Oryzon Genomics — Awaiting for eventful 2019

Oryzon was founded in 2000 by the CSO Tamara Maes and the CEO Carlos Buesa. It develops epigenetics-based therapeutics for patients with cancer and neurodegenerative disorders. Oryzon has two products in the clinical stage and an active preclinical programme in the LSD1 inhibition field, which is the company’s area of expertise. The lead assets are ORY-2001 for neurological and neuropsychiatric disorders and ORY-1001 for haematological and solid tumours. Oryzon is running two Phase IIa clinical trials with ORY-2001 in AD and MS and plans to initiate a basket trial in several neuropsychiatric conditions. The results from the Phase I/IIa study with ORY-1001 in acute leukaemias were reported in December 2016 and the company has recently presented further development programme in blood and solid cancers after it had regained global rights to ORY-1001 following Roche’s decision to reshape its R&D portfolio and discontinuation of the licensing deal signed in 2014. Oryzon is headquartered in Barcelona, Spain, with a US office in Cambridge, MA, and employs around 40 people. Oryzon listed its shares on the Madrid Stock Exchange on 14 December 2015.

We maintain our financial estimates following our last revision after the Q118 results, which were largely in line with expectations. Our R&D cost estimates stand at €8.5m for FY18 and €9.5m for FY19, which are the main cost drivers. The reported Q118 cash position was €30.9m (cash and short-term investments; net cash €9.2m). Our model suggests this should be sufficient to reach 2020.

As Oryzon is on track to develop its assets in all the indications we include in our valuation, we leave our assumptions unchanged. Our updated valuation is €328m or €9.6/share, marginally up from €322m or €9.4/share due to rolling our model forward. Key catalysts within cash reach include readouts from two Phase IIa trials with ORY-2001 in AD and MS and results from the basket trial in neuropsychiatric disorders in 2019. Interim data readouts next year from both planned trials with ORY-1001 in AML and SCLC are also possible.

Oryzon is subject to the usual risks associated with drug development, including clinical development delays or failures, regulatory risks, competitor successes, partnering setbacks, and financing and commercial risks. Following the discontinuation of the partnership deal with Roche, Oryzon is now developing ORY-1001 on its own. We believe the asset has not been compromised and the Roche’s decision was based on the perspective of portfolio management. Oryzon is continuing the development on its own. We have assumed a licensing deal in our valuation after Phase II for both assets, but we have limited visibility on the timing and terms. Oryzon is in a comfortable cash position to finance the operations to early 2020.

Simplistically, epigenetics can be defined as the study of changes in how genes are ‘read’ (expressed). A number of external factors can switch genes on and off, modifying expression, but without actually making any changes in the sequence of DNA. These changes are called epigenetic modifications. Epigenetics is relatively young field in terms of drug development and histone deacetylase (HDAC) inhibitors were among the first epigenetic therapeutics brought to market. However, one of the key drawbacks is low selectivity and resulting side effects. Oryzon and some third-party researchers1 have started classifying HDAC inhibitors as the first generation of epigenetic modifying agents and Oryzon’s products can be assigned to a second generation of selective inhibitors of histone demethylases (KDMs) alongside other newer compounds in the R&D stage, such as histone methyltransferases (HMTs), BET inhibitors, PRMT5 inhibitors, etc (see Competitive landscape, page 10; a more detailed introduction to epigenetics can be found in our initiation report). Oryzon has developed a proprietary platform to create therapeutic inhibitors for a class of enzymes known as histone lysine demethylases, also known as KDMs. The two most advanced compounds in Oryzon’s pipeline are ORY-1001 and ORY-2001. ORY-1001 is a potent and highly selective LSD1 (lysine specific demethylase 1, also called KDM1A) inhibitor, whereas ORY-2001 is a bispecific LSD1/MAOB inhibitor. Oryzon’s third preclinical candidate, ORY-3001, is also an LSD1 inhibitor. The current status of the projects is summarised in Exhibit 1.

