Schizophrenia: challenges in a crowded market

Schizophrenia is a devastating mental health condition that affects around 1 per cent of adults across all cultures, and is generally more common in men than women. Research has shown that genetics play a major role in the development of the illness, but it is also clear that environmental and other factors will determine a person's likelihood of suffering.

It is a complex condition: at one time researchers suggested at least 8 sub-groups of the illness existed, each with different symptoms. These are now mostly subsumed under the general treatment target of schizophrenia by the FDA and EMA, and antipsychotics are used across the board. Unsurprisingly, the illness places a huge burden on healthcare systems. Estimates of direct and indirect costs suggest that in 1990 the total economic burden of schizophrenia in the US alone was $32.5 billion. Of this, $17.3 billion were direct medical costs.

Unfortunately, there is a general recognition that both older and newer antipsychotics are not effective for a number of patients. This includes patients who exhibit persistent negative symptoms - sometimes called chronic resistant schizophrenia - defined by lack of motivation, emotional decline and a lower score on positive than negative symptoms. In parts of Europe the generic amisulpiride is licensed for the treatment of negative symptoms on the basis of very old studies which do not meet recent standards. The only antipsychotic which has completed the high standard criteria studies required by the EMA is Vraylar (cariprazine), manufactured by Gedeon Richter/Allergan, which shows clear efficacy in treating persistent negative symptoms. Approved in the US last year, it was filed for EU approval in 2016. Another possible target for new treatments is cognitive dysfunction in schizophrenia, though it overlaps with the negative symptom grouping. Finally, there are opportunities for treating resistant schizophrenia - schizophrenia which is unresponsive or poorly responsive to conventional antipsychotics. Again, this overlaps to some degree with the negative symptoms grouping. The only licence for a drug to treat this population is held by clozapine which is not permitted for general use because of potentially fatal agranulocytosis. Treatment with clozapine therefore requires close blood monitoring but is nevertheless widely preferred in resistant schizophrenia.

What strategies are most likely to lead to success for the pharma industry?

One challenge is that new treatments with a similar efficacy profile to existing generic compounds will have difficulty staying competitive. Lower side effects were sufficient for the majority of atypical antipsychotics to gain widespread use, but these are now almost uniformly generic. Improvement in adverse events, such as weight gain, are a possible target. Long acting versions of these atypicals that achieve better compliance are a useful extension of patent exclusivity but many of these are now becoming generic. New antipsychotics need to show significant advances compared to the generic competition in terms of efficacy (such as in the treatment of negative symptoms, cognitive symptoms or in resistant schizophrenia) to provide a significant breakthrough.

Current treatments

There are more than 30 drug therapies in development for schizophrenia, many solely targeted at cognitive symptoms, including a number of updates for older drugs. There has been a flood of generic entries to the schizophrenia market as a number of ‘so-called’ second-generation antipsychotic drugs go off patent. These drugs include Risperdal (risperidone) from Janssen, Lundbeck/Otsuka’s Abilify (aripiprazole) and Pfizer’s Geodon/Zeldox (ziprasidone).

Clinical evidence shows that long-acting antipsychotics can have a significant impact on outcomes; helping to reduce hospitalisations, achieve better remission rates, and improve patient scores of disease severity. As a result, a number of these off-patent drugs have been given a new treatment role as extended release forms. This includes Eli Lilly’s Zyprexa Relprevv (olanzapine extended release), approved in 2008, Abilify Maintena (aripiprazole depot) from Lundbeck/Otsuka, which was approved in 2013, along with AstraZeneca’s now generic Seroquel XR (quetiapine fumarate). Aristada (aripiprazole lauroxil), from Alkermes was FDA approved in 2015, and provides an alternative to Abilify Maintena as it is injected in prodrug form, which metabolises to the active form in the body.

Meanwhile Johnson & Johnson has developed two long-acting monthly injectables: Risperdal Consta and Invega Sustenna (paliperidone palmitate). These have now been joined by Invega Trinza/Trevicta (paliperidone palmitate) which was FDA approved in 2015 and EU approved the following year. Invega Trinza uses a three-monthly injection regime to further reduce relapse, providing the longest dosing interval available. This drug seems to have potential efficacy advantages, including an advantage with regard to compliance.

As well as oral and injectable forms, pharmaceutical companies have developed alternatives such as the sublingual Saphris/Sycrest (asenapine maleate), from Allergan/Lunbeck, which was FDA approved in 2009. The inhaler delivered Adasuve (loxapine and Staccato inhaler), from Ferrer and AOP Orphan, was approved in 2012.

One recent addition in the US is Allergan/Gedeon Richter’s Vraylar (cariprazine) which was FDA approved in 2015 and filed in the EU in 2016. This drug aims to reduce the negative symptoms associated with schizophrenia, it acts by modulating dopamine dysfunction, rather than creating an extreme dopaminergic blockade. It appears able to antagonise receptors when a patient has high dopamine levels, yet agonise receptors when dopamine levels are low. Most currently marketed antipsychotics do not elicit this response. Cariprazine is supported by good clinical trial data, rather than hopes based on mechanism of action.

Although treatment for schizophrenia is covered with good generics, the treatment of persistent negative symptoms is not, with no other drug licensed in the US.

On the horizon: medication in phase III.

Although antipsychotics have proved their worth in treating symptoms of the illness, many patients are resistant to current medications. Although some of the newer antipsychotics produce fewer motor side effects, other concerns have emerged, notably in safety and weight gain. For these reasons, a range of new pharmacological approaches are in testing, including compounds that act on targets besides the usual dopamine D2 receptor. In the longer term, other options such as cannabidiol or stem cell therapy could also prove effective.

