Oryzon Genomics — First vafidemstat efficacy data

The Phase II REIMAGINE is a single-arm, open-label study being carried out at the Hospital Vall d’Hebrón in Barcelona and enrolling six patients per indication: Alzheimer’s disease (AD), Lewy bodies dementia (LBD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and borderline personality disorder (BPD). Patients will undergo an open-label treatment with vafidemstat for eight weeks. The study objectives are:

The REIMAGINE trial with vafidemstat is a so-called basket trial, which employs an innovative design borrowed from drug development in oncology, where the drug is initially explored in a variety of indications before selecting the most promising for the late-stage development. Aggression is often seen in a variety of neurodegenerative and neuropsychiatric conditions. Oryzon believes it can employ a similar strategy to develop vafidemstat for neuropsychiatric disorders due to observed holistic effects on aggression and behaviour in preclinical models with vafidemstat.

Oryzon used these common neuropsychiatric scales to assess the patients:

The first dataset from the REIMAGINE trial was presented from the borderline personality disorder (BPD) cohort at the 27th European Congress of Psychiatry (EPA 2019) in Warsaw, Poland, on 8 April 2019. In this cohort six subjects with diagnosed BPD were treated for two months. Vafidemstat met all the primary and secondary endpoints:

The second dataset from the REIMAGINE trial was presented from the attention deficit hyperactivity disorder (ADHD) cohort at the 7th World Congress on ADHD, 25–28 April in Lisbon, Portugal. Similarly, in this cohort six subjects with diagnosed ADHD were also treated for two months. Vafidemstat again met all the primary and secondary endpoints:

In addition, Oryzon provided some aggregated BPD and ADHD data.

Treatment with Vafidemstat in these patients was safe and well tolerated without significant adverse events, including no apparent negative haematological effects, which is a primary consideration of the epigenetic class drugs. This was not surprising, as the dose used in the REIMAGINE trial was substantially below the highest dose reached in Phase I trials (2.5mg). The fact that effectiveness was achieved with relatively low dosing is especially beneficial given that in BPD the treatment most likely would be chronic.

In two different indications vafidemstat not only significantly improved scores across several commonly used subscales that measure agitation and aggression, but also significantly improved the total scores of those psychiatric scales. Albeit the cohorts were small, the consistency of results across several scales and in two different indications is rather promising, in our view. Although the primary purpose was to assess the effect on aggression management in these patients (based on insights from the preclinical trials), the fact that overall scores improved as well suggests that vafidemstat could have a broader psychiatric effect beyond agitation and aggression.

The next data readout from the autism spectrum disorder is scheduled for the 32nd ECNP Congress, Copenhagen on 9 September 2019. However, in its latest press release about the ADHD data last Thursday, Oryzon clearly indicated that it will explore vafidemstat for psychiatric disorders beyond those currently in clinical trials: AD and MS. The company mentioned that it is now consulting with specialist KOLs to establish a precise target indication and patient population where vafidemstat would be best positioned. We believe that, specifically, BPD appears to be an interesting opportunity characterised by a high unmet need (no specific treatment approved) and a large population of adult patients. We therefore now include this indication in our valuation (more details follow in the valuation section).

BPD is characterised by pervasive, marked instability in functioning, mood, interpersonal relationships and, on the severe end of the symptom scale, reality perception distortion. In addition, other conditions are also present, such as major depression, substance abuse or psychotic disorders. Around 70–75% of BPD patients have attempted self-harm at least once, while the estimated rate of completed suicides is 9% (eMedicine/Medscape). Symptoms typically begin in adolescence or young adulthood, but at this early stage typically psychotherapy involving family members is used. Pharmacological intervention tends to be prescribed once a person reaches adulthood. The initial diagnosis is rarely made in patients older than 40 years. The severity of the disease often decreases with age. No laboratory tests are useful and the condition is typically diagnosed by psychiatrists using behavioural diagnostic criteria listed in the guidelines.

Management of the disease is difficult and involves a number of psychotherapeutic and pharmacological interventions, which are selected on a case by case basis. The presentation of the disease can vary substantially and pharmacological treatment usually targets symptoms. There are no drugs specifically approved for the condition in the western markets, but pharmacological treatment is being used to treat impulsivity, mood instability and psychosis. So far, mostly selective serotonin reuptake inhibitors (SSRIs) class drugs have been used in BPD patients. SSRIs are mainly indicated to reduce impulsivity and aggression. Neuroleptics (antipsychotics) and opiate receptor antagonists (naltrexone) are also sometimes used, but in smaller number of patients and for a short period of time.

Given the diversity of the disease, no definitive data exists about the prevalence of BPD, but widely reported estimates suggest that 1–2% of the general population could be affected (eMedicine/Medscape). Percentage of patients that actually receive treatment is also not well understood, but some researchers estimate 50% receive diagnosis and of those 50–80% receive treatment (Gross et al, 2002; Lieb et al, 2010). Existing epidemiological findings also agree on the fact that BPD is much more prevalent among women, with a female to male ratio of as high as 4:1 (Nasiri et al, 2013). No drugs are specifically approved for BPD.

ADHD is a developmental condition of inattention and distractibility, with or without accompanying hyperactivity. Therefore, ADHD can be classified into three forms: inattentive, hyperactive-impulsive, and combined (Moffitt et al, 2015). Symptoms can range from mild to severe, affecting daily functioning to different extents. Similar to BPD it is diagnosed using behavioural psychiatric tests, as no specific laboratory tests exists. However, MRI, functional MRI and PET scans have been shown in studies to be useful to determine functional and anatomical alteration in certain brain structures of the patients, when compared to healthy persons.

In some cases, behavioural therapy involving the person and their family can be effective, but unlike in BPD, psychostimulants are considered the mainstay pharmacological treatment of this disease. Common first-line therapies include:

Because of relatively well-defined symptoms of ADHD, the epidemiology is understood relatively well. ADHD symptoms start most often in childhood and in 2016 there were 5.4 million children diagnosed with the condition at that time in the US, which corresponds to an 8.4% prevalence rate of all US children. 62% of children with current ADHD were taking medication and 47% had received behavioural treatment for ADHD in the past year; 23.0% had received neither treatment (Danielson et al, 2018). As many as 65% of these children will have ADHD or some residual symptoms of ADHD as adults. The prevalence rate of ADHD in the adult general population is 4–5% (Goodman and Thase, 2009). ADHD is three to five times more common in boys than in girls, while in adults, the ratio is closer to even (eMedicine/Medscape).

Our valuation is higher at €430m or €11.0 per share, versus €364m or €9.3 per share previously, mainly due to the addition of a new indication in our rNPV. As discussed, the most recent REIMAGINE data and Oryzon’s indication that it will pursue more psychiatric indications warrant, in our view, the expansion of the potential of vafidemstat in our model. We chose to include BPD due to several reasons:

Due to the lack of similar drugs that could be used as benchmarks, we have used a bottom-up approach with the following assumptions in our project model:

We note that these assumptions are subjection to revision as more information is released by Oryzon about a more specific positioning of vafidemstat, eg the design of the next trial.

We maintain our near-term financial and operating forecasts unchanged, but these are subject to revision once more precise plans for additional clinical trials are announced.