Addex Therapeutics (SIX Swiss: ADXN) Q4 2020 Earnings Call

0:00 Dear ladies and gentlemen, welcome to the DEX conference of Edex 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. If any participant has difficulties hearing the conference, please press star key followed by zero on your telephone for operator assistance. and now I hand you over to Tim Dyer who will lead you through this conference. Please go ahead.

0:34 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 Lugins, 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. Despite the global pandemic, we have made solid progress in 2020 and now have three clinical stage programs which are all scheduled to start clinical studies in the first half of this year.

1:25 The company was founded based on a leading drug discovery technology platform which is focused on allosteric modulator drug discovery. It is this platform which has generated the deep pipeline of in-house discovered programs focused on unmet medical needs in urology. We have active partnerships with Indivior and Johnson & Johnson, which were entered into at the discovery phase and provide significant validation of our technology platform. These partnerships are providing significant funding for our GABA-B-PAM and epilepsy programs. Under these agreements, we are eligible for more than 400 million in success-based milestones in addition to royalties. We're a Swiss company founded in 2002 with operations in Geneva and San Francisco.

2:12 We're listed on the Swiss Stock Exchange since 2007 and in January last year we successfully listed an American depository share representing six ordinary shares on the NASDAQ capital market. And in January this year we completed our first offering of new shares in the form of ADSs on the NASDAQ and raised $11.5 million in gross proceeds. Now to our pipeline. As mentioned, our pipeline has been discovered in-house from our discovery platform and comprises nine small molecule out-of-state modulator programs, all focused on neurological disorders. In addition to our LEAD program for PD-LID, we are developing a long-acting formulation of Diproglont for dystonia and expect to start a Phase II study in blepharospasm patients using the immediate release formulation in the coming months.

3:02 Our partner Janssen is on track to start a Phase 2 POC study in epilepsy with dosing of patients expected in the second quarter of this year. We have made solid progress in our GABA-B-PAM programme and expect to deliver clinical candidates by the end of 2021 for both Indivio and for our independent CMT1A programme. Our mGluR7-NAM and mGluR2-NAM programmes have also made significant progress and are advancing towards clinical candidate selection phase. I remind you that the MGLA7 NAMM program for PTSD is funded by a Eurostars inner Swiss grant of €4.85 million. Now to the key activities that have driven our 2020 financial results.

3:51 In January last year, we completed one of our long-term objectives, which was the listing of American depository receipts on the NASDAQ capital markets, and this January we completed a small capital increase of 11.5 million through the issue of shares in the form of ADSs. Despite the constraints imposed by COVID-19 situation, we have continued to advance our PD-LID registration program with the completion of several non-clinical activities. We also made good progress in our dystonia program with the preparation of a Phase 2 study with diprachloron for blepharospasm. Our partner Janssen took the decision to advance ADX 71149 into a phase 2 epilepsy study which is expected to start dosing patients in the coming months. We recognized 3.6 million Swiss francs of revenue in 2020 under our funded research partnership with Indivio and in October extended the research term with 2.8 million dollars of additional research funding.

4:49 We have continued to invest in our early stage pipeline and advanced our mGluR2-Nam and mGluR7-Nam programs into late lead optimization during 2020. InnoSwiss awarded us and our academic partner SIB a 600,000 grant to deploy a computational approach to identify novel therapeutic areas for ADX161, a highly selective D1 antagonist. ADX161 is a clinical stage assay which we deprioritized in 2008. Depending on the outcome of the SIB collaboration, we may consider restarting this program. Now I would like to briefly review our financial results. Now on to the income statement, we recognize 3.6 million of revenue from Indivio in 2020 compared to 2.8 million in 2019.

5:38 Revenue is recognized based on the costs incurred and the increase in 2020 is primarily due to the progress of the program to more expensive activities as molecules advance towards clinical candidates. We also recognize 266,000 of revenue under our Eurostainer Swiss grant, which is partially funded out of EMGLU-R7-NAM PTSD program. R&D expenses of 10.4 million are primarily related to Dipraglont PD-LID and blepharospasm programs, and to a lesser extent, our GABA-B-PAM program for addiction and Charcot-Marie-Tooth 1A neuropathy. The reduction in R&D expense is primarily due to us suspending certain clinical activities due to the global pandemic. G&A expenses have increased significantly in 2020, mainly due to costs associated with the listing of American depository shares on the NASDAQ and certain other costs associated with operating as a U.S. listed company. The financial result is an expense primarily due to Lénaic Teyssédou On the liabilities side of the balance sheet, the main item is payables and accruals related to clinical and preclinical research organisations.

