There’s more than meets the eye to the story of the seemingly surprising "complete response" letter for Amylin’s ultra-high-profile once-weekly diabetes injectable Bydureon.

On Oct. 19, Amylin announced that FDA had issued a "complete response" letter requesting a thorough QT study (tQT) of Bydureon, the once-weekly diabetes drug partnered with Lilly and Alkermes. QT prolongation has been linked to rare abnormal heart rhythms, including an arrhythmia known as torsades de pointes, which can cause sudden death. Screening is a routine requirement for drug development.

The "complete response" letter seemed like a complete surprise. After all, there had been no reports about FDA raising concerns about QT in a previous action letter issued in March, or other earlier communications (Also see "FDA's "Complete Response" Letter For Byetta