Addex Therapeutics Ltd
Q4 2020 Earnings Call Transcript

Published: 11 Mar 2021

[Operator:]

Ladies and gentlemen, welcome to the Webex Conference of Addex Therapeutics regarding the announcement of the Full Year 2020 Financial Results. At our customer's request this conference will be recorded. As a reminder, all participants will be in a listen-only mode. After the presentation there will be an opportunity to ask questions. I now hand you over to Tim Dyer, who will lead you for this conference. Please go ahead.

[Tim Dyer:]

Hello, everyone. I would like to thank you all for joining our 2020 full year financial results webcast. I am here with Roger Mills, our Chief Medical Officer, and Robert Lutjens, our Head of Discovery Biology. I draw your attention to the disclaimer, we will be making certain forward-looking statements which are based on the knowledge we have today. I will start by giving a quick overview of the company and reviewing our 2020 financial results. I will then hand over to Roger and Robert, who will provide an update on our clinical and preclinical programs.

[Roger Mills:]

Thank you, Tim. Good afternoon to those of you in Europe, and good morning to those in the United States. Together with Robert, I would like to give an update on how dipraglurant and clinical programs for Parkinson's disease levodopa induced dyskinesia, or PD-LID and blepharospasm, as well as an introduction to the epilepsy program being started by our partner, Janssen. The development of LID in PD represents a therapeutic challenge for both patients and their doctors. This is a large underserved market, in need of improved treatment options, and represents a significant commercial opportunity with limited competition. Dipraglurant have an ideal PK profile to treat blood. And the program is supported by strong preclinical data, together with our previous Phase 2 proof-of-concept study, and is underpinned by a mechanism of action. And I'll pass you to Robert to give you more detail.

[Robert Lutjens:]

Thank you, Roger, and hello everyone. This is a rather complex slide describing different neurons motive action. There is a wide body of experimental data pointing to mechanisms underlying LID indications and several lines of evidence, explaining the role of mGlu5 receptors in healthy and diseased brains. I'd be happy to go into the details of the science behind this, but in the interest of time I'll summarize here. This slide shows the main take home messages and why we believe dipraglurant by inhibiting amplify receptors presents a strong rationale for addressing PD-LID. It is factorized by several physiological symptoms of which three are believed to play essential role. Firstly is the D1 receptor priming which direct result of synaptic changes occurring while limpid , and which leads to an abnormal over activation of downstream defectors together called the maladaptive changes. Secondly is excessive glutamatergic transmission, a phenomenon that is indirectly validated by amantadine, reformulated form Gocovri, marketed by Adamas. Indeed, it is believed that the anti dyskinetic effects seen with amantadine and Gocovri comes from its weak inhibition of NMDA, which results in a reduction of glutamatergic transmission.

[Roger Mills:]

Thank you, Robert. Our pivotal clinical program consists of two efficacy and safety studies, together with a 12-month open label safety study. The first pivotal study is our 301 trial, there's a one-to-one randomized placebo-controlled study of 100-milligrams of dipraglurant, taken three times daily in conjunction with the patient's levodopa dose. The study duration is 12-weeks, patients who completes the 12-weeks, the 301 study, then able to roll over into the 12-month open label safety study after ERT study, where all patients who received dipraglurant 100-milligrams three times daily. The 301 study will recruit PD patients with moderate to severe dyskinesia recruited in the United States. You'll recall that we’ve delayed starting the study due to the impact of the COVID-19 pandemic, and the potential risk to patients and the restrictions that were in force across the country. With the changing situation, following the availability of a number of effective vaccines against COVID, we're working together with a clinical study sites under our CRO to start the 301 study in the first-half of this year. The primary endpoints of the 301 study is a unified dyskinesia rating scale, or UDysRS. This scale was developed specifically to address dyskinesia symptoms in Parkinson's patients. It is the scale recommended by the Movement Disorder Society and has regulatory precedent with the FDA approval of Gocovri for PD-LID. Importantly, we have included a number of measures to manage placebo response. These include the use of the UDysRS scale, which is less prone to placebo response and other scales used for dyskinesia. The use of the brief psychosocial therapy adapted for dyskinesia to be used in a screening period of the study, and the requirement for patients to have moderate to severe symptoms both at the screening visit, as well as a study baseline visit. We'll also be using expert reviews of the ratings to ensure quality.

