.

Please move to slide seven. There is a large unmet medical need in post-stroke recovery and rehabilitation. Stroke is among the leading causes of chronic, often lifelong, disability as it leads to motor, sensory, cognitive impairment and multiple comorbidities. There are over one hundred million stroke survivors worldwide, and the number is growing at the annual rate of 12 million.

A variety of rehabilitation therapies are used with post-stroke patients, but the recovery is slow and often inadequate. There is an urgent need for pharmacological agents that can facilitate the recovery stimulated by rehabilitation therapies. Slide eight. mGlu5 receptor is a suitable target to address post-stroke recovery, as it is densely expressed in the brain, involved in neuroplasticity, and modulates excitable inhibitory equilibrium. In fact, activation of mGlu5 has been observed in a range of neurological disorders, including stroke, where it plays a role in maladaptive rewiring of the brain following stroke. Inhibition of mGlu5, on the other hand, can facilitate adaptive rewiring of the brain, promoting neuroplasticity and creating of new functional pathways, moving the neural network towards pre-lesion state. Slide nine.

Exciting new evidence recently published in the journal Brain suggests that the negative allosteric modulator of mGlu5, mTEP, administered daily in rats following stroke, results in a sustained and growing improvement in sensorimotor function in comparison to vehicle treatment. Similar improvement in sensorimotor function was observed in animals treated with our mGlu5 NAM, dipraglurant. Please move to slide 10. MRI imaging of the resting state functional connectivity in post-stroke rodents shows that daily administration of mTEP also stimulates intra and interhemispheric connectivity, the brain disrupted by stroke. It is important to note that improvement in brain connectivity after stroke is known to correlate with functional recovery and is observed across species. Slide 11. Dipraglurant is ideally suited to be used in tandem with rehabilitation therapies in post-stroke patients, as it has a fast onset of action and short half-life.

It has shown good tolerability in healthy subjects and in Parkinsonian patients, showing only mild to moderate CNS-related adverse effects. We have a drug product ready and a strong patent position, and believe dipraglurant can become a first-in-class drug to facilitate post-stroke recovery. We can also speculate that dipraglurant-mediated adaptive rewiring and facilitational recovery following brain damage, would also be seen in traumatic brain injury patients. Please move to slide twelve. Let me now switch to our GABAB positive allosteric modulator program, which is partnered with Indivior. The aim of this collaboration is to deliver a better baclofen for substance use disorders. Slide 13.

As a reminder, GABAB receptor activation has been clinically validated in a number of disease areas, including, baclofen, a GABAB allosteric agonist. Baclofen is FDA approved for treatment of spasticity and is widely used off-label to treat numerous diseases, including substance use disorders.

However, baclofen has a short half-life and comes with significant side effects, hampering its wider use. Thus, there is a strong need for better baclofen. We believe this can be achieved with positive allosteric modulators and their differentiated pharmacology, having the efficacy of baclofen, but longer half-life and improved side effect profile. Our partner, Indivior, has selected a GABAB PAM drug candidate for development in substance use disorders, and expects to start IND-enabling studies in H1, 2025. Please move to slide 14. As part of our agreement with Indivior, Addex has exercised its right to select a compound to advance its own independent GABAB PAM program for the treatment of chronic cough. I will now present this exciting opportunity. Slide 15. There is a strong rationale for developing GABAB PAMs for chronic cough.

Chronic cough is a persistent cough that lasts for more than eight weeks and can be caused by a variety of factors, including respiratory infections, asthma, allergies, and acid reflux, but also possibly by overactive cough reflex. There is a large unmet medical need in novel antitussive drugs, as current standards of care are ineffective in 30% of patients, or only moderately effective in up to 60% of patients. In addition, the current treatments carry risks of serious side effects. Slide 16. On the next slide, we show that GABA-B PAMs are likely to have a superior tolerability profile in comparison to the current standards of care, and show no taste-related side effects, as seen with newly approved P2X3 inhibitor, gefapixant. Please move to slide 17.