7:07 These amounts decreased significantly in 2020 due to the lower clinical related supplier payables at the year end. Contract liabilities and deferred income relates to amounts received from Indivior and Eurostar Inner Swiss which have not yet been recognised as income. Now to the cash flow statement. We started the year with 31.5 million, consumed 15.4 million in our operations and received 3.1 million in research funding from Indivior. We have a paper loss of 0.6 million in forex when US dollar cash balances are converted to Swiss francs for the end of the year financial reporting purposes, resulting in 18.7 million at the end of the year.

7:56 I will now hand over to Roger who will provide an update on our clinical programs.

8:05 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 our different 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. Dipreglorant has an ideal PK profile to treat LID and the program is supported by strong preclinical data together with our previous Phase 2 proof-of-concept study.

9:02 And it is underpinned by a mechanism of action. And I'll pass you to Robert to give you more detail.

9:09 Thank you, Roger, and hello, everyone. This is a rather complex slide describing the progleron's mode of action. There is a wide body of experimental data pointing to mechanisms underlying lead and EE patients. 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 Mglu5 receptors, presents a strong rationale for addressing PD-LID. It is characterized by several physiological symptoms, of which three are believed to play a central role. Firstly, is the D1 receptor priming, which is a direct result of synaptic changes occurring while lived, and which leads to an abnormal overactivation of downstream effectors, together called the maladaptive changes.

10:09 Secondly, is excessive glutamatergic transmission, a phenomenon that is indirectly validated by amantadine, a reformulated form of recovery marketed by Adamas. Indeed, It is believed that the anti-diskinetic effect seen with amantadine in recovery comes from its weak inhibition of an MDA, which results in a reduction of glutamatergic transmission. And thirdly, a process that is believed to be at the basis of bidirectional synaptic plasticity called LTP depotentiation, a mechanism important for signal pruning. This phenomenon is thought to play a crucial role in movement control. Mglu5 receptors are expressed on the post-synaptic side of synapses and modulate glutamatergic transmission, and blocking Mglu5 leads to a decrease of excessive glutamatergic transmission.

11:02 In addition, Mglu5 inhibition stops the maladaptive changes and restores LTP dipotentiation. Diprogluant is a highly potent and selective inhibitor of Mglu5, and thus we strongly believe can efficiently address these key physiological symptoms that play a central role in. Back to you, Roger.

11:26 Thank you, Robin. 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 dipreglorin taken three times daily in conjunction with the patient's levodopa dose. The study duration is 12 weeks. Patients who complete the 12 weeks of the 301 study are then able to roll over into the 12-month open-label safety study, our 302 study, where all patients will receive diprachlorine 100 milligrams three times daily. The 301 study will recruit PD patients with moderate to severe dyskinesia recruited in the United States.

12:19 You'll recall that we 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 the clinical study sites and our CRO to start the 301 study in the first half of this year. The primary endpoint of the 301 study is a unified dyskinesia rating scale or UDIS-RS. 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 GoCoffery, a PD lib.

13:08 Importantly, we have included a number of measures to manage placebo response. These include the use of the UDIS-RS scale, which is less prone to placebo response than other scales used for dyskinesia, the use of the brief psychosocial therapy adapted for dyskinesia to be used in the screening period of the study, and the requirement for patients to have moderate to severe symptoms both at the screening visit as well as the study baseline visit. We'll also be using expert reviews of the ratings to ensure quality. In addition, the 12-week duration study will be expected to mitigate the placebo response. The second clinical program we're initiating this year is our Diplogram Program for Blepharospasm.