[Robert Lutjens:]

Thank you, Roger. Firstly, it is important to note that blepharospasm is a neuro functional rather than a neurodegenerative disease. Pictures on the right is the brain neuro circuitry involved in the control of muscles responsible for eye blinking and closure. Without going into too much details blepharospasm seems to be the result of an imbalance in the signals within this neural circuitry, leading to an over activation of muscles, specifically involved in the eye blinking reflex. Several of the connections between brain structures of the circuitry are glutamatergic, and neurons and these structures express mGlu5 receptor. So, the hypothesis is that by inhibiting mGlu5, we will reduce the hyper glutamatergic signaling and correct the over activation of the eye muscles observed in blepharospasm. Supporting this hypothesis, we have accumulated robust data and preclinical dystonia models with different neurons. Firstly, in the MPTP-lesioned monkey model, we measured a dose dependent effects on the dystonia component observed in the model. And then secondly, in a genetic rodent model called the tottering mouse model, which shows an early onset generalized dystonia phenotype. Dipraglurant was able to reverse this phenotype. And finally, in two genetic models of dystonia, the DYT1 mouse model and the DYT25 rats model, we demonstrated dipraglurant could restore some central mechanisms in neuronal transmission lost in dystonia. We also have an indication of an anti-dystonic effect of dipraglurant from the Phase 2 clinical trial, with a small number of patients did not allow for a statistical analysis of data. Taken together, our data strongly suggests dipraglurant is effective on some of the core dysfunctions identified with dystonia, possibly common to several forms of dystonia, including blepharospasm.

[Roger Mills:]

Thank you, Robert. We intend to start a Phase 2 feasibility study in BSP with dipraglurant in the first-half of 2021. The study will enroll patients with benign essential BSP, who experienced moderate to severe symptoms prior to their regular doses of botulinum toxin. This will be a single center, double blind, placebo controlled study with approximately 15 patients will be randomized to dipraglurant immediate release 50-milligrams, 100-milligrams on matching placebo, taken over a two day period. Efficacy endpoints will include the computational motor objective rater or CMOR, clinician rating scales and patient reported outcomes. In parallel, we are developing an extended release formulation dipraglurant with the intention of performing a Phase 2 proof-of-concept study in BSP in 2022. Our third clinical program will also be initiated by mid-year 2021. Our partner Janssen, a subsidiary of Johnson & Johnson, is planning to initiate a placebo controlled Phase 2a proof-of-concept clinical trial, or mGlu2 PAM compound, ADX71149 in epilepsy patients in the second quarter of 2021. The epilepsy market is projected to reach $20 billion by 2026, a high proportion of patients are considered to be refractory. And today, combination treatments have shown limited therapeutic benefit. The market leader is Keppra, but there remains a large underserved patient population who are in need of improved treatment options. 149 a positive allosteric modulator the mGlu2 receptor exhibits a true synergy with Keppra. This offering the potential for the first rational combination therapy for epilepsy. There is already extensive preclinical and clinical data for 149, with a previous Phase 1 studies and two Phase 2 studies, the latter in other indications. The synergistic effect with Keppra can be seen in the pharmacoresistant mouse epilepsy model. Over to Robert for this slide.

[Robert Lutjens:]

This is the compelling data obtained by Nance and colleagues and the 6Hz model are highly predictive model of epilepsy, with a combination of ADX71149 and Keppra, and which has been instrumental in the decision taken by Janssen to move this program into epilepsy. The left graph shows how the effects of Keppra is dramatically increased in presence of a low dose of 71149, producing a 35-fold shift in efficacy. The important point here is that one can basically get 30 times smaller dose of Keppra in combination with 71149 to obtain the same anti-epileptic effects. And the right graph shows the result obtained when the paradigm was reversed, where a low dose of Keppra reduces a 14-fold increase in efficacy of a ADX71149. Isobolographic analysis demonstrated the shift in potency is the result of a true synergistic effect of the two compounds, and not a simple pharmacokinetics effect. The important message here is if this translate into patients, this approach can result in a complete change of paradigm, where patients would receive a much smaller dose of Keppra in combination with ADX71149, and achieve high efficacy comparable to that which they would experience with a high dose of Keppra, but potentially without any of the side effects linked to a high dose of Keppra. This novel approach could be the first polypharmacy approach to treat epilepsy. Back to you Roger.

[Roger Mills:]

The Phase 2a clinical trial enroll patients who have partial onset seizures, who have a suboptimal response to Keppra. A 28-day seizure count we established prior to receiving the drug, and patients will be randomized at baseline to either continue on their Keppra dose plus placebo, or to add 50-milligrams of 149 to their Keppra regimen. The primary endpoint will be the time to return to their baseline seizure count. But suddenly we will have two periods, the first is a four week efficacy phase, followed by an eight week maintenance phase for those who do not reach or exceed their baseline 28-days seizure count during the first period of therapy. The advent of COVID in 2020 posed numerous challenges, as a well reacted to contain the spread of the virus to try to limit the mortality and morbidity. It was appropriate for us to pause the start of our dipraglurant clinical program in response. However, with the current availability of a number of effective vaccines, we're now really pleased to be able to start clinical studies, involving three separate indications this year. We feel the 2021 will be a transformative year for Addex, and we look forward to moving forward with these clinical programs. I'll now hand back to Robert, who will provide an update on our preclinical programs.