Support for using GABAB PAM in treatment of chronic cough comes from the clinical evidence that baclofen, a GABAB agonist, is used off-label in cough patients, and from anatomical evidence that GABAB receptors are strongly expressed in airways and in the neuronal pathway regulating cough. Therefore, we believe that GABAB PAMs could offer superior efficacy in cough patients. Slide 11. The pre-IND activities, including in vivo proof of concept, non-GLP tox, and CMC, have been completed, and our clinical candidate has shown favorable efficacy, tolerability, and developability profiles. Our clinical candidate has demonstrated a consistent minimum effective dose of one mg/kg and ED 50 of six mg/kg in cough frequency.

No signs of tolerance were seen after subchronic dosing, and a tenfold safety margin was demonstrated based on tolerability biomarkers. The IND-enabling studies are planned to start in 2025. Slide 19.

The next set of slides describes the in vivo proof-of-concept studies in models of cough. In a model of citric acid-induced cough in guinea pigs, acutely administered compound A delivered a robust antitussive activity cough profile, reducing the cough number and increasing the latency to the first cough. The antitussive profile of baclofen in the same model was more modest, as cough latency remained largely unchanged. Slide 20. In the same experiment, compound A was better tolerated than baclofen, as there were no marked changes in respiratory rate, body temperature, and plasma concentration of growth hormone at up to 16 mg/kg. In contrast, baclofen suppressed respiratory rate, reduced body temperature by nearly two degrees Celsius, and increased growth hormone concentration in plasma, starting at 3 mg/kg dose.

Thus, we believe we achieved our goal to discover a better baclofen for chronic cough. Please move to slide 21.

In a model of citric acid-induced cough in guinea pigs, subchronically administered compound A showed signs of improved efficacy and potency and no signs of tolerance in comparison to an acute treatment. Slide 22. As expected, signs related to safety and tolerability of compound A remained largely unchanged under subchronic versus acute treatment regimens. Slide 23. In the model of ATP-potentiated citric acid cough in guinea pigs, in a head-to-head comparison experiment, acutely administered compound A and the P2X3 inhibitor had similar efficacy and tolerability profiles.

Please move to slide 24. In summary, we have selected a clinical candidate for chronic cough with a robust, reproducible, antitussive efficacy of one mg/kg and a good PK/PD. The compound showed a favorable developability profile in non-GLP tox studies performed in rats, dogs, and non-human primates. We are on track to start IND-enabling studies early H1, 2025.

This concludes our prepared remarks on the progress of our R&D programs. Now I hand it back to Tim.

Tim Dyer (Board Director and CEO)

Thanks, Mikhali. So slide 25. Now, before I move on to the financials, I would like to spend a few moments to speak about the Neurosterix transaction. Slide 26. Due to the excellent progress made by our R&D team in advancing our own partnered preclinical portfolio, our M4 PAM, mGlu7 NAM, and mGlu2 NAM programs reached a stage of development where they needed significant amounts of financing to progress into the clinic. Unfortunately, given the low market capitalization of Addex, raising the amounts of capital needed would have been extremely challenging and highly dilutive to our shareholders. So we decided to spin out these programs and our platform into a new private company and raise the necessary capital directly into a new private company.

We believe this is an excellent transaction for Addex shareholders, as it has secured $5 million for Addex and removed the financing overhang on the Addex stock. We have retained a 20% interest in Neurosterix, so we can benefit from the upside from advancing the programs into the clinic, which is now secured by $63 million of capital from a high-quality investment syndicate led by Perceptive Advisors. As part of the transaction, we have divested our allosteric modulator technology platform, including the majority of our staff. However, we have entered into a service agreement with Neurosterix to ensure that we can access the skills needed to execute on our business strategy. Now moving on to slide 27, financials. Now for a review of our half year and Q2 2024 financials.

Following the Neurosterix transaction, we are, were required under IFRS to identify continuing operations related to our retained business and discontinued operations related to the divested business sold to Neurosterix. All income and expense items related to the discontinuing operations have been reclassed under a specific line of the comprehensive loss called Net Profit of Loss, sorry, Net Profit or Loss from Discontinued Operations. Slide 28. Starting with the income statement, which related to continuing operations, we continue, we recognize $0.1 million of income in Q2 2024, compared to $0.6 million in Q2 2023.