13:54 Blepharospasm, or BSP, is a type of dystonia affecting the muscles of the eyelids, which can lead to sustained eyelid closure, resulting in substantial visual disturbance and functional blindness, and can involve other craniofacial muscles in over half of the patients. There are at least 50,000 BSP patients in the US, with about 2,000 new cases The mainstay of treatment is by injecting botulinum toxin, and this is the only treatment approved by the FDA for BSP. With waning benefit or in more severe cases, patients may undergo surgical interventions, often with limited benefit or resulting in poor cosmetic outcomes.

14:40 There is a clear need for improved therapy with an oral therapeutic. I'll ask Robert to summarize preclinical support. for pursuing the program to treat BSP and other dystonias.

14:52 Thank you, Roger. Firstly, it is important to note that blepharospasm is a neurofunctional rather than a neurodegenerative disease. Pictured on the right is the brain neurocircuitry involved in the control of muscles responsible for eye blinking and closure. Without going into too much detail, blepharospasm seems to be the result of an imbalance in the signals within this neurocircuitry leading to an overactivation of muscles specifically involved in the eye blinking reflex. Several of the connections between brain structures of the circuitry are glutamatergic, and neurons in these structures express mGlu5 receptors. So the hypothesis is that by inhibiting mGlu5, we will reduce the hyperglutamatergic signaling and correct the overactivation of the eye muscles observed in blepharosclerosis.

15:42 Supporting this hypothesis, we have accumulated robust data in preclinical dystonia models with Dupregurant. Firstly, in the MPTP lesion monkey model, we measured a dose-dependent effect 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, Dupregurant was able to reverse this phenotype. And finally, in two genetic models of dystonia, the DYT1 mouse model and the DYT25 rat model, we demonstrated that diplogluon could restore some central mechanisms in neuronal transmission lost in dystonia.

16:28 We also have an indication of an anti-dystonic effect of diplogluon from the Phase II clinical trial, but a small number of patients did not allow for a statistical analysis of data. Taken together, our data strongly suggests dipreglurant is effective on some of the core dysfunctions identified for dystonia, possibly common to several forms of dystonia, including blepharospasm. I'll hand it back to Roger for the blepharospasm Phase II study design.

16:59 Thank you, Robin. We intend to start a Phase II feasibility study in BSP with dipreglurant in the first half of 2021. The study will enroll patients with benign essential BSP who experience 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 who will be randomized to dipreglurant, immediate release 50 mg, 100 mg or 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.

17:46 In parallel, we're developing an extended release formulation dipreglurant with the intention of performing a Phase II proof-of-concept study in BSP in 2022. A 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 IIa Proof-of-Concept Clinical Trial or NGlu2-PAM compound, ADX71149, in epilepsy patients in the second quarter of 2021. The epilepsy market is projected to reach $20 billion A high proportion of patients are considered to be refractory, and to date, combination treatments have shown limited therapeutic benefit.

18:42 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 of the Englu2 receptor, exhibits a true synergy with Keppra, thus offering the potential for the first rational combination therapy for epilepsy. There is already extensive preclinical and clinical data for 149 with eight previous phase one studies and two phase two 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.

19:28 This is the compelling data obtained by Janssen colleagues in the 6Hz model, a highly predictive model of epilepsy, with a combination of ADX 71149 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 effect of Levitiracetam or 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 give 30 times a dose of Keppra in combination with 71149 to obtain the same antiepileptic effect. And the right graph shows the result obtained when the paradigm was reversed, where a low dose of Keppra induces a 14-fold increase in efficacy of ADX 71149.

20:21 Isobullographic analysis demonstrates a shift in potency is the result of a true synergistic effect of the two compounds and not a simple pharmacokinetic effect. The important message here is if this translates into patients, this approach could result in a complete change of paradigm where patients would receive a much smaller dose of Kefron in combination with ADXM149 and achieve high efficacy comparable to that The Phase IIa clinical trial will enroll patients with partial onset seizures who have a suboptimal response to Keppra. A 28-day seizure count will be established prior to receiving the drug

21:19 and patients will be randomized at baseline to either continue on their CAPRA dose plus placebo or to add 50 milligrams of 149 to their CAPRA regimen. The primary endpoint will be the time to return to their baseline seizure count. The study 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-day seizure count The advent of COVID in 2020 posed numerous challenges as the world 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 difficult and clinical program in response.

