FDA clearance for PORTICO-2 expected in Q325

In June 2025, Oryzon submitted the Phase III protocol to the FDA to initiate the PORTICO-2 trial. PORTICO-2 has been designed to target agitation and aggression (A/A) in BPD patients. The selected primary endpoint measure is the STAXI-2 Trait Anger score, a patient-reported measure in which vafidemstat demonstrated statistically significant improvements in the prior Phase IIb trial. The key secondary endpoint will be the score on the clinician-rated Modified Overt Aggression Scale (OAS-M). As discussed at the company’s key opinion leader event, the use of these two endpoints in parallel should effectively capture both how patients feel at any given time and how their A/A changes over time. We anticipate FDA clearance for PORTICO-2 in September 2025, and expect the trial to start in 2026.

Iadademstat presents expanding opportunities

Iadademstat is being evaluated across a range of cancers, including AML, small cell lung cancer (SCLC) and myelodysplastic syndrome (MDS). In its Q225 update, Oryzon announced the expansion of iadademstat into non-malignant haematological indications, with an initial focus on SCD, based on encouraging preclinical research and the role of LSD1 (the target of iadademstat) in the disease. A response on the CTA for Phase Ib is also expected in September.

Valuation: €887.2m or €11.3 per share

We raise our probability of success for vafidemstat in BPD to 40% (30% previously) following the Phase III protocol submission. As a slight offset, we now conservatively assume a licensing deal in H126 versus H225 previously. All other long-term assumptions for Oryzon’s clinical programmes remain unchanged. After updating for the latest pro-forma net cash position and rolling our model forward, our valuation stands at €887.2m or €11.3/share (from €862.4m or €11.0/share previously).

Broad clinical development pipeline continues to progress

Oryzon continues to boast a diverse clinical development pipeline, with assets focused on both central nervous system (CNS) conditions (vafidemstat) and oncology/haematology indications (iadademstat), somewhat offsetting the company’s exposure to binary risk events, such as the outcome of clinical trials. The programmes comprise a mix of self-funded trials, as well as investigator-initiated studies and collaborations. Orzyon is a leader in the field of epigenetics, and management remains confident that its two proprietary candidates (both inhibitors of lysine-specific demethylase 1, LSD1, also known as KDM1A) may effectively address unmet needs across the range of indications being targeted (Exhibit 1).

Vafidemstat: Optimised to address CNS conditions

Borderline personality disorder

Oryzon’s most advanced clinical programme is focused on vafidemstat’s potential to address A/A in BPD patients, a neglected condition with no FDA-approved drugs, despite its global prevalence of c 1–2%. Clinicians are currently limited to prescribing medications, such as antipsychotics and/or mood stabilisers, off-label, though this approach often has limited durability and is associated with undesirable side effects. Hence, we see a potentially sizeable opportunity in this space for Oryzon, should subsequent clinical data be supportive. Most recently in the clinic, the drug candidate completed a Phase IIb trial (PORTICO), and although the primary endpoints were not met with statistical significance, vafidemstat was favoured over placebo in all measures, and the key secondary endpoint, STAXI-2 Trait Anger score, was met with statistical significance (Exhibit 2). Following a productive end-of-Phase II meeting with the FDA, Oryzon has been focused throughout late-2024 and H125 on preparing to submit a formal protocol to the regulators for PORTICO-2. This was finalised based on discussions with the FDA, as well as input from leading US psychiatry experts, and submitted in June 2025.

PORTICO-2 has been designed as a randomised, double-blinded, placebo-controlled, multi-centre Phase III trial (expected n=350), which aims to evaluate the safety and efficacy of vafidemstat in BPD patients. While the STAXI-2 Trait Anger score had been previously defined as the primary endpoint, we note that the key secondary endpoint, OAS-M, is a clinician-rated scale used to assess aggression in psychiatric conditions. Beyond these two key endpoints focused specifically on A/A, additional secondary outcome measures will be utilised to evaluate more general improvements in BPD symptoms and quality of life. As discussed above, we expect a regulatory outcome for PORTICO-2 in September 2025, which we anticipate will be followed by a trial launch from 2026, potentially under a partnering agreement.