The primary source of revenue is research funding from our collaboration with Indivior, which is recognized that the associated research costs are incurred. Continuing R&D expenses primarily relate to our GABAB PAM program and remain stable at $0.3 million in Q2 compared to Q2 2023.

Continuing operations in G&A expenses primarily relate to corporate development activities and remain stable at $0.7 million in Q2 2024 compared to Q2 2023. The finance result in Q2 2024 is primarily related to foreign exchange losses and, to a lesser extent, to interest income on USD cash deposits. Slide 29. Now to the balance sheet. Our assets are primarily held in cash, and we completed Q2 2024 with CHF 3.8 million of cash held in Swiss francs and US dollars. Other current assets amounted to $0.9 million, primarily relate to prepaid retirement benefit annually paid at the beginning of each year. Due to the Neurosterix transaction, we expect $0.6 million to be reimbursed in the short term.

Current liabilities of $0.9 million as of June 30, 2024, decreased by CHF 1.9 million compared to June 30, 2023, primarily relate to accruals and payables related to clinical research organizations and other outsourced service providers. Non-current liabilities of CHF 0.1 million decreased by CHF 0.5 million compared to December 31, 2023, primarily due to stocks transferred to Neurosterix. Now on to slide 30, sorry. Slide 30. To summarize, I hope you have understood how transformative the Neurosterix deal is for Addex. We've strengthened the balance sheet and secured the financing to execute on the development of our preclinical portfolio, including the very exciting M4 positive allosteric modulator program for schizophrenia.

We've made excellent progress in our GABAB PAM program with our partner, Indivior, selecting a compound for development in substance use disorders, with IND-enabling studies expected to start in the H1 of next year. Dipraglurant is ready to restart clinical development for brain injury recovery, and our independent GABAB PAM cough program has demonstrated excellent preclinical efficacy and tolerability, with IND-enabling studies ready to start. We are validating partnerships with industry, supportive investors, and a strong balance sheet, which puts us on a solid position to deliver on our strategic objectives. This concludes the presentation, and we will now open the call for questions.

Operator (participant)

Thank you. Dear participants, as a reminder, if you wish to ask a question, please press star one one on your telephone keypad and wait for your name to be announced. To withdraw your question, please press star one one again. Alternatively, you can submit your questions via the webcast. Please stand by, we'll compile the Q&A roster. This will take a few moments, and now we're going to take our first question, and it comes from the line of Raghuram Selvaraju from H.C. Wainwright & Co. Your line is open. Please ask your question.

Raghuram Selvaraju (Managing Director and Senior Healthcare Analyst)

Thanks so much for taking my questions, and congratulations on all the progress on so many fronts. Firstly, I wanted to ask if you have some sense of the specific clinical indications in which you expect the chronic cough program to proceed, you know, with highest probability. Clearly, chronic cough is a serious symptomatic hallmark of many different respiratory, pulmonary, and inflammatory diseases. But I wanted to know which ones you consider to be particularly attractive and what we might expect to be the clinical path forward. You know, for example, would you be considering advancement in COPD or sarcoidosis or related indications, please?

Tim Dyer (Board Director and CEO)

We haven't finalized the clinical patient population to aim at. Currently, we are considering refractory and unexplained chronic cough as one possibility, but we are open to the ideas of also aiming at COPD or IPF-related chronic cough. So this is still being discussed.

Raghuram Selvaraju (Managing Director and Senior Healthcare Analyst)

Also, just from a clarificatory standpoint, I wanted to know whether you use the terms MED and ED50 interchangeably or not?

Tim Dyer (Board Director and CEO)

Oh, no. No. MED is minimum effective dose, and ED50 is a dose that reaches 50% of the effect.

Raghuram Selvaraju (Managing Director and Senior Healthcare Analyst)

The confusion stems from the fact that sometimes they use the MED abbreviation to mean median effective dose, which is the same as ED50. But if you use it as minimum effective dose, then that explains how you are using those terms.

Tim Dyer (Board Director and CEO)

Mm-hmm.

