PRISMA-3 readout expected in Q219
The ongoing Phase III PRISMA-3 (ClinicalTrials.gov Identifier NCT03160521) clinical trial is evaluating the efficacy, safety and tolerability of DORIA (75mg and 100mg administered intramuscularly into the gluteal or deltoid muscle once a month for three successive months) in patients with acute schizophrenia in a multi-centre, randomised, double blind, placebo-controlled trial. Patients who have never taken risperidone before are required to undertake a brief trial of oral risperidone to ensure there is no clinically significant adverse hypersensitivity reaction before receiving the first DORIA dose. The primary outcome measure is the PANSS score mean change from baseline to endpoint over a 12-week period (plus one year follow-up). The Positive and Negative Syndrome Scale (PANSS) is a standardised clinical interview assessing and scoring 30 standardised symptoms (seven positive symptoms, seven negative symptoms and 16 general psychopathology symptoms). PRISMA-3 is assessing whether an improvement in PANSS from day 4 is achievable and statistically significant. If so and if included in its label, DORIA would have a unique selling point versus its competitor LAIs. Secondary outcome measures are the Clinical Global Impression-severity (CGI-S) score mean change from baseline to endpoint, CGI-I score mean at endpoint, overall response rate and PANSS response rate at endpoint. The trial is also looking at health economic-related outcomes (Exhibit 3), which could be relevant in pricing and reimbursement negotiations. PRISMA-3 is expected to read out in Q219, leading to NDA and marketing authorisation applications (MAAs) filing in late 2019. We forecast DORIA launch in 2021.
Exhibit 3: DORIA – PRISMA-3 study HEOR variables
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Source: ROVI presentations
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DORIA: Clinical and practical advantages
Exhibit 7 provides a visual guide to DORIA’s advantages versus competing LAIs on the market and about to launch. While we highlight these advantages we note that the complexity of schizophrenia means one size does not fit all and DORIA provides an additional formulation for physicians to consider on an individual patient basis. Later in this note we highlight the scientific evidence from medical literature on why LAI antipsychotics on the whole are increasingly considered to be better than oral medications in disease control. While we would not expect LAI to replace oral medications completely, the reality is that LAIs are underutilised, particularly in the US. DORIA’s advantages are as follows:
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no need for oral supplementation;
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no need for loading dose or maintenance dose one week after initial injection;
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once-a-month intramuscular injection coincides with once-a-month maintenance outpatient visits; and
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potential for PANSS reduction from day 4 on the prescribing label. The primary efficacy measure in schizophrenia is the PANSS total score. PRISMA-3 is assessing whether an improvement in PANSS from day 4 is achievable and statistically significant. If so and if included in its label, DORIA would have a unique selling point versus its competitor LAIs.
DORIA: Regulatory strategy
In the US ROVI will pursue regulatory NDA filing under section 505(b)(2) of the FD&C Act (as agreed at the special protocol assessment [SPA] meeting with the FDA). Under this section provision (2) of the 505 act, the FDA is permitted to rely on data not developed by the applicant for approval of an NDA. ROVI will use the published literature on oral risperidone as part of the application for the treatment of schizophrenia, in addition to the PRISMA-1, PRISMA-2 and PRISMA-3 efficacy outcomes and safety data. Under the amendment to the act, the FDA aimed to have a slighter faster approval time frame to NME (by months), but in practice this has not panned out.
In Europe ROVI will file a hybrid application with the European Medicines Agency (EMA) for the treatment of acute exacerbation of schizophrenia. The EMA defines a hybrid medicine as “a medicine that is similar to an authorised medicine containing the same active substance, but where there are certain differences between the two medicines such as in their strength, indication or pharmaceutical form”. We forecast a normal approval time frame for DORIA rather than an expedited one.