We note that Oryzon has continued to make headway in strengthening its intellectual property profile for the candidate. In July 2025, the company announced that it had received new ‘decision to grant’ communications from the Canadian Intellectual Property Office and the Israel Patent Office. This is for its patents, titled ‘Methods of treating behavior alterations’, for vafidemstat as a potential treatment to address aggression and social withdrawal. Once granted, these patents will remain in force until at least 2038 in Canada and Israel, excluding any potential patent term extensions (which have the potential to add additional years of protection). Management also noted that corresponding patents have been granted or allowed in Europe, Australia, Hong Kong, South Korea, Malaysia, the Philippines and Russia, and additional applications are pending in other countries, fortifying the protection of the candidate.

Schizophrenia

Vafidemstat is involved in the EVOLUTION programme, focused on schizophrenia. This is a double-blind, randomised, placebo-controlled Phase IIb trial exploring the drug candidate as a potential treatment for the negative symptoms of schizophrenia as the primary focus, with secondary outcome measures based on positive symptoms and cognitive impairment. While the precise number of patients currently enrolled in the trial has not been disclosed, management has communicated that, based on insights from the PORTICO trial in BPD, it has been determined that 84 patients (previously 220) should be sufficient to demonstrate any potential clinically meaningful effect of vafidemstat. The programme was previously limited to hospital sites across Spain, as it was partially funded by the Spanish Ministry of Science and Innovation. However, according to the latest update, thanks to increased funding at hand, Oryzon is expanding the trial to additional European countries. In our view, this represents a positive update to the programme, offering the potential to include a wider demographic and accelerate the pace of patient recruitment. We await further details on the next update for EVOLUTION.

Potential to expand

Given the promise that vafidemstat has shown in treating A/A in BPD, Oryzon has taken steps to expand the application of the candidate to other neurological conditions where A/A is common. Prior research (notably, the Phase IIa REIMAGINE trial) has highlighted vafidemstat’s potential to address A/A in conditions such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder, as well as in Alzheimer’s disease (REIMAGINE-AD trial). As per the Q225 update, Oryzon has confirmed that it is taking further action in this area, with plans to initiate a new Phase II programme to evaluate vafidemstat in aggression associated with ASD, which will be financially supported by the ‘Important Project of Common European Interest’ (EU-IPCEI) grant (Med4Cure project). This new Phase II trial, named HOPE-2, will include both genetically-defined ASD subpopulations, such as Phelan-McDermid Syndrome patients, as well as sporadic (non-genetic) ASD subpopulations. Given vafidemstat’s track record in the clinic to date, including its favourable safety profile and efficacy in A/A in BPD, we believe this could represent a potentially sizeable opportunity for Oryzon, should efficacy in these additional indications be sustained.

In the recently recorded executive interview below, Carlos Buesa, CEO of Oryzon Genomics, provides a detailed overview of the company’s current activities in the CNS space.

Oryzon Genomics – executive interview (July 2025)

Source: Edison Investment Research

Iadademstat: Potential in oncology (and additional) indications

Acute myeloid leukaemia

Oryzon’s lead oncology programme, the self-sponsored Phase Ib US-based FRIDA trial (expected n=45), is assessing iadademstat in combination with gilteritinib in patients with relapsed/refractory AML harbouring the FLT3 mutation, targeting the second-line setting. The primary analysis is focused on safety and a recommended Phase II dose, while secondary endpoint measures are focused on efficacy. Preliminary data have been encouraging, and the next update is due to be presented at the American Society of Hematology meeting in December 2025, potentially representing an upcoming catalyst for Oryzon. Should the results of the FRIDA programme be positive, Oryzon has an agreement with the FDA to conducting a meeting to discuss the most effective plan for further development efforts in this indication, which could include an accelerated pathway.

In addition to FRIDA, iadademstat is also being evaluated in the first-line setting for AML in two separate dose-finding Phase I studies, both of which explore potential synergy of the drug candidate in combination with venetoclax and oral azacitidine (standard of care treatments in AML). One of these studies is under a cooperative research and development agreement (CRADA) with the National Cancer Institute (NCI), and the other is an investigator-initiated trial in collaboration with Oregon Health & Science University. Both studies are underway, and we expect updates as information becomes available.

