Evenamide: A novel approach to schizophrenia
Newron announced plans for a pivotal Phase IIb/III clinical trial programme for Evenamide, as an add-on therapy to atypical antipsychotic drugs (APD) for the treatment of schizophrenia. Schizophrenia is a common, chronic and severe mental disorder with many patients resistant or refractory to available drug treatments; there is a huge opportunity for novel MOA drugs given the unmet need in patients who do not adequately respond to current treatment options.
Evenamide (NW-3509) is an internally developed asset that originates from Newron’s ion channel discovery platform. It is a novel, oral, APD in development for schizophrenia and acts through pathways that are not targeted by available APDs, which mainly exert their efficacy through blockade of dopamine receptor. Evenamide’s differential feature is that it does not target the same dopamine pathways as current (atypical) APDs, it is a selective voltage-gated sodium channel blocker that inhibits post-synaptic glutamate release. Evenamide may act synergistically with antipsychotics drugs as it targets the abnormal neuronal activity (excessive glutamatergic signalling) thought to play a role in the pathology of patients that do not respond to current APDs. The hypothesis is that combination of Evenamide therapy would enable better efficacy with minimal safety impact and provide a new era of treatment options for inadequately treated or TRS patients.
Pivotal Phase IIb/III clinical trial programmes planned to start in Q219
Newron has been in active discussions with multiple regulatory bodies including Spain, Denmark, Sweden, Germany, UK (CHMP), US FDA (end of Phase II meeting) and Canada. The upshot of these meetings is the design of two Phase IIb/III clinical trials has been agreed, investigating Evenamide in two schizophrenia patient population:
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Study 003/005 for non-treatment resistant patients: chronic schizophrenic patients inadequately responding to atypical antipsychotic monotherapy (risperidone, aripiprazole, paliperdone, olanzapine or quietipine). This trial will evaluate efficacy, safety and tolerability of three fixed doses of Evenamide (or placebo) as an add-on to the patient’s current atypical antipsychotic medication. The trial will aim to recruit 520 patients (across the four groups) monitoring patients (double-blinded) for six weeks before moving into a separate 46-week double-blind extension maintaining patients on the same dose regiment.
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Study 004/006 for treatment resistant patients: defined as TRS patients whose psychotic symptoms have failed two or more prior lines of pharmacotherapy and are not adequately responding to clozapine after 12 weeks. This trial will evaluate efficacy, safety and tolerability of two fixed doses of Evenamide (or placebo) as add-on to clozapine. The trial will aim to recruit 450 patients (across the three groups) monitoring patients (double-blinded) for eight weeks before moving into a separate 44-week open-label extension, transitioning all patients to dose-titrated Evenamide.
Newron believes both trials could complete in H220. Both trials will have a primary endpoint of efficacy, looking at improvement in positive and negative symptom score with a secondary endpoint looking for an improvement in clinical global impression of change. Regulatory bodies have indicated that both efficacy endpoints are likely to be considered prior to approval with a positive result in study 004/006 likely to lead to breakthrough designation as an add on to clozapine for treatment-resistant patients. Positive results in both 003/005 and 004/006 would be enough to cover the efficacy requirements for submitting an NDA across both indications; if study 003/005 is positive alone, another confirmatory Phase III trial would be needed for the larger patient subset, we note this scenario would require us to revisit our forecast 2022 US and EU launch date (Exhibit 2).
Exhibit 2: Likely pathways following Phase IIb/III trial readouts in 2020
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Study 003/005 Non-treatment-resistant patients (add-on to any atypical APD) |
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Negative readout |
Positive readout |
Study 004/006 Treatment-resistant patients (add-on to clozapine) |
Negative readout |
No regulatory approval |
Confirmatory Phase III trial of similar design |
Positive readout |
Approval for TRS as an add-on to clozapine (breakthrough designation) |
Approval for both treatment-resistant and non-TRS as an add-on to any atypical antipsychotic drug |
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Source: Edison Investment Research
As an add-on to atypical APDs in wider schizophrenia patient populations, the scope for Evenamide is potentially huge and Newron would need to partner for the wider schizophrenia indication as an add on to APD. Newron, however, could elect to market the smaller sub indication of TRS as defined by resistant to clozapine. An estimated 20–50% of schizophrenia patients become resistant to treatment after 10–20 years; these patients are eligible for clozapine. Newron estimates only 70k schizophrenia patients are on clozapine (we discuss clozapine later in the note) and 30% of these patients are resistant to drug. This translates to 21k patients in the US who could be eligible for Evenamide plus clozapine in TRS. Newron could potentially commercialise for this indication alone without partnering, and would rapidly capture this subset of patients if breakthrough designation was granted.