22:09 However, with the current availability of a number of effective vaccines, we're now really pleased to be able to start clinical studies Let me now share with you an overview of our discovery activities and focus on some exciting progress we have made during the year 2020 in the GARV program.

22:41 As mentioned by Tim, we are conducting research that is fully funded by a partner, Indivio, 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 molecules that will enter IND-enabling studies by H1 2021. It is important to note that GRIB activation is validated through the use of baclofen, Agarva B. Orthosteric Agonist that is FDA approved for spasticity and certain spinal cord injuries but is also used off-label for several other disorders including alcohol use disorder. Aclofen is efficacious but shows dose-limiting side effects hampering its wider use.

23:29 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 to receptor desensitization. A PAM, 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 study. So this lack of tolerance over the long term should result in potential advantages in safety and efficacy compared to baclofen.

24:19 The program is now in clinical candidate selection and we aim to bring candidates into IND enabling studies in H1 2022. One important aspect of this collaboration is while in the view of funding research at ADDx, ADDx actually has the right to select clinical candidates from the research and independently developed them in a selection of reserved indications where we have an exclusivity, including for Ashako-Maritus 1A. CMT1A is a peripheral neuropathy affecting approximately 1 in 5,000 people worldwide and qualifies for orphan drug dosification. It is the most common inherited neurological disease, resulting from a duplication of the gene encoding PMP22, a protein playing a central role in myelination of axons.

25:16 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 GABA-B positive out-of-state modulator in preclinical models of CMT1A that we are as effective as Baclofen in regularizing the expression of the duplicated PMP22 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.

26:02 The combination is not approved, but the FDA has set out the 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 IND enabling studies in the first half of 2022. And I'll now hand it over to Tim for his closing remarks.

26:29 Thanks Robert. I will now review the milestones. We expect to start the PD-LID Phase 2b3 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 GABA-B 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 ADHECS with three programs starting clinical studies and one of them reporting data.

27:20 We have a leading technology platform which has delivered a deep pipeline of in-house discovered 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 US investors backing 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. Thank you. So if you have a question for our speakers, please dial 0 and 1 on your telephone keypad now to enter the queue. Once the name has been announced, you can ask the question. If you find your question is answered before it is your turn to speak, you can dial 0 and 2 to answer your question. If you are using speaker equipment today, please lift the handset before making your selection. One moment please for the first question.

28:23 The first question is from Ron Sabaraciu. Your line is now open.

28:30 Ron Sabaraciu. Ron Sabaraciu. Ron Sabaraciu. Ron Sabaraciu. Ron Sabaraciu. Ron Sabaraciu. How about now?

28:55 Yeah, it's much better.

29:03 Okay, so I was just interested in the off-time secondary objectives. I know Gacobri picked up an indication for the episodes back in February. Does this make the off-time end point of a more increased importance, and might you seek this as an invitation in the future?

29:31 So, Roger, would you like to take that question?

29:35 Yeah, sure. Sorry. Apologies. I assume it was hard to hear. So I'm assuming you're asking about the off-time with Carburetor. Yeah, we're measuring off time. We actually did see some benefit on that in the Phase 2. So we'll measure it in the first, obviously include that as an assessment in the upcoming 301 study. We'll see what the data unfolds from there. 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 an advantage of us being able to do the study sequentially.

30:25 We don't see a benefit, we just don't. Obviously, with the data as we run through, we would expect to see a benefit in the upcoming two pivotal studies.

30:39 Okay, that makes sense. And just the second one, pivoting on COVID, I know you mentioned you have a COVID appendix in the study protocol for the Prodoran study. Are you concerned at all about some of the reported neurological impacts of SARS-CoV-2 in terms of the study population? Might you exclude infected patients?

31:06 So... COVID obviously poses a number of challenges in terms of running studies. And one of 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, a patient can't come for a visit, how is that addressed? So it's really giving guidance to the sites to help them 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 come into the study. Obviously, across the United States, there are differing criteria for people getting vaccines. Clearly, we would expect PD patients to be Lénaic Teyssédou, Mikhail Kalinichev Lénaic Teyssédou Patients at the diagnosis

32:59 of COVID would then be dropped from the study. During the screening period, in terms of prior COVID, which I'm assuming you're alluding to, patients who do have other neurologic sequelae of their COVID or any other illness, would probably not meet the entry criteria to come into the study.