Small cell lung cancer

Iadademstat, in combination with immune checkpoint inhibitors (ICIs), is being assessed in SCLC as part of a CRADA with the NCI, in patients with extensive disease, targeting the first-line setting. Patient recruitment commenced in April 2025, and the programme ultimately aims to enrol 45–50 patients. Primary objectives are focused on safety, tolerability, dose-finding and efficacy. Multiple leading US-based cancer centres are involved in this trial (expected to include over 30 sites), including the Memorial Sloan Kettering Cancer Center (MSKCC) as one of the main sites. Should the results of this programme be positive, they may support Oryzon’s plans for its STELLAR programme, a randomised, multi-centre Phase II study of iadademstat in combination with an ICI for first-line extensive-stage SCLC.

Additional indications

Oryzon is also exploring iadademstat in MDS, a rare form of blood cancer, in an investigator-initiated Phase I programme, with patient dosing having commenced in January 2025. The programme, led by the Medical College of Wisconsin, continues to actively enrol patients. We await further updates.

In its Q225 results update, Oryzon laid out its plans to expand the potential application of iadademstat, by exploring its potential in non-malignant haematological indications, such as SCD and essential thrombocythemia (ET). It was announced that the initial focus will be on SCD, with a CTA submitted to the EMA for this indication. The trial, named RESTORE, will aim to enrol 40 patients, with the primary endpoint relating to safety and tolerability, while determining the recommended dose for Phase II. One of the key secondary endpoints will measure the activity of iadademstat in inducing foetal haemoglobin. A regulatory decision is anticipated in September 2025. Management believes that the commercial potential could be sizeable in this indication, given the performance of Pfizer’s Oxbryta (generic name: voxelotor), before it was withdrawn from the market due to safety concerns. The field has evolved significantly in recent years with the approval of gene therapies for the condition, however, given their large price tags, we believe the opportunity remains for effective treatments that may come in at a more accessible price point. Management has also noted that a second trial, to assess iadademstat in ET, is in preparation, with the intention to submit the CTA to the EMA within H225.

Financials

Oryzon’s Q225 and H125 results were broadly in line with our expectations. R&D expenses for the quarter were €2.5m, up c 14% from €2.2m in Q224, and at a similar run-rate to the Q125 figure of €2.4m. The H125 R&D expenses were €4.9m (H124: €4.6m) of which €4.2m have been capitalised, which management accounts for as other income in the profit and loss statement. Personnel expenses rose materially in H125, up 40% y-o-y to €2.4m, with a 64% y-o-y jump in H2. Management has attributed this primarily to the accrual of a provision (€435k) related to the long-term incentive plan (2023–25) in H125, as well as lower salary and wage expenses in H124 (due to the reversal of a €198k provision). Overall, operating loss for the period was €2.9m versus a loss of €2.4m in H124.

Notably, Oryzon reported a net financial income of €4.1m in H125 versus a loss of €454.6m in H124. This material difference was driven by lower implicit interest related to the November 2023 €45m convertible bond programme with Nice & Green (Oryzon has drawn down €15m to date), resulting in lower interest expenses (€335.5k vs €528.8k in H124) and higher interest income (€380.1m vs €62.2m in H124). We note that this convertible financing agreement has subsequently been terminated (as of July 2025). Of the €15m drawn down, €9.52m had been converted to equity by June 2025 and a further €1.97m was converted in early July (against an issue of 1.3m shares), prior to the termination of the agreement. As part of the agreement closure, Oryzon has paid a total of €4.7m to Nice & Green as consideration for the convertible debt outstanding at end-H125 (c €3.0m), as well as in exchange for the 1.3m shares issued under the latest July conversion (these shares will be deemed as treasury shares). Net loss for the period was €1.6m, up from €1.0m in H124. The free cash outflow for H125 was €5.3m, an improvement over the €8.1m recorded in H124, supported by €1.7m in tax benefits recognised in H225.