Raghuram Selvaraju (Managing Director and Senior Healthcare Analyst)

Also, I wanted to see if you had any commentary regarding what you expect to be the most appropriate comparator or competitor molecules that have historically been tested clinically in chronic cough, that you would look to be the benchmark for, your chronic cough program, you know, in the clinical context?

Mikhail Kalinichev (Head of Translational Science)

We can consider baclofen and lesogavirant. Those two have been tested in the clinic. There are clinical studies, and they are GABAB agonists, so we'd like to achieve similar, if not better, efficacy with improved tolerability. So that will be our aim.

Raghuram Selvaraju (Managing Director and Senior Healthcare Analyst)

But, not camlipixant. Is that correct?

Tim Dyer (Board Director and CEO)

I think clearly we're expecting camlipixant to be standard of care by the time we get, you know, to later stage development. So we will be definitely looking to compare, you know, our compound with camlipixant. Absolutely.

And we aim to achieve efficacy in a broader population of patients. As you know, up to 25% of patients do not respond to camlipixant. And we'll be aiming to have a higher percentage of responders based on the mechanism that we are using.

Raghuram Selvaraju (Managing Director and Senior Healthcare Analyst)

Yeah. And I think probably many of you, the folks listening today, will remember last year's transaction, in which the developer of camlipixant was acquired for $2 billion. So clearly, if you show broader efficacy than camlipixant, you know, that's potentially a very high-value program. Just wanted to ask also about some recent developments in the neurology, neuropsychiatry space that may have applicability to the prospects of the Neurosterix spin-out. In particular, the label that was granted to Cobenfy, formerly known as KarXT, which was developed by Karuna Therapeutics and which subsequently was acquired by Bristol. So I was wondering if there are any takeaways you got from looking at the label for Cobenfy, that may provide more of an opportunity within the schizophrenia context, particularly with regard to the prospects for the M4 positive allosteric modulator.

Tim Dyer (Board Director and CEO)

But we haven't yet had a chance to have a good look through the label, but what we do know is that it's quite a broad label, and therefore, this bodes very well for, you know, other M4 compounds that are gonna come up for regulatory approval.

Raghuram Selvaraju (Managing Director and Senior Healthcare Analyst)

Yeah. And in that context, you, I believe, have also previously indicated that the pharmacophore in question that you folks are working on with regard to M4 modulation is distinct from the emraclidine pharmacophore, is it not?

Tim Dyer (Board Director and CEO)

Yes, correct. It's novel chemistry, completely different from any described M4 chemistry that's out there, whether it's the emraclidine program or any of the other M4 PAM programs that are out there. Our chemistry is different. Yeah.

Raghuram Selvaraju (Managing Director and Senior Healthcare Analyst)

Can you just refresh my memory with respect to when you anticipate the first of the Neurosterix portfolio compounds to potentially complete IND-enabling studies?

Tim Dyer (Board Director and CEO)

Yeah, so we're on track to complete the IND-enabling studies in the middle of next year and rapidly file the IND, so that we can move into phase I in the H2 of 2025.

Raghuram Selvaraju (Managing Director and Senior Healthcare Analyst)

Not sure if you're in a position to speculate at this juncture regarding the prospects for public listing of Neurosterix itself.

Tim Dyer (Board Director and CEO)

I'm certainly not at liberty to talk about the strategy of Neurosterix on this conference call, I'm afraid.

Raghuram Selvaraju (Managing Director and Senior Healthcare Analyst)

Thank you very much for taking my questions. Appreciate it.

Tim Dyer (Board Director and CEO)

Thanks.

Operator (participant)

Thank you. Dear participants, as a reminder, if you wish to ask a question over the phone, please press star one one on your telephone keypad and wait for your name to be announced. Alternatively, you can submit your questions via the webcast. Dear speakers, we'll just give a moment to our participants to press star one one or just to ask the question on the webcast. Just give us a moment. Thank you. Thank you, ladies and gentlemen. This brings the main part of our conference to a close, and I would now like to hand back to Tim Dyer for closing remarks.

Tim Dyer (Board Director and CEO)

Thank you, everyone, for attending our half-year 2024 conference call, and we look forward to speaking to you again soon.