A team of researchers (unrelated to Oryzon) at the Harvard Medical School has found that inhibiting LSD1 could lead to the activation of immune response and increased response to checkpoint inhibition. This detailed fundamental study used in vitro and in vivo with results published in Cell in June 2018. Key findings include:

This study identified LSD1 as a potent inhibitor of anti-tumour immunity and suggested that LSD1 inhibition combined with checkpoint inhibition (PD-(L)1 blockade in this case) is a viable cancer treatment strategy. Once a cancer develops, it often also has mechanisms that suppress the immune response enabling the tumour to ‘hide’ from the immune cells. The goal of cancer immunotherapies is to change this tumour microenvironment so the patient’s own immune system can fight the disease. Checkpoint inhibitors are very effective in certain indications with sales of this new class of drugs growing rapidly. However, a very significant part of the patient population is non-responsive to the treatment (from 40% of melanoma patients to >80% non-small cell lung cancer). The demonstrated ability of LSD1 inhibition to convert a tumor resistant to PD-1 blockade to a tumour responsive to PD-1 blockade may turn ‘cold’ tumours ‘hot’ and provide a solution for patients not responding to checkpoint inhibitors.

This study, to our knowledge, for the first time linked the benefit of LSD1 inhibition in the immunooncology setting, adding a new dimension to ORY-1001’s potential in terms of what indications it could target and increasing the scope in terms of partnering discussions. In our view, the new findings form strong basis for Oryzon to actively start exploring the potential of its technology in combination with checkpoint inhibitors in a form of internal preclinical programme or by collaborating with external partners interested in such combinations. The combinations of checkpoint inhibitors and epigenetic drugs are already being explored in the industry. For example:

What sets Oryzon’s technology apart, in our view, is that this new study shines light on the very detailed fundamental mechanisms involved in LSD1 inhibition from an immunooncology perspective.

Biogen antibody brought attention back to AD; questions remain

After years of high profile failures in AD research targeting Abeta plaques, the biotech industry received a much-needed positive message in July 2018. Biogen announced that its anti-amyloid beta protofibril antibody BAN2401, partnered with Eisai and originally developed by BioArctic (a Swedish biotech, met its primary endpoint in the Phase II study with mild cognitive impairment or mild AD patients (collectively early AD; n=856). Biogen’s and Eisai’s share prices increased by 20% and 39% respectively on the news (both large caps), whereas BioArctic’s share price jumped 334%. The trial was previously analysed at 12 months using Bayesian analysis with the aim of creating a faster path to market, but an independent data monitoring committee determined that BAN2401 did not meet the criteria for success. However, Biogen and Eisai decided to continue the trial to 18 months. At this point a traditional statistical analysis was performed on the data, which “demonstrated a statistically significant slowing in cognitive decline and reduction of amyloid beta accumulated in the brain”. No other data were provided, which will presented at a relevant scientific conference in due course. Even though this announcement is encouraging, it is premature for Abeta targeting antibodies to claim victory, because:

Given the many failed late-stage attempts in targeting the Abeta plaque theory over the last several years, the investor appetite for AD assets has been reduced. Although questions for Biogen and Eisai remain, the announcement was still sufficient to revive hopes. Just this year three BACE inhibitors that were being explored in late-stage AD trials by large pharma companies failed. Axovant’s intepirdine (5-HT6 antagonist), vTv Therapeutics' azeliragon (RAGE receptor antagonist) also failed over the last few months, while Alzheon’s IPO was not successful.

If the excitement around Abeta MAbs continues, it could be a positive driving force for the development of other drug candidates within AD, in our view, even beyond therapies targeting various forms of Abeta, such as Oryzon’s epigenetic approach. When it comes to any potential direct read-through for Oryzon’s ORY-2001, there is no known connection with Abeta theory besides that ORY-2001 reduces S100A9, a pro-inflammatory protein that has been linked to the physical accretion of Abeta protofibrils. Instead of specific targeting, Oryzon’s epigenetic technology induces changes in gene expression with profound biological effects, therefore it is differentiated from Abeta theory products. Oryzon believes this could allow developing drugs not only for AD, but for various other neurological and psychiatric conditions (as discussed below).

ORY-2001 is a first-in-class, selective dual inhibitor of LSD1/MAOB. The first clinical data from Phase I with healthy volunteers were reported in March 2017. Oryzon has developed a broad R&D programme for this asset and is targeting a range of neurological disorders. AD and MS are the leading indications with two Phase IIa trials underway, while a new basket trial is planned to commence in H218, which will explore ORY-2001 use in a variety of neurological indications where aggression is a hallmark.