[Robert Lutjens:]

Let me now share with you an overview of our discovery activities and focus on some exciting progress we have made during year 2020 in the GABAB program. As mentioned by Tim, we're conducting research that is fully funded by our partner in digital, who has repeatedly committed additional support as we announced at the end of last year, totaling now $8.4 million. We have now reached clinical candidate selection stage and aim to identify the molecule that will enter IND enabling studies by H1, 2021. It is important to note that GABAB activation is validated through the use of baclofen or GABAB orthostatic agonist, but as FDA approved for specificity and certain spinal cord injuries. But it's also used off label for several other disorders, including alcohol use disorder. Baclofen is efficacious, but shows dose limiting side effects hampering its wider use. Now, one of the key advantages of a positive allosteric modulator approach compared to an agonist approach is the lack of tolerance observed in a chronic administration paradigm. Let me explain this in more details, because this is very important and provides superiority of a positive allosteric modulator approach. When a receptor gets constantly activated in presence of an agonist, gradual tolerance is observed due mainly through receptor desensitization. Upon on the contrary, because it respects the natural physiological rhythm of receptor activation does not induce tolerance. And we have been able to demonstrate this in our preclinical studies. So this lack of tolerance over the long-term should result in potential advantages in safety and efficacy compared to baclofen. The program is now in clinical candidate selection, and we aim to bring candidates into IND enabling studies in H1, 2022. An important aspect of this collaboration is while Indivior are funding research of Addex, Addex actually has the right to select clinical candidates from the research, and independently develop them in a selection of reserved indications, where we have an exclusivity, including Charcot-Marie-Tooth 1A. CMT1A is a peripheral neuropathy, affecting approximately one in 5,000 people worldwide, and qualifies for orphan drug densification. It is the most common inherited neurological disease, resulting from a duplication of the gene encoding PMP-22, a protein playing a central role in myelination of vaccines. There is currently no drug treatment available for patients. As for addiction, baclofen is used off label and provides some significant validation to the target, as it has demonstrated efficacy in CMT1A patients. And we have demonstrated with a positive allosteric modulator in preclinical models of CMT1A, that we are as effective as baclofen and regularizing the expression of the duplicated PMP-22 gene, and significantly reduce the symptoms observed in the disease. Another important point for our program, the regulatory path is paved by a French company developing a fixed dose combination of baclofen, naltrexone and sorbitol. The combination is not approved, but the FDA has set up a path to NDA submission. And to recap where we currently stand in the program, we have now entered clinical candidate selection stage, with the aim of bringing a clinical candidate into an IND enabling studies in the first-half of 2022. And I'll now hand it over to Tim for his closing remarks.

[Tim Dyer:]

Thanks, Robert. I will now review the milestones. We expect to start the PD-LID Phase 2b/3 study in the coming months and report data in Q4, 2022. Our blepharospasm Phase 2a study should also start this half and report data by the end of this year. The epilepsy Phase 2a proof-of-concept being run by J&J is expected to start in Q2, 2021, and report data in the first-half of 2022. We also expect to deliver clinical candidates in our GABAB PAM program by the end of the year, and start IND enabling studies shortly thereafter. Now, I'd like to conclude our prepared remarks. As you can see, 2021 will be an important year for Addex, with three programs starting clinical studies and one of them reporting data. We have a leading technology platform, which has delivered a deep pipeline of in-house discover proprietary programs, and an experienced team of drug developers capable of driving these programs to their next value inflection points. We have managed to secure significant industry partnerships, which are providing significant funding for two of our programs. We have top tier U.S. investors back in the company and a rich pipeline of news flow in 2021. Thank you for your attention, and we will now open the call for questions.

[Operator:]

Thank you. The first question is from Ram Selvaraju. Your line is now open.

[Unidentified Analyst:]

Hey this is on behalf of Ram. Congrats on the progress. My first question just pertains to the off time indication. So Gocovri picked up this second indication for in February. I know you've missed both primary and secondary objectives in your patient diaries that ---

[Tim Dyer:]

Sorry, we can't really hear you.

[Unidentified Analyst:]

Okay. How about now?

[Tim Dyer:]

Yes, it's much better.