DORIA: The commercial opportunity for ROVI
ROVI’s commercialisation strategy for DORIA will vary between the US and EU. In the US ROVI is filing for ‘treatment of schizophrenia’ as the labelled indication vs ‘treatment of acute exacerbation of schizophrenia’ in Europe. The small but important nuance here is that the US label implies DORIA can be used at any time during the course of the disease. In practice, US physicians are more likely to consider an LAI in the acute setting (either onset or relapse) as this is the most pertinent time to consider changing a medication or switching to a long-acting formulation, given that, in many cases, lack of patient adherence to medication may have precipitated the relapse. ROVI has developed DORIA specifically as a once-a-month administration (vs weekly, fortnightly or every three months) to coincide with monthly outpatient visits. LAIs facilitate regular contact between patients and psychiatrists, which is essential for monitoring patient welfare and clinical progress.
We anticipate that in Europe ROVI will launch via its subsidiaries in key European markets: Germany, UK, Spain, Italy, France and Portugal. ROVI will need to hire specialist medical reps to support launch and marketing to physicians. In terms of sales and marketing expenses, it will need to extend its sales rep footprint to target the psychiatrists working in the acute medical setting – these physician numbers are relatively small and we believe ROVI can service the major European countries through a salesforce the size of 100 reps. In Europe LAI pricing is $3,650 pa on average and use of LAIs is estimated at 40% penetration. As such, we believe the US opportunity is larger (due to higher pricing – $10,700 pa and relative underutilisation of LAIs versus oral meds). In the US ROVI will need to build a salesforce of a similar size (80 reps) to cover the ~4,000 psychiatrists working in the acute clinical setting. However, ROVI could elect to partner the product in return for royalties and milestones on sales. Competition in the US is entrenched, with J&J, BMS, Lilly and AstraZeneca dominating the market. Nonetheless, given DORIA’s profile and assuming ROVI elects to market, we believe a 5% share of the relevant market is achievable. Furthermore, we expect DORIA to piggyback on the LAI segment versus the oral market from the increasing detailing by competitors.
Schizophrenia: A complex and chronic disorder of the brain
Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels and behaves. Prevention of relapse is a key challenge in schizophrenia as poor adherence to antipsychotic medications leads to high rates of hospitalisation rates and related burden of care, particularly at the onset or during acute episodes/relapses. Genetic predisposition (multiple genes have been implicated) combined with environmental exposures (eg recreational drugs) and/or stresses during pregnancy and childhood are thought to contribute or trigger risk of disorder. The condition affects 1.1% of the world’s population over the age of 18 (source: National Institute of Mental Health); actual rates vary slightly from country to country (about 0.5-1% of the population). Patients are typically diagnosed with the disorder in early adulthood.
The disorder is characterised by a breakdown in the relation between thought, emotion and behaviour, leading to faulty perception and the inability to function normally. Signs and symptoms of schizophrenia can vary by severity, duration and frequency, although the incidence of severe psychotic symptoms often decreases during a patient’s lifetime. Non-adherence to taking medications as prescribed, use of alcohol or recreational drugs, and stressful situations tend to increase symptoms. Generally, symptoms are classified into several categories:
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Positive symptoms include hallucinations, delusions, thought disorders and movement disorders.
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Negative symptoms include flat effect (reduced expression of emotion), social withdrawal and lack of interest in everyday activities.
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Cognitive symptoms include trouble focusing, poor ‘executive functioning’ and problems with ‘working memory’.
While the condition cannot be cured, the success rate of treatment with antipsychotic medications and psychosocial therapies can be high but is dependent on a variety of factors (eg side effects, patient compliance and adherence, patient insight and insurance coverage). Drug therapy usually requires long-term maintenance treatment using one or more antipsychotic drugs (the two main classes of drugs are the ‘typical’ and the ‘atypical’ antipsychotic drug classes). Antipsychotic medications can be taken orally on a daily basis or less frequently (fortnightly/monthly) by intramuscular or subcutaneous injection of LAI formulations of antipsychotic drugs.
Atypical antipsychotics are main stay of drug treatment
There is no cure for schizophrenia and drug treatments focus on eliminating symptoms; the current mainstay of which are the atypical and typical antipsychotic drugs. Both oral and long-acting injectable antipsychotics have shown efficacy, tolerability and safety as treatments for patients with schizophrenia.