Rationale for bi-specific effect in neurological disorders

Historically, the recognition of the role of epigenetics and its importance was first described in oncology and then extended to neurodevelopment and neurodegenerative diseases.2 The potential use of LSD1 inhibitors is not limited to oncological diseases and Oryzon’s decision to choose oncology and neurodegeneration as primary areas of interest is supported by a significant amount of preclinical work.3 ORY-2001 is a unique dual inhibitor and its mode of action is possible due to the structural similarity of MAOB and LSD1.

Monoamine oxidases (MAO) are a very well-researched family of enzymes that are targets for already marketed drugs, such as first-generation antidepressants, and has two forms, A and B. Non-specific monoamine oxidase inhibitors were the first type of antidepressants developed but, due to the inhibition of MAOA, suffered from numerous side effects associated with its more widespread presence. A new generation of selective MAOB inhibitors (eg selegiline) was developed, which cause fewer side effects and are used in early-stage Parkinson’s disease. Due to an abundance of data about the effects of MAOB inhibition and its relatively good safety profile, we believe the downside of potential ‘negative’ interactions between inhibition of LSD1 and MAOB is significantly reduced, while there is potential upside from synergistic effects. This idea is also supported by Oryzon’s preclinical studies.

Two Phase IIa trials with ORY-2001, a dual LSD1/MAOB inhibitor for CNS indications, are underway. A randomised, double-blind, placebo-controlled, 36-week Phase II SATEEN study (n=24) will evaluate ORY-2001 in patients with relapsing-remitting MS and secondary progressive MS. A second randomised, double-blind, placebo-controlled, 24-week Phase IIa ETHERAL trial (n=90) with ORY-2001 in mild-to-moderate AD started enrolling patients in June 2018. The data readouts from both studies are planned around mid-2019 and represent the main catalysts in the near term.

Oryzon has identified different biomarkers that could be used to monitor the response to treatment with ORY-2001. At this stage, the most promising is S100A9, which is a pro-inflammatory protein typically upregulated in the context of inflammation-related neurodegenerative diseases, such as in patients with AD, postoperative cognitive dysfunction and traumatic brain injury. Therefore, the observed downregulation of the S100A9 protein by ORY-2001 is particularly interesting. While the work is still early stage, a progression biomarker may eventually prove invaluable in the context of a late-stage clinical trial designed to prove the disease-modifying effect of a drug. This is because it may be difficult to clearly differentiate between symptomatic and disease-modifying effects just with clinical endpoints (eg cognition, function).4 The key to convincing regulators of disease-modifying effects (which have never happened in the case of AD) may be the link between the slowdown in the progression of symptoms and a significant effect on validated biomarkers.

Most recent update from Oryzon on its R&D plans includes a newly designed concept to conduct a so-called basket trial with ORY-2001 in a variety of neuropsychiatric conditions. This concept is similar to drug development strategy in oncology. For example, vemurafenib is an inhibitor of mutated BRAFV600E kinase. Vemurafenib received FDA approval for the treatment of late-stage melanoma with BRAFV600E in August 2011. During the development, vemurafenib was explored in a variety of tumours with BRAFV600E before the specific melanoma indication was determined for late-stage trials. Trials in subsequent indications followed and clinicaltrials.gov lists around 70 active trials with this drug in a variety of combinations.

Oryzon believes it can employ a similar strategy to develop ORY-2001 for neuropsychiatric disorders due to observed holistic effects on aggression and behaviour in preclinical models with LSD1/MAOB inhibition (described below). Aggression is one of the more widespread alterations in patients with neurodegenerative and developmental disorders, as a well as social withdrawal and depression. To establish a more specific psychiatric setting where ORY-2001 could be used, Oryzon plans to initiate a Phase IIa trial (CTA filed with a Spanish agency) and enrol at least six patients per each indication: Alzheimer’s dementia, dementia with Lewy bodies, attention deficit hyperactivity disorder, autism spectrum disorder and borderline personality disorder. The open-label treatment with ORY-2001 will last for eight weeks with the last patient out expected in Q418/Q119. The main goal is the assessment of reduction in aggression.

Aggression is a widespread issue in various psychiatric conditions especially where dementia is involved or neurodevelopment is impaired. Therefore, we find such basket trial strategy is the fastest route to establish more precise indications or settings. Given the novelty of the trial design, the small sample sizes and lack of visibility of a more concrete regulatory pathway that could lead to the market, we do not make any change to our OUR-2001 valuation approach. But if this study delivers efficacy signals sufficient to progress to more advanced trials, we will revisit this direction, which would be clearly a step beyond currently targeted AD and MS.