[Unidentified Analyst:]

So, I was interested in the off time secondary objectives. I know Gocovri an indication for the in February. That just make the off time endpoint. Are there more increased importance, and might you take this as an indication in the future?

[Tim Dyer:]

So Roger, would you like to take that question?

[Roger Mills:]

Yes. Sure. So obviously I'm assuming, it was hard to hear. So I'm assuming you're asking about the off time with Gocovri. Yes, we were measuring off time. We actually did see some benefit on that in the Phase 2. So we're measuring in the first obviously include that as assessment in the upcoming 301 study. And we'll see what the if it's positive then certainly we will then look at how best to address that in the second pivotal study that we do. So, that is actually good advantage as being able to do the study sequentially. But we get a benefit. We just don't obviously, with the data or the data as we run through, but we would expect to see a benefit in the upcoming two pivotal studies.

[Unidentified Analyst:]

Okay. Makes sense. And just a second one, everything on the COVID. I know you mentioned you have a COVID appendix in the study protocol for the dipraglurant study. Are you concerned at all about some of the reported neurological impact of in terms of the study population, might you exclude infected patients?

[Roger Mills:]

So, COVID obviously poses a number of challenges in terms of running studies. And we were able to -- the key things in terms of the appendix is actually just helping, it's really to help sites how to manage the study, if there are, say, for example, your patient can't come for a visit, how is that addressed? So, it's really giving guidance to the sites to help them to be able to manage through the pandemic, with the study and study visits. In terms of vaccinations, we're not requiring patients to be vaccinated to enter the study. Obviously, across the United States, there are different criteria for people getting vaccines. Clearly, we would expect PD patients to be at the forefront of other conditions. But we're not requiring vaccination to come into the study. Likewise, however, the patient hasn't been vaccinated is in the study and has the option to get a vaccine, that's really important. Patient should get the vaccine. We don't believe there's no rationale why that would interfere with the treatment for the dyskinesia. So, we clearly allow patients to have -- to be able to get that vaccine during the course of the study. In terms of complications of COVID, patients who developed COVID during the study will be terminated. And the most important thing is the patients to be at their COVID managed and to do so appropriately. So, that will be -- certainly we would patients of the diagnosis of COVID, but then it would be dropped from the study. During the screening period, in terms of prior COVID, which I am assuming you're alluding to patients who do have other neurologic, so clearly of their COVID or any other illness, we'll probably not meet the entry criteria to come into the study.

[Unidentified Analyst:]

Okay. That's a great color. And next, I was wondering about I don't know if you guys have ever done this before, but is it feasible or possible to model how much the levodopa the therapeutic window could be increased with dipraglurant in terms of years of disease, post diagnosis as in the therapeutic window be activated for the duration of all of the PD disease course?

[Roger Mills:]

We've not considered that right now. We've got a -- I think as we -- first, we've not considered that. Secondly, haven't really looked at how that could be done. But thirdly, we're going to run through a program of a couple of efficacy studies here, the large studies in the pivotal program. And we'll understand a lot more about the implications of therapy during that period.

[Unidentified Analyst:]

Okay. Thanks. And then just finally, just wanted to get developmental update on your in-house discovered molecules. Four of which you've mentioned are slated to deliver at the end of the year beginning of 2022 are going to be progressing faster than others as a result of possible partnership deals, or, in response to some of the competitive landscape.

[Tim Dyer:]

Yes, so I'll take that one. So, on the GABAB is a very active program and it's making great progress. The mGlu7 is using ahead just behind, and the CMT program which is part of the GABAB program is actually unpartnered. And the mGlu7 is unpartnered. And the mGlu2, which is also looking to deliver clinical candidates around the end of the year, early 2022 is also unpartnered. And then we've got two early stage programs. And Addex continues to discuss openly with potential partners. And we're not promising anything, but our strategy is very much to be very open in the dialogue with potential partners. And we have a track record for doing partnerships at the sort of the preclinical late lead optimization, early clinical candidate selection phase. So it's certainly something that we continue to work at.

[Unidentified Analyst:]

Okay. Thanks so much for the update, Tim, Roger and Robert. We look forward to the coming year from Addex. Thanks so much.

[Tim Dyer:]

Thank you.

[Operator:]

The next question is from Vakhija of ValuationLAB. Your line is now open.

[Unidentified Analyst:]

Good afternoon, gentlemen. Thank you for the excellent presentation. A few questions, if I may. Just coming back to the PD-LID trial, I was actually expecting that you would include vaccination as a criteria. Why not include vaccination as a criteria for the patients? Because then you could probably limit the exclusion if patients to develop COVID-19.