Oryzon ended H125 with a net cash balance of €13.0m. This includes €31.1m in cash and cash equivalents, €9.4m in short-term debt (bonds – €3.0m; credit institutions – €5.7m; other – €0.7m) and €8.7m in long-term debt (credit institutions – €5.0m; other – €3.6m). The cash position was supported by a €30m equity issue in April 2025 against an issue of 12.8m new shares, at €2.35 per share. As highlighted above, this allowed the company to prematurely close out the €45m convertible debt facility. With this new financing, management plans to accelerate patient recruitment (n=84) in the ongoing Phase II EVOLUTION trial in schizophrenia by expanding test centres into five other European countries (it was previously conducted exclusively in Spain).

Post-period, on 25 July 2025, Oryzon received the €13.26m ( US$15m) non-dilutive grant under the Med4Cure initiative, part of the EU-IPCEI framework, launched in May 2024. The grant represents c 64% of the €20.68m accepted budget for the project, which will run until August 2026. As part of this initiative, Oryzon has announced its plans to initiate a new Phase IIb trial (HOPE-2) to evaluate vafidemstat as a treatment for aggression in specific genetically-defined subpopulations of ASD, such as Phelan-McDermid Syndrome. The trial will be conducted in Spain initially.

Estimates revision

Based on the H125 results and improved pipeline visibility, we have made certain adjustments to our near-term estimates. For FY25, while we had previously assumed a partnering deal for vafidemstat in H225, with a risk-adjusted upfront payment of €30m, we now conservatively move this timeline to H126. This is based on the update by management that the FDA decision on the clinical trial protocol submission in BPD is now expected in late Q325. Our R&D estimate for FY25 is unchanged at €8.5m. With the clinical trial protocol for vafidemstat in BPD submitted to the FDA in June 2025 (a decision is anticipated in H225 with Phase III likely to commence in H126), R&D expenses related to the BPD programme will potentially decrease in H2, although we expect this to be offset by the expansion of the EVOLUTION trial into other European geographies as well as preparatory activities for the new trials planned, including HOPE-2. For personnel expenses, we raise our FY25 expectations to €4.1m (from €3.5m previously) to reflect the H125 figure. We note that while our last published estimates had accounted the entire €13.26 Med4Cure grant as income, we now understand that this would be capitalised and amortised over a longer duration (€0.4m to be recognised in the FY25 P&L). We therefore adjust our other income estimate for FY25 to reflect this. Overall, we now project an operating loss of €3.8m in FY25 versus an operating profit of €39.8m previously. For FY26, we estimate an operating profit of €36.5m versus €31.8m previously. We continue to see the company funded through 2027 with the current capital on books (excluding trial costs related to the BPD programme, which we assume will be borne by the licensing partner).

Valuation

We value Oryzon using a risk-adjusted net present value (rNPV) approach to its ongoing clinical programmes, forecasting to the end of the patent lives and using a flat discount rate of 12.5%. Following the H125 results, we keep our underlying long-term estimates unchanged across all clinical programmes, save for BPD, where we raise our probability of success to 40% (from 30% previously) after the successful submission of the Phase III clinical trial protocol to the FDA in June. This raises our rNPV of the programme to €343.3m (from €308.7m previously) with the increase partially offset by the slight timeline change we have introduced in relation to the expected licensing deal for vafidemstat (we now expect this in H126 versus H225 previously).

This, along with the latest pro-forma net cash position (€26.3m, including the €13.26m grant payment received in July 2025), results in our valuation for Oryzon adjusting to €887.2m or €11.3 per share, from €862.4m or €11.0 per share previously.
A breakdown of our rNPV valuation is shown in Exhibit 3.

As noted above, we now model a licensing deal for vafidemstat in H126, supporting profitability and cash flow positivity in FY26. As an added sensitivity, if Oryzon were to self-develop and commercialise all its programmes, we estimate it needing to raise c €90m between FY27 and FY29. If these requirements are fulfilled through equity issues, we calculate Oryzon needing to issue 33.7m shares (at the current trading price of €2.67). This would lead to an increase in shares outstanding to 112.3m (from 78.5m currently) and would dilute our per-share valuation to €8.7 per share (from €11.3 per share currently).