The results of the Phase I trial with ORY-2001 in healthy volunteers were the first in-human data. The study was double-blind with a single ascending dose (SAD; subjects receive single doses from the dose range selected for the study) and multiple ascending dose (MAD; subjects receive repeated, increasing doses) and included more than 100 healthy volunteers. A dose range of 0.2-4.0mg was explored. The main safety and PK/PD findings were:

Highlights of preclinical data in AD

AD was the first indication for which Oryzon published ORY-2001’s preclinical data. Oryzon tested the drug in 10 different oral treatment studies with more than 340 SAMP8 mice, a non-transgenic model for accelerated ageing and AD. The effect on cognition was examined with an established test, the novel object recognition task (NORT), which uses a calculated discrimination index. Key findings include:

ORY-2001’s holistic effects may improve behavioural alterations

Oryzon’s more recent preclinical data with ORY-2001 suggested that in addition to rescuing memory impairment, the drug could help to treat the behavioural alterations seen in patients with neurodegenerative diseases. The new data were first presented at the Society for Neuroscience 47th annual meeting, Washington DC, on 11-15 November 2017.

The SAMP8 mice were treated with a range of clinically feasible doses of ORY-2001 or a vehicle. SAMR1 mice were treated with a vehicle only and acted as a normal control. The new data demonstrate ORY-2001’s effects on behavioural alterations after six weeks of treatment using a so-called resident intruder (RI) test, which is an established test for aggression and evaluates the response of the test mouse to a new animal introduced to its environment. Gene expression analysis was then carried out on the mice’s prefrontal cortices. The main findings were:

The RI test was also conducted in the rat isolation model with ORY-2001. Rats are very social rodents and do not tolerate isolation. Rat isolation therefore was used as a model for social avoidance seen in AD patients. Rats were divided into control arm (three to four animals per cage) or isolated (one animal per cage). Isolated animals were treated with vehicle or ORY-2001 for five weeks; control animals were given vehicle. After that all animals were tested in the RI test. The findings were:

These results suggest that ORY-2001 could have an effect on both cognitive decline and behavioural alterations in AD patients. Specific treatments for behavioural alterations such as aggression and social isolation are lacking and so tackling these could help to make ORY-2001 more competitive in the market. A large proportion of AD patients (20-50%) exhibit clinically significant aggression. Currently this is managed by non-pharmacological as well as pharmacological means. There is no FDA approved specific medication for the treatment of aggression in AD or other neuropsychiatric disorders. Memantine is the only drug approved for AD that has also been shown to reduce agitation and aggression, whereas other drugs used are more general antipsychotics, antidepressants or anxiolytic drugs and often have unfavourable safety profiles.

Preclinical proof-of-concept of ORY-2001 in multiple sclerosis

MS emerged as a second potential indication after AD for ORY-2001 following publication of preclinical data from specific inflammation models by Oryzon at multiple conferences over the last two years. ORY-2001 has been tested in preclinical proof-of-concept trials using the experimental autoimmune encephalomyelitis (EAE) mice model, a widely used proxy for MS. One of the EAE studies included three controlled arms: EAE mice treated with ORY-2001 (dual LSD1/MAOB inhibitor), ORY-LSD1 (proprietary selective LSD1 inhibitor) or rasagiline (a widely used, selective MAOB inhibitor).

During these studies mice were injected with a specific peptide, which triggered an autoimmune reaction and the production of antibodies against the myelin sheet protecting the motor neurons. A gradual demyelination (destruction of the neurons’ protective sheet) leads to the development of different degrees of paralysis, mimicking the natural course of MS. Key findings include:

Cumulatively, these findings indicate that ORY-2001 shows an ability to counteract a number of pathophysiological processes associated with MS and that the dual inhibition of LSD1-MAOB (ORY-2001’s mechanism of action) appears to be more efficacious in this context than LSD1 inhibition alone.

Oryzon has also presented a head-to-head comparison of ORY-2001 in MS against fingolimod (Gilenya, Novartis; $3.2bn in 2017) in the EAE mouse model. The data showed that ORY-2001 performed as well as or better than fingolimod in reducing immune cell infiltration of CNS tissues, providing neuroprotection and thereby reducing demyelination (detailed analysis in our 14 December 2017 report).