First-generation or so-called typical antipsychotics were developed in the 1950s. Examples include chlorpromazine (1950s), fluphenazine (introduced in the 1960s) and haloperidol. These drugs are dopamine (D2) antagonists so side effects include sedation, hypotension and in some cases non-reversible tardive dyskinesia (drug-related involuntary movements).
Clozapine was the first second-generation drug developed; these drugs work as serotonin/dopamine antagonists, D2 partial agonists or serotonin partial agonists at 5-HT. Clozapine was not available in the US (risk of agranulocytosis) but is available in some countries in Europe. Subsequently, other second-generation or atypical antipsychotics were developed in the 1990s. Examples include risperidone (Janssen’s Risperdal), aripiprazole (BMS’s Abilify), olanzapine (Lilly’s Zyprexa), and quetiapine (AstraZeneca’s Seroquel). While this newer generation of atypical antipsychotics improved on the toxicity profile of the typical antipsychotics, drug-related side effects remain troublesome and include sedation, metabolic changes (weight gain, diabetes, hyperlipidemia) and endocrine changes (sexual side effects). Nonetheless, second-generation oral antipsychotics have become the first-line treatment in schizophrenia. In terms of unit volume, risperidone is the most used active drug principle.
Antipsychotic drugs with LAI formulations were developed to reduce the problem of non-adherence, which is estimated to be as high as 40%. The first LAI antipsychotic to be developed was fluphenazine enanthate (ER Squibb & Sons) in 1966, which displayed numerous potential advantages (including better correlation between dose and blood plasma concentrations, better monitoring of compliance, ease of administration and less risk of overdose). Disadvantages included slow titration to dose and a longer duration to therapeutic dosing. During the past 20 years improved versions of second-generation LAIs have been available on the market: Risperdal Consta in 2004 and its follow-up, Invega Sustenna, in 2009.
Long-term drug treatment of schizophrenia has major limitations
Long-term drug treatment of schizophrenia has major limitations; the US National Center for Biotechnology Information (NCBI) estimates that 25-33% of patients are treatment resistant and relapse rates remain high (relapse rates over two years in medication-treated chronic schizophrenia patients are approaching 41% (source: Crow et al 1986); the cumulative relapse rate for first-episode patients with good adherence over a three-year period was 36%, whereas the rate for poorly adherent patients was 57% (Chen et all Schizophr Res. 2005). Non-adherence to antipsychotic medication is common among patients with schizophrenia, and is the greatest challenge for recovery and prevention of relapse with greater risk of hospitalisation. This is particularly so during the early days of diagnosis when patients are coming to terms with their disorder and may not appreciate the necessity of adhering to the medication regimen. Discontinuation of antipsychotic medication in patients achieving remission leads to a relapse in more than 52% of patients in 6.5 months (source: Gilbert et all, 1995). Leucht et all points to a higher risk of relapse if antipsychotic drug medication is discontinued in patients despite them being stable on treatment for five years; this is reflected in treatment guidelines such as those of the World Federation of Societies of Biological Psychiatry, which recommend continuation of antipsychotic drugs for the treatment of first-episode psychosis for at least two years after first remission, and with a minimum of five years relapse-free stability (maybe even throughout life) before considering slow drug withdrawal (over six to 24 months). There is an unmet need in schizophrenia for novel mechanism and new formulations of antipsychotic drugs that can improve patient adherence, reduce persistent psychotic symptoms in antipsychotic-treated patients with fewer side effects and improve on negative and cognitive symptoms.
Evidence supports use of LAI antipsychotics
LAI antipsychotics are often used only when oral medications have failed rather than first-line therapy. Evidence increasingly supports their use as a first choice (WFSBP 2013 updated guidelines). Multiple effectiveness studies show the superiority of LAI antipsychotics, particularly in the case of risperidone.
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Kenneth et al reported the link between risperidone non-adherence and the return of positive symptoms during the early course of schizophrenia (n=49).