There are some two dozen novel drugs in trials, many of which aim to target the core symptoms of schizophrenia, while also reducing known side effects. Currently in Phase III, ALKS 3831 (samidorphan plus olanzapine) from Alkermes is blended to maintain antipsychotic efficacy, while minimising weight gain. Olanzapine causes weight gain, often to a significant extent, but is a very potent antipsychotic. In early trials, the blend resulted in a 37% reduction in weight gain compared to treatment with olanzapine alone. While this strategy of co-therapy to reduce weight gain is possible, the weight gain potential of different atypicals varies widely. To be successful any combination would need to reduce weight gain below that of existing drugs, such as generic ziprasidone.

Also in Phase III is EVP 6124 (encenicline), from Forum Pharma, which has shown promise in early trials; it appears well-tolerated and could offer improved function for schizophrenia patients with cognitive impairment. Studies revealed that 85% of patients treated experienced reduced adverse effects compared to conventional treatments. However, one safety extension trial was placed on hold due to gastrointestinal side effects, and two phase III trials missed their co-primary endpoints, so success is in the balance. Reviva Pharmaceutical’s RP 5063 is also targeted at reducing cognitive impairment. Currently entering phase III trials, RP 5063 showed a very good safety and tolerability profile with no weight gain, metabolic, cardiac or movement side effects to date. This was combined with a robust remission level efficacy for acute schizophrenia, and promising efficacy signs for common comorbid conditions of cognition impairment and mood disorders.

There are also longer-acting versions of conventional therapies still in trials. RBP 7000 (risperidone subcutaneous sustained release) from Indivior, holding company of Reckitt and Benkiser, is a reworked version of longer acting Risperdal designed for once-monthly subcutaneous injections. It is expected to show a reduced burden of extra-pyramidal side effects (EPS) of schizophrenia – namely parkinsonian symptoms, dystonia, akathisia and tardive dyskinesia. It is currently in phase III trials, with filing expected in 2017. However, such an attempt to reduce EPS by a different formulation of risperidone would need to improve upon the better generic atypicals to demonstrate advantage, bearing in mind the high costs of new treatments.

Other drugs are looking to benefit from new receptor targeting strategies. ITI 007 from Intra-Cellular Therapies differs from most other antipsychotics in that it functions primarily as a 5-HT2A receptor antagonist. If approved, it will be the only antipsychotic to exhibit nearly 60 times the affinity for 5-HT2A receptors compared to D2 receptors. The idea of targeting the 5-HT2A receptors more than the D2 receptors is an attempt to ameliorate side effects. If successful, ITI 007 could improve social abilities, reduce negative symptoms and  reduce depression, while minimising side effects such as weight gain. Lundbeck has invested in Lu AF 35700, which it hopes will be an improvement over its Lu 31130 (zicronapine) – a second-generation antipsychotic that had progressed through Phase II trials, after which development ceased. Lu AF 35700 is a modified form and it is expected to have greater efficacy than Lu 31130 via its unique mechanism of targeting the D1 dopamine receptor. It is suggested that it will show similarities to clozapine, with reduced weight gain and metabolic impact.

Over the horizon: Phase II and early trials.

Nuplazid (pimavanserin), from Acadia Pharma, currently in Phase II trials, is an inverse agonist of the serotonin receptor subtype 5-HT2A, with 10x selectivity over 5-HT2C receptors. Early trials for schizophrenia showed faster drug impact and reduced side effects in combination with a low dose of risperidone. The drug has already been approved for psychosis in Parkinson’s disease. The success of pimavanserin in obtaining approval for this is important, since only clozapine has a similar indication. This provides early signs for potential efficacy in schizophrenia with or without movement disorders, and possibly efficacy in resistant schizophrenia with some subsyndromal symptoms of Parkinson’s disease.

Like a number of pharma companies, AbbVie is hoping to offer improved efficacy with fewer side effects by altering which receptors its drugs target. For instance, ABT 126, currently in Phase II trials, was developed to treat cognitive deficits in schizophrenia, while trying to eliminate the significant side effects. One hope is that ABT 126 may decrease inflammation while enhancing cognitive function. AQW 051 from Novartis seems to be targeting similar aims. In the first phase of clinical trials, AQW 051 was considered well-tolerated with a safe pharmacokinetic profile.

OMS 824 from Omeros is aimed at an under-explored therapeutic target for the treatment of cognitive deficits associated with diseases, but has garnered increased attention from drug developers. OMS 824 selectively inhibits PDE10, an enzyme expressed in areas of the brain linked to a wide range of diseases that affect cognition, including schizophrenia and Huntington's disease. In early trials, the drug was well tolerated and demonstrated comparable systemic pharmacokinetics when administered alone, and concomitantly with approved antipsychotic agents in patients with schizophrenia. In addition to potential benefits for cognition, OMS 824 could also improve psychiatric manifestations, such as hallucinations and the flat affect symptoms of schizophrenia.

Which, if any, of these new therapies will pay off?

The efficacy of different pharmacological approaches and potential advantages will have to wait for completed efficacy studies rather than optimistic assumptions, particularly with cognitive function, which is difficult to establish with the measures mandated by the FDA.

References:

Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Leiberman JA. Mol Psychiatry. 2012 Dec 17 (12):1206-27. doi: 10.1038/mp.2012.47. Epub 2012 May 15.

Treatment-Resistant Schizophrenia. Elkis H, Buckley PF. Psychiatric Clinics of North America, Volume 39, Issue 2, June 2016, Pages 239-265.

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer?s and Parkinson?s diseases. Shettya AK, Bates A. Brain Research, Volume 1638, Part A, 1 May 2016, Pages 74–87.