ORY-1001 is a highly selective LSD1 inhibitor that can be orally administered. Oryzon’s initial focus in developing ORY-1001 was on acute leukaemias. The drug candidate entered a Phase I/IIa trial in January 2014 and in April 2014 it was licensed to Roche, which has paid $21m in upfront and milestones to Oryzon during the engagement period. Under the terms of the agreement, Oryzon was responsible for finalising the leukaemia Phase I/IIa study (that was already ongoing and sponsored by Oryzon at that time). In December 2016, Oryzon reported supportive preliminary efficacy results from this trial at the ASH conference, which was a major milestone. In parallel, Roche, which was responsible for the global development of ORY-1001, initiated a clinical trial in SCLC.

In July 2017, Roche decided to discontinue the development of ORY-1001 and return the rights to Oryzon; according to Oryzon the decision was due to Roche reprioritising its portfolio and not driven by data. Oryzon regained the rights from Roche for ORY-1001 in January 2018 and reiterated its plans to continue the development of ORY-1001 in both clinical-stage indications. Oryzon also mentioned that around the time when ORY-1001 was out-licensed to Roche in April 2014, it was contacted by several other companies interested in epigenetic programmes in oncology. In our view, this suggests the company could potentially replace Roche with another partner interested in epigenetics and LSD1 inhibition.

Oryzon has now resumed the development in both AML and SCLC (requests for clinical trial authorisation submitted). Oryzon initially expects to start a Phase IIa study in SCLC and a follow-on Phase IIa in AML in H218. The Phase IIa ALICE study will recruit elderly AML patients who will receive ORY-1001 in combination with azacitidine. Part 1 will explore the recommended dose, while Part 2 will evaluate initial clinical activity. The Phase IIa CLEPSIDRA trial will recruit relapsed, extensive-stage disease SCLC patients who will receive ORY-1001 in combination with platinum-etoposide chemotherapy. Oryzon will use biomarkers to select more precise patient population. Similarly, Part 1 will establish recommended dose, while Part 2 will evaluate clinical activity. Interim results from both studies are expected in 2019.

In December 2016 at ASH, Oryzon presented data from the positive Phase I/IIa trial. The study included different subsets of relapsed or refractory acute leukaemia patients treated with ORY-1001. The dose-escalation Part 1 (Phase I) included 27 patients treated for 28 days. Part 2 (Phase IIa) was an extension arm with an additional 14 patients with the goal of establishing initial efficacy results and a PK/PD profile.

The most common, likely drug-related side effects included low blood platelet count (16.7% of total adverse events), neutropenia (6.7%), fatigue (6.7%), changes in taste (6.7%) and petechiae (6.7%). Initial efficacy was explored in 14 patients included in the extension arm, of which one dropped out. Since specific subtypes of acute leukaemia are especially susceptible to LSD1 inhibition, the extension arm included patients with mixed lineage leukaemia (MLL; n=6), other MLL gene rearrangement or mutation (n=4) and acute erythroid leukemia (AML M6; n=4). The main findings included:

Following ASH and once the final results were available, the company has reported that from all patients in the study, anti-leukaemic activity was observed in 29% of patients (12/41), including one CRi (complete remission with incomplete blood count recovery) in the dose finding part of the study. Although the study was small and the focus was on safety, the efficacy findings can be interpreted as showing potential in acute leukaemia. Notably, impaired differentiation/maturation of the leukaemic blasts is at the core of the disease’s pathophysiology. ORY-1001’s ability to induce the differentiation of blasts (turn them into normal, mature blood cells) demonstrates that it does what it was designed for. More detailed analysis of ORY-1001’s preclinical data can be found in our initiation report.

The precise indication for ORY-3001, a specific LSD1 inhibitor Oryzon’s third asset, has not been disclosed yet, only that it will be a non-oncological disease. However, in December 2017, the first published preclinical in vivo data on ORY-3001 revealed it could be effective in sickle cell disease (SCD), which currently has no cure and has an adverse prognosis. SCD is a genetic disease where an adult gene for haemoglobin (a protein responsible for oxygen transport in red blood cells) is mutated, resulting in abnormal shaped red blood cells that resemble a sickle. This leads to anaemia as red blood cells are not able to pass through the smallest blood vessels, the capillaries. This results in vaso-occlusive crisis, acute or chronic pain, and decreased supply of oxygen to organs, which causes damage and many other symptoms. Currently there is no cure and only symptomatic treatment is used.