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Significantly lower rates of rehospitalization and treatment failure (defined as psychiatric rehospitalization, suicide attempt, discontinuation or switch to other medication, or death).Tiihonen et all (JAMA Psychiatry July 2017) compared the real world effectiveness of antipsychotic treatments for patients with schizophrenia through a prevalence cohort from the Swedish population of 29,823 patients. During a mean follow-up period of 5.7 years, 43.7% of patients were rehospitalized and 71.7% experienced treatment failures. The authors reported that the risk of rehospitalization is c 20-30% lower during LAI treatments compared with equivalent oral formulations and suggested that the improved efficacy of LAIs may be due in part to improved patient adherence on LAI. However, this prospective study did not evaluate other outcome measures.
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Olivares et al reports on the cost effectiveness of switching antipsychotic medication to long-acting injectable risperidone in patients with schizophrenia using the e-STAR patient database in Spain. The authors state: “In terms of effectiveness, at 12 months after switching to long-acting injectable risperidone, there was a higher percentage of patients who did not require hospitalization (89.1%), did not relapse (85.4%) or neither required hospitalization nor relapsed (82.4%) as compared retrospectively with the same period for the previous treatment (67%, 47.8% and 59.8%, respectively)”. Furthermore, while LAI risperidone was more costly per month at €405.8 vs oral at €128.2, cost effective ness per month per patient was lower in three patient scenarios: without hospitalization (€539.82 vs €982.13), without relapse (€519.67 vs €1,242.03), and without hospitalization and without relapse (€597.22 vs €1,059.39).
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Underutilising LAIs appears to originate more from psychiatrist and physician inertia rather than patients’ negative attitude to these formulations. However, there is an increasing acceptance that physicians should be considering the use of LAIs more often in the treatment of schizophrenia and at an earlier point of diagnosis (Heres, S: Long-Acting Injectable Antipsychotics: An Underutilized Treatment Option, Journal of Clinical Psychiatry 2014).
Exhibit 4: Advantages and disadvantages of LAI antipsychotics vs oral antipsychotics
Antipsychotic drugs a vast market for oral and LAI antipsychotics
According to IMS Midas, the US was the largest market for antipsychotics, with 2015 sales of $14.2bn, and sales in the top five largest European markets were $2.6bn. In the US oral formulations represented 87% of the value ($12.4bn) and LAIs accounted for the remaining 13% ($1.8bn) of the value. In the top five European markets, oral represented 69% and injectable 31% in terms of value in 2015. However, as antipsychotic drugs are used to treat a myriad of conditions (including schizophrenia but also depression, bipolar disorder, schizoaffective disorders and are also used off-label to treat acute psychotic episodes in dementia), a better understanding of market opportunity is required to assess the historic schizophrenia injectable market size.
US market opportunities: LAI for schizophrenia
According to IMS Midas, the US is the largest schizophrenia injectable market with MAT Q317 sales of €2.8bn and 2.0m units. Exhibit 5 shows the 25% CAGR (2011-15) in the injectables segment in value. Average pricing for LAIs in the US is ~$10,700 per annum. The market leader by volume (in units) in 2015 was risperidone (32% market share) followed by paliperidone (25% market share). In terms of value in 2015, paliperidone had the highest market share (60%), followed by risperidone (25%). The difference between unit and value relate to pricing; risperidone generics have been available in the US since 2008.
Exhibit 5: US schizophrenia injectable market (US$m)
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Exhibit 6: Top 5 schizophrenia injectable market (US$m)
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Source: ROVI presentations, IMS Midas
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Source: ROVI presentations, IMS Midas
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Exhibit 5: US schizophrenia injectable market (US$m)
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Source: ROVI presentations, IMS Midas
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Exhibit 6: Top 5 schizophrenia injectable market (US$m)
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Source: ROVI presentations, IMS Midas
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IMS Midas reports top five European injectable market sales of €793m and 3.2m units. Exhibit 6 shows the 7% CAGR (2011-15) in the injectables segment by value – average LAI pricing per annum is €3,650. IMS Midas forecasts monthly/fortnightly formulations to have 55% market share in 2021 (every two months or every three months formulations). The market leader by volume (in units) is risperidone (59% market share) followed by paliperidone (33% market share). In terms of value in 2015 paliperidone had the highest market share (55%) followed by risperidone (39%).