33:28 Okay, that's great, Tyler. 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 therapeutic window could be increased with diplogram in terms of, you know, years of disease post-diagnosis? As in, could the therapeutic window be activated for the duration of all of the TB disease course?

34:00 We've not considered that right now. I think first we've not considered that. Secondly, we 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, large studies in the pivotal program, and we'll understand a lot more about the implications of therapy during that period.

34:32 Okay, thanks. And then just finally, just wanted to get a developmental update on your in-house discovered molecules, four of which you've mentioned are slated to deliver candidates at the end of the year, beginning of 2022. Are any of you progressing faster than others as a result of possible partnership deals or, you know, in response to some of the competitive landscape?

34:58 Yeah, so I'll take that one. The GABA-B is a very active program and it's making great progress. The MGOR-7 is moving ahead, just behind. The CMT program, which is part of the GABA-B program, is actually unpartnered. The MGOR-7 is unpartnered. The MGOR-2, 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. Adex continues to discuss openly with potential partners.

35:45 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 preclinical, late lead optimization, early clinical cancer selection phase. So it's certainly something that we continue to work at.

36:09 Okay. Thanks so much for the update, Tim, Roger and Robert. We look forward to the coming year from edX.

36:17 Thanks so much. Thank you. As a reminder, if you would like to ask a question, please press 0 and 1. The next question is from Bob Truder of Evaluation Lab. Your line is now open.

36:41 Good afternoon, gentlemen. Thank you for the excellent presentation. A few questions, if I may. Just coming back to the PD-LIFT 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 exclusions if patients do develop COVID-19.

37:10 So, Roger, one for you, I think.

37:14 I think we'll find that actually Most of the patients coming into the study actually will be vaccinated. The study is 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 the likelihood of boosters? There's going to be some booster vaccines. Lénaic Teyssédou 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 require 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

38:45 situation.

38:47 Okay. And then I gather that probably across the US, it might be like a staggered approach. So if there's places where the infection rates are quite high, you would delay start of the trial sites there and go into those where the infection rates at the moment are low.

39:10 Yes, what we're doing is working very closely with the sites. We've had this protocol, we were ready to go last year, so the protocol itself is well documented for us with the sites. So really the work with the sites has been around the risk of COVID, both across the US, 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 a continued interaction with the sites such that 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 who are more comfortable and confident with the COVID situation locally than perhaps other sites are.

40:07 I hope you can soon start the trials there and that it can be in a safe environment to

40:37 You've been waiting for this quite long and also for the patients there as well. So good luck with that. Just on the pricing strategy of Dipragluron for PD-Lid versus BSP, could you maybe give some feedback on that, how you see that progressing?

40:58 Yes, so Dipragluron 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. At the moment, we haven't done any particular sophisticated analysis or modeling for pricing. Many dystonias are orphan drug, qualified for orphan drug designation. And, I mean, PD-LID is Lénaic Teyssédou, Lénaic Teyssédou, Mikhail Kalinichev Yeah, yeah, the dystonias will use the extended release formulation,

42:11 absolutely. Okay. Then on ADX 71149 for epilepsy, what's the patent life? And do you see also room for combination patents, for instance, with Kepper or so possible?

42:27 Yeah, so there is an NC patent, which is... 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. I mean, that's a very young patent. 2035. Yeah, 2035. 2035. Yeah, without extensions.

42:56 Okay. And then a final question, just on the financials, your cash print for this year, what do you expect? and I assume that the G&A is going to decrease and that probably more to the second half compared to the first half.

43:13 Yeah, 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 at the moment. What we're guiding is that we have cash through the mid of 2022 on a very conservative basis.

43:44 Okay. Yeah, that excludes any partners. You have a lot of assets that might be partnered in the meantime as well.

43:49 Yeah, that excludes any partnership income, yeah.

43:54 Okay, well, thank you for answering the questions, and I wish you a successful 2021 with all the trials going on.

44:01 Thanks very much. As there are no further questions, I am back to the speakers for the conclusion.

44:11 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. Goodbye everyone. Ladies and gentlemen, thank you for your attendance. This call has been concluded. You may disconnect now.