There two types of haemoglobin: foetal (HbF) and adult. While HbF represents most of haemoglobin in foetal life, it drops to <1% in normal adults and is found in a few F-cells. The purpose of this study was to investigate whether ORY-3001 has the potential to increase HbF, which could replace the function of the mutated adult Hb. The results showed that oral administration of ORY-3001 increased HbF 10-fold in SCD transgenic mice. So called F reticulocytes (young red blood cells containing HbF) increased 300%. In baboons, F-reticulocytes increased 8-fold. As a next step Oryzon indicated it might continue the development of ORY-3001 for SCD, although no specific details were announced.

HDACs are regulators of gene expression, which remove the acetyl group from histones. There is already a handful of first-generation HDAC inhibitors approved by the FDA, with the first being vorinostat (Zolinza) developed by Merck & Co for third-line therapy of cutaneous T-cell lymphoma and marketed in 2006. Because of a lack of specificity, the common feature of these HDACs is a rather unfavourable safety profile. For example, vorinostat received a critical review in 2009 from the European Medicines Agency about the risk/benefit ratio and the trial design, following which Merck & Co withdrew its marketing application.

Despite these hurdles, a number of other HDACs are still being explored in different stages for oncological indications, but we believe that second-generation epigenetic inhibitors are a more relevant peer group for Oryzon’s technology since, like the LSD1 inhibitor, they also have greater selectivity for their molecular targets (Exhibit 8). Second-generation compounds can be broadly classified into demethylase inhibitors, methyltransferase inhibitors and bromodomain and extra‐terminal (BET) inhibitors or acetyl lysine readers. Methyl lysine readers are also emerging in preclinical research. Second-generation epigenetic inhibitors are still considered in their infancy, with most companies having a lead programme in Phase II or earlier. Oryzon is focused on LSD1 inhibition and is leading in this field in terms of clinical development. It also has programmes in neurodegenerative diseases, while the majority of peers are focused on oncology.

It is worth noting that epigenetics company Constellation Pharmaceuticals is undergoing an IPO process. The company aims to raise $80m by offering 5.3m shares at a price range of $14-16. At the midpoint, Constellation’s market capitalisation would be $430m on a fully diluted basis. The company’s main asset is CPI-1205, an EZH2 inhibitor, being explored in two Phase Ib/II trials in metastatic castration resistant prostate cancer and solid tumours in combination with ipilimumab or pembrolizumab. Another asset CPI-0610, BET inhibitor is being tested in Phase II trial in myelofibrosis.

Oryzon is subject to the usual risks associated with drug development, including clinical development delays or failures, regulatory risks, competitor successes, partnering setbacks, and financing and commercial risks. We believe ORY-1001 has not been compromised and Roche’s decision was based on the perspective of portfolio management. Oryzon is continuing the development on its own and we believe a new partner will have to come on board before ORY-2001 enters large-scale Phase III studies, the timing of which is difficult to forecast. ORY-2001 will also need to be partnered, as later-stage studies in CNS indications can be very costly due to large populations. However, Oryzon has enough cash to progress ORY-2001 through mid-stage development to reach meaningful data. We have assumed a deal in our valuation after Phase II for both assets, but we have limited visibility on the timing and terms. Future pricing and market dynamics are hard to predict, especially if competitors are successful. Oryzon is in a comfortable cash position to finance operations to early 2020. Future financing needs will depend on the scale of operations with preclinical candidates, the progress with ORY-2001 and ORY-1001 and any potential revenues from partnerships.

We maintain our financial estimates following our last revision after the Q118 results, which were largely in line with expectations. Our R&D cost estimates stand at €8.5m for FY18 and €9.5m for FY19, which are the main cost drivers. The reported Q118 cash position was €30.9m (cash and short-term investments; net cash €9.2m). Our model suggests this should be sufficient to reach 2020.

As Oryzon is on track to develop its assets in all the indications we include in our valuation, we leave our assumptions unchanged. As discussed above, we will revisit ORY-2001 for neuropsychiatric disorders once more detail about the development pathway emerges after the basket trial data are announced. Our new valuation is €328m or €9.6 per share, marginally up from €322m or €9.4 per share due to rolling our model forward. Detailed discussion about assumptions is in our initiation and earlier outlook reports. The changes to ORY-1001’s valuation after Roche’s departure are described in our August 2017 report.