Fate of Takeda’s Actos to be assessed by UK regulators this week
By Kirsty Barnes in London
Published: June 13 2011 15:51 | Last updated: June 13 2011 15:51
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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The UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) will meet this week to discuss the fate of Takeda Pharmaceutical’s (TYO:4502) diabetes blockbuster pioglitazone (Actos) in the UK, a source told BioPharm Insight.
An MHRA spokesperson confirmed that a meeting will be held on Thursday and possibly Friday to discuss the Actos situation, although the specific agenda remains confidential.
Following this, the European regulator, the Committee for Medicinal Products for Human Use (CHMP), will meet on 20 June to assess the matter, the source said. The MHRA spokesperson confirmed this.
In an emailed statement, Takeda noted that a pan-European review of pioglitazone is ongoing within the European Medicines Agency (EMA) and Takeda is fully cooperating with the EMA on its review and has provided all data available to it to all regulatory authorities worldwide.
On Thursday the French Health Products Safety Agency (AFSSAPS) announced the suspension of the use of drugs containing pioglitazone (Actos and Competact). Germany has since taken the same decision, it has been reported.
This follows an announcement by the US Food and Drug Administration (FDA) in September 2010 that pioglitazone was under review by the agency after possible associations with a heightened risk of bladder cancer were identified in preliminary findings of a 10-year study sponsored by Takeda.
The source, who is also familiar with the data, commented: “It is a real issue. I think pioglitazone does cause a problem with bladder cancer, probably growth promotion.”
The source explained that this because pioglitazone stimulates the peroxisome proliferator-activated receptor (P-PAR) gamma and alpha receptors and this bladder growth promotion is a class property of alpha/gamma agonists in rodents.
Another setback to Takeda’s diabetes franchise
The situation serves as another blow to Takeda’s diabetes franchise, which has already been impacted by the FDA’s rejection in 2009 of its investigational diabetes drug alogliptin after the agency ruled it didn’t have enough cardiovascular safety data to approve it.
The decision set back the drug’s potential market launch by a number of years as the firm had to go back and run more trials and also has to resubmit its approval application. If approved, alogliptin would then be the fourth DPP-4 inhibitor - instead of the second - to reach the market in its class.
Despite this, it was reported by this news service at the time that Takeda would continue to invest in alogliptin’s development because it was counting on using the drug in a combination pill with Actos to keep this important franchise alive. Although Actos could be generic by the time the combination tablet reaches the market, Takeda will still be able to command a premium price for the combination with branded alogliptin.
Takeda has a lot riding on the alogliptin franchise because of the combination tablet, as it is intended to differentiate alogliptin from being just a “me too” drug to a combination therapy with data. Takeda wants to stay established in the diabetes field and needs the combination tablet approved to do so.
The Japanese drugmaker said in a statement that it is working in cooperation with the French agency AFSSAPS and noted that the decision to suspend the two products was taken on the basis of a small increased risk of bladder cancer in patients treated with pioglitazone observed in a French database study (CNAMTS) independently conducted.
Takeda said it has a large pharmacovigilance programme already in place to monitor any potential association, including interim analyses from the Kaiser Permanente Diabetes Registry (KPNC) study in the US, set up in 2002, which demonstrated no overall statistically significant increased risk of bladder cancer among patients treated with Actos. The study is still ongoing.
The company remains confident in the positive risk/benefit profile of pioglitazone, adding that as part of its commitment to understanding any possible concerns relating to the safety of pioglitazone, it is currently supporting a large, long-term, observational study, (EC 455 PROactive extension trial) which will be reporting in 2015.
The MHRA commented that it is aware of the French medicines regulator’s decision to suspend the use of pioglitazone-containing medicines in France. This is based on the results from an observational study carried out in France which has just become available, the agency noted.
Company remains committed to further investigation
The EMA is currently reviewing all relevant information, including the results from the French study, and will discuss the issue at its meeting later this month, following which a recommendation for the EU will be made, said the spokesperson. The MHRA is contributing to the current EU assessment and the Agency is working closely with all authorities involved in the review and will communicate developments as quickly as possible within the UK, the spokesperson added.
The possible risk of bladder cancer with pioglitazone is known, as bladder cancer was seen in male rats in one of the animal toxicity studies supporting the initial authorisation, said the spokesperson. Takeda is committed to investigate it further in animal studies and is also committed to further observational studies in humans, the spokesperson noted.
In 2005 the EMA’s CHMP assessed the results of the studies in bladder cancer performed since first authorisation and concluded that no clear association could be confirmed and that no regulatory action was needed, although it would be closely following new results as they emerged, said the spokesperson.
Further assessments were conducted by CHMP in 2007, 2009 and 2010 which also concluded that the evidence did not confirm an association, but following an increase in reports of bladder cancer from healthcare professionals, in March 2011 the EMA initiated another European-wide review to further investigate this safety signal, the spokesperson said.
Actos is in a class of drug called thiazolidinedione (TZD), the same as GlaxoSmithKline’s (LON:GSK) infamous Avandia (rosiglitazone), although rosiglitazone only stimulates the P-PAR gamma receptor.
Although Avandia is not an alpha/gamma agonist, regulatory agencies still asked GSK to perform further long-term safety reviews on the drug regarding bladder cancer, the source noted. This class of drugs has been in the media spotlight for the past few years over safety concerns. Avandia and Actos were both linked to a possible increase in bone fractures in a study released in 2009.
Meanwhile, Avandia courted controversy for some time before it was finally announced in late 2010 that, following a review of its safety data, the EMA decided to suspend the marketing authorization for all rosiglitazone-containing medicines (Avandia, Avandamet and Avaglim) in Europe. The FDA took a slightly more lenient approach, and decided that in the US all rosiglitazone-containing medicines will remain available with additional safety labeling and restrictions for use.
The FDA also mandated that the drug continued to be closely monitored in a Risk Evaluation and Mitigation Strategy (REMS) program.
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