[Tim Dyer:]

So, Roger, one for you, I think.

[Roger Mills:]

I think we'll find that actually most of the patients coming into the city actually will be vaccinated. The study is running for -- its going to run throughout the year and obviously into next. And we don't know if we put an inclusion criteria of vaccination, we don't know how the vaccinations will roll out. Do we then address that, there's likely to be boost, because it's going to be some booster vaccines, undoubtedly, either at the end of this year or probably into next year. So trying to determine exactly what will unfold like at this point I think is difficult. For example, do you then require them to have a booster and which booster do they get versus other things. One of the things we're doing, obviously, is working very closely with the sites. And the sites are spread across the United States. So they're in different states with different requirements. And I think what we'll find is working with the investigators is that they will try and bring patients in safely for the patients and obviously safely for the integrity of the study. But, I think, if we put a vaccination requirement in now, we could end up excluding a lot of patients, just because of the changing face of the COVID situation.

[Unidentified Analyst:]

Okay. And then I get it that probably across the U.S. might be like a staggered approach, so if there's places where the infection rates are quite high, you would delay the start of the trial sites there and go to those where infection rates are at the moment are low.

[Roger Mills:]

Yes. What we're doing is working very closely with the sites. We've had these protocols ready to go last year. So the protocol itself is sort of well documented for us with the site. So it really the work with the sites has been around the risk of COVID both across the U.S., but also importantly down to not just state level, but actually local level to the sites. So we've really been working very closely, had the continued interaction with the sites such that, we're I think we work with each site to ensure that they get the best start. And it may well be that certain sites start later than other sites, and we start with sites are more comfortable and confident with the COVID situation locally, than perhaps other sites. But, I think what we'll find is the if we look at the countries that have really gone further with the COVID vaccination, but very soon once we get a better spread of people taking actually getting the vaccine, then the COVID situation will dampen considerably. We will have a lot more freedom to operate.

[Unidentified Analyst:]

I hope you can soon start the trials there and that it can be in a safe environment. We've been waiting for this quite long and also for the patients here as well. So good luck with that. Just on the pricing strategy as dipraglurant for a PD-LID versus BSP? Could you maybe give us some feedback on that? How you see that progressing?

[Tim Dyer:]

Yes. So dipraglurant is going to be the immediate release formulation in PD-LID. And in the dystonia indications, including blepharospasm, we'll be using a different formulation. And at the moment, we haven't done any particular sophisticated analysis or modeling for pricing. Many dystonias are orphan drug, and qualify for orphan drug designation. And I mean, PD-LID is currently -- Gocovri is currently priced at $34,000 a year. So, we would expect to be getting similar pricing. But again, we'll be launching dipraglurant probably in about four to five years. So, sometime where the environment will no doubt change.

[Unidentified Analyst:]

Okay. And also probably the dystonias will be the ER formulation, most of them are or all of them?

[Tim Dyer:]

Yes. The dystonias will use the extended release formulation. Absolutely.

[Unidentified Analyst:]

Okay. Then on ADX71149 for epilepsy. What's the patent life? Do you feel there is a room for combination patents for you with Keppra still possible?

[Tim Dyer:]

Yes. So there is an NC patent, which I believe it's through till 2027 without extensions. But there is then a combination with Keppra patent. And that is taking it much longer. And that's a very young patent, 2035 without extensions.

[Unidentified Analyst:]

Okay. Then my final question just on your financials. Your cash burn for this year, what do you expect? And I assume that the G&A is going to decrease that probably more extensively and more to the second-half compared to the first-half?

[Tim Dyer:]

Yes, G&A should come down. We're not guiding cash burn at the moment for this year, because it very much depends on how the studies -- when the studies start and how quickly the sites come on board. And that's very difficult to the moment. What we're guiding is that we have cash through the mid of 2022, on a very conservative basis.

[Unidentified Analyst:]

Okay. Yes, that exclude any partner, so you have a lot of assets that might be parked in the meantime as well?

[Tim Dyer:]

Yes, that exclude any partnership income.

[Unidentified Analyst:]

Okay. Well, thank you for the answering the questions. And I wish you successful 2021 with all the trials going on.

[Tim Dyer:]

Thanks so much.

[Operator:]

As there are no further questions, I hand back to the speakers for the conclusion.

[Tim Dyer:]

Okay. Well, thank you very much, everybody for attending our call. We wish you a very nice day, a very nice evening. And we look forward to the next time we have the opportunity to update you. Good bye, everyone.

[Operator:]

Ladies and gentlemen, thank you for your attendance. This call has been concluded. You may disconnect now.