Unmet needs in schizophrenia
According to the National Institute of Mental Health’s Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, 74% of schizophrenia patients discontinue treatment with atypical APDS after 18 months (including drug discontinuation due to side effects). As such, new classes of antipsychotic drugs are required that can:
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improve the negative and cognitive symptoms which are not managed well with current pharmacotherapies, reducing the disease burden
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reduce the side effects of atypical antipsychotic medications through dosage reduction, improving patient compliance and clinical response
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reduce persistent psychotic (positive) symptoms in treated patients that do not respond adequately to atypical antipsychotics, where the underlying pathology is thought to be driven by other mechanisms
All currently marketed APDs used in the treatment of schizophrenia primarily work by attenuating dysregulated dopaminergic signalling by either antagonism (ie risperidone or clozapine) or low efficacy, partial agonism (ie aripiprazole) at post-synaptic dopamine D2 receptors. The current generation of APDs is largely effective in treating the positive symptoms of schizophrenia, delusions and hallucinations (stemming from elevated dopaminergic signalling within the mesolimbic pathway of the brain). These have an episodic pattern and can be effectively controlled for the majority (~80–90%) of treatment-naive patients that initially present with symptoms. Negative and cognitive symptoms show limited improvement to current APDs and tend to persist despite treatment with these drugs; this leads to reduced emotional expression, social withdrawal, problems with working memory and trouble focusing, causing patients difficulties reintegrating back into communities and further burdening primary caregivers. As such, there is a need for drugs with novel mechanisms of action that can effectively manage the negative and cognitive symptoms. The two Phase IIb/III studies planned for Evenamide will determine whether its unique mechanism of action can also benefit patients who are not adequately responding to their current treatment.
Side effects from current APDs (which target dopaminergic pathways) tend to cause patient dissatisfaction and poor compliance, perpetuating difficulties in managing the disease. These include on-target side effects such as Parkinsonian-like motor symptoms (extrapyramidal side effects) and sexual-dysfunction (caused by hyperprolactemia), and off-target side effects including weight gain and abnormal heart rhythms (QT prolongation). Although second generation, atypical antipsychotics have significantly improved side-effect profiles (compared to first-generation, typical antipsychotics), novel treatments that can maintain or improve the efficacy with a lower dose of atypical APDs could be beneficial in improving patient compliance and treatment response.
Although there is a strong response to APDs initially in 80–90% of patients, 30–60% of these treatment-responsive patients become resistant or partially responsive to APDs. Schizophrenia patients that do not respond adequately to two (or more) dopaminergic antipsychotics (after an adequate dose and duration) are defined as having TRS. The effective management of TRS has been a longstanding challenge to clinicians and clozapine (Clorazil) is the only approved drug treatment (recommended as a third-line treatment in clinical guidelines issues by American Psychiatric Association, NICE and the World Federation of Societies of Biological Psychiatry). Clinically, clozapine is underutilised for a variety of reasons, but primarily this is due to the potential risk (black box warning) for agranulocytosis, which occurs in ~1% of patients, a potentially severe and life threatening condition due to lower white blood cell count and patients require monthly blood testing. Even though clinical guidelines recommend starting clozapine after two APD treatment failures, clozapine treatment is often delayed by several years (Exhibit 3) and 30% of TRS patients do not respond adequately.
Exhibit 3: Points of clozapine intervention in TRS
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Persistence of symptoms in TRS may be associated dysregulation of glutamatergic pathways as patients have been shown to exhibit higher levels glutamate in certain areas of the brain (the anterior cingulate cortex) while maintaining relatively normal dopamine function in comparison to treatment-responsive patients (who have an abnormally high dopamine function). Newron believes Evenamide could have an incremental impact in treatment without any additional safety issues given its unique mechanism of action of modulating excessive post-synaptic glutamate release (via inhibition of VGSC. Positive data from the Phase II proof of concept study indicated Evenamide was effective and well tolerated as an add-on therapy for patients who were not adequately responding to atypical antipsychotics (risperidone and aripiprazole).
During previous R&D days, Newron has presented preclinical data that have demonstrated the ability of Evenamide to treat numerous symptoms of schizophrenia (both as a mono- and combination therapy). Highlighted in Exhibit 4, and what we feel most relevant, is a preclinical model that demonstrates Evenamide exhibiting a synergistic effect when administered with clozapine in a ketamine induced model for schizophrenia (which induces glutamate dysfunction). Notably, full reversal was achieved when Evenamide was co-administered with clozapine at a dose where clozapine was ineffective by itself. How well this translates into the clinic will be established following the readout of study 004/006 (expected in H220), but could provide the much-needed breakthrough for patients that do not respond to clozapine treatment.
