February 28, 2013 3:59 pm

Lundbeck and Otsuka’s once-monthly schizophrenia drug advantageous though late market entry could hinder uptake

This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com

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Lundbeck (CPH:LUN) and Otsuka Pharmaceuticals’ once-monthly depot formulation of antipsychotic aripiprazole is likely to provide benefits over existing injections, experts told BioPharm Insight. Yet, those interviewed voiced trepidation over its usage given the crowed nature of the market for depots, despite the simple, once-monthly administration and good safety profile for aripiprazole.

The US Food and Drug Administration is expected to decide on aripiprazole once-monthly approval on 28 February. In December 2012, Lundbeck and Otsuka filed an approval application with the European Medicines Agency (EMA), and the agency’s Committee for Medicinal Products for Human Use (CHMP) is expected to make its recommendation in 4Q13, a Lundbeck spokesperson said. If CHMP is positive, European approval will be sometime in the beginning of 2014.

Aripiprazole once-monthly looks very good and patients who participated in the trials did fantastically, noted Dr Peter Ventre, principal investigator, Research Centers of America, Florida.

Lundbeck and Otsuka will jointly promote the product in the US, the spokesperson said. Lundbeck does not provide forecasts for individual products in a specific year; however, aripiprazole once-monthly can generate annual sales in the DKK 2-2.5bn range for Lundbeck, the spokesperson added.

Peak sales for aripiprazole once-monthly is expected to be around USD 800m, according to recent analyst report.

Aripiprazole is the active ingredient in Abilify, a medication marketed by Japan-based Otsuka and Bristol-Myers Squibb (NYSE:BMS). It was approved for schizophrenia in the US in 2002 and in the EU in 2004. Otsuka reported global sales for Abilify of USD 4.4bn (JPY 411,600m) in 2012, according to a recent analyst report.

Antipsychotic medications come in immediate-release injectable formulations, while depots are long-acting. Currently available depots include fluphenazine decanoate, a generic dosed once every two to five weeks, and haloperidol decanoate, also a generic dosed every two to four weeks. Additionally, Sanofi’s (EPA:SAN) Piportil (pipothiazine palmitate) is a once-monthly injection, while Lundbeck’s Clopixol (zuclopenthixol decanoate) is given every one to four weeks. Johnson and Johnson’s (NYSE:JNJ) Risperdal Consta (risperidone) is administered every two weeks, and Invega Sustenna (paliperidone palmitate) is a once-monthly depot.

Aripiprazole could improve compliance due to better tolerability

Aripiprazole is thought to work by partially activating the D2 dopamine as well as the 5-HT1A receptors and blocking activity at the 5-HT2A receptor, according to public information.

It would provide a new treatment option to address the ongoing need for relapse prevention in patients with schizophrenia, the spokesperson said. The latest research suggests only 18% of schizophrenics are fully compliant to their treatment regime, Ventre added, noting compliance is greatly improved by reducing dosing frequency. Risperdal Consta requires twice-monthly administration, which is much more difficult for a patient to comply with, he added. It’s likely aripiprazole once-monthly is going to be a lot more expensive than existing options, said Dr Steven Dubovsky, professor and chair, department of Psychiatry, University at Buffalo, Colorado.

However, Risperdal Consta is hard to store and prepare, Dubovsky said. Before reconstitution, the entire dose pack for Risperdal Consta should be stored in the refrigerator and protected from light, according to the label. It should not be exposed to temperatures above 25°C, and if refrigeration is unavailable, it can be stored at temperatures not exceeding 25° for no more than seven days.

Potentially, aripiprazole once-monthly will not have storage and preparation issues, Dubovsky noted. Aripiprazole once-monthly will be provided in a kit that allows healthcare providers to reconstitute the product powder with sterile water, a Lundbeck spokesperson said.

In addition, aripiprazole once-monthly theoretically will be better than other drugs used to treat schizophrenia such as the neuroleptics and Haldol decanoate, the once-monthly depot of generic haloperidol, Dubovsky said; although aripiprazole’s efficacy can be a little unpredictable, it is better tolerated. Aripiprazole once-monthly is expected to be less effective but is associated with a more favourable side-effect profile than Haldol depot, Ventre agreed. The issue with Haldol decanoate is that patients who used the oral version may have had reactions to chronic drug use, he explained.

Aripiprazole once-monthly use is linked to less weight gain and sedation, and many patients report they are able to function better than on Eli Lilly’s (NYSE:LLY) olanzapine, AstraZeneca’s (LON:AZN) quetiapine or generic risperidone. Aripiprazole has a more complex mechanism of action compared to other depot formulations, Ventre explained.

Depot market already crowded

The big issue is whether there is room in the market for another long-acting antipsychotic, said Dr Philip Harvey, professor, Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Florida. Antipsychotic depots were largely abandoned in the US in the 90s, said psychiatry professor, Dr Stephen Stahl, University of California San Diego. But the introduction of Risperdal Consta and then Invega Sustenna has brought them back in to use, he added. Risperdal Consta was approved in 2003 and Invega Sustenna in 2009.

The issue is that aripiprazole once-monthly is a late market entry, Stahl noted. Johnson and Johnson’s Invega Sustenna set a high efficacy bar, Harvey said. Once stable on this once-monthly depot, it is often possible to reduce the dosage, he explained. Therefore, aripiprazole once-monthly will need to prove to be as good, he added. Invega Sustenna “will be tough to beat,” as it is an extremely useful drug, one expert agreed.

In the US it is likely that aripiprazole will be targeted to patients newly diagnosed with schizophrenia, as the depot can offer good tolerability in this segment, Stahl said. However, because of its perceived lower efficacy than other options it will be tough to compete in the hard-to-treat setting, he added.

The only reason Invega Sustenna is not used in more patients is the price, the expert added. The schizophrenia depot market is small, and it would be much bigger if companies did not insist on charging huge prices, Harvey noted. He said he hoped there would be some movement in the prices, as Risperdol Consta will soon be generic.

In Europe, companies will need to negotiate on price with reimbursement agencies and will likely come under a fail-first policy, Stahl said. The question will be whether patients are able to move onto the aripiprazole once-monthly after not improving with an oral drug or whether they would have to have failed a previous depot, he added.

Lundbeck’s market cap is USD 3.3bn, and Otsuka Pharma is a private subsidiary of Otsuka Holdings (TYO:4578).

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