Exhibit 4: Preclinical schizophrenia models demonstrating synergistic effects of Evenamide with clozapine
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Source: Newron. Note: EVE: Evenamide; CLO: clozapine; KET: ketamine.
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A unique mechanism of action for the treatment of schizophrenia
Evenamide (NW-3509) is one of Newron’s proprietary assets, developed internally during a discovery programme conducted between 2003 and 2006 to identify small-molecule inhibitors of VGSC; Newron has been granted patent protection for composition of matter, retaining exclusive rights for Evenamide across a range of countries (including US and Europe) until 2028 and could extend with a five-year patent term extension, should regulatory approval be given.
From screening against over 130 targets, Newron has established that Evenamide works exclusively at VGSCs (also known as NaV1 channels). VGSCs play a crucial role in the CNS, mediating neuronal signal transduction and cycle through three states: closed (resting), open and inactive. Conformational changes that occur between these states mean inhibitors can bind and inhibit one preferentially; rapidly firing channels will exist longer in an inactive state than a resting state, as such inhibitors can preferentially modulate a channel based on the frequency it is firing. It is these features that enable Evenamide to attenuate excessive signalling in glutamatergic systems. This is exemplified with a set of preclinical models performed by Newron: on the left of Exhibit 5 shows the ability of Evenamide (NW-3509) to selectivity attenuate high frequency firing neurons over low frequency and on the right, shows how this translates in vivo to a reduction in excessive glutamate release caused by high frequency firing (induced by veratridine), without causing a reduction to normal (basal) levels of glutamate release.
Exhibit 5: Evenamide attenuates glutamate release from hyperexcitable neurons
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No other marketed antipsychotic drugs have the same MOA as Evenamide. If this preclinical efficacy translates into the clinic, Evenamide could shift treatment paradigms, particularly in treatment-resistant patients. We note the recent Phase III failure of Lundbeck’s asset (Lu AF35700) highlights the need for drugs with novel MOAs for the treatment of TRS patients; Lu AF35700 acted primarily through blockade (antagonism) of dopamine receptors (D2 and D1).
The anti-psychosis market is vast
According to a Grand View Research report, the global antipsychotic drug market was $11.7bn in 2015 and is forecast to grow at a 2.1% CAGR from 2017–25. Most of the branded drugs used widely to treat the anti-psychotic symptoms of schizophrenia (eg AstraZeneca’s Seroquel, BMS’s Abilify, Lilly’s Zyprexa) are out of market exclusivity, with generics widely available. Market growth in this segment will be a function of volume growth in underlying patients and the availability of new drugs. Bristol-Myers Squibb’s Abilify (aripiprazole) was the number one antipsychotic drug, reporting peak sales of $9.2bn in 2014 (before generics hit the market). Much of Abilify’s success is due to its better tolerability profile (lower incidence of weight gain, QT prolongation, sedation) versus second-generation compounds such as risperidone. Abilify’s reported sales are across multiple indications including schizophrenia, bipolar disorder (including maintenance) and autistic disorders. The opportunities for novel MOA drugs (including Evenamide) are wide and could extend beyond schizophrenia; much of this will be dependent on conducting a wide range of clinical trial programmes and this highlights the eventual need to seek a partner for this asset.
Peak sales of €0.9bn as add-on therapy in schizophrenia alone
According to the US National Institutes of Health, the prevalence of schizophrenia in the US adult population is 1.1%. We apply the same prevalence rate to the European population to derive US/EU schizophrenia patient numbers of 5.6 million. According to the National Institute of Mental Health’s Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), 75% of patients are incomplete responders (including drug discontinuation due to side effects) and 33% of incomplete responders are on combination therapy. This derives our Evenamide eligible patient population as defined as incomplete responders on combination treatment. We apply a peak penetration rate of 8% (six years from our assumed 2022 launch year) to these patients who would be eligible for Evenamide as an add on to an atypical ASD. We price in line with Abilify in the US at $12,000 per year and assume an average $6,000 per year price in Europe. We therefore forecast peak sales for Evenamide of €0.9bn as add-on therapy. In a real-life setting its potential would be dependent on the breadth of clinical trials conducted including as monotherapy in clozapine-resistant patients as well as mania and depression patients suffering psychosis symptoms. While we assume a 20% royalty rate on sales, we do not book any partnering milestones at this point; the announcement of a partnering deal and or compelling Phase IIb/III efficacy data could represent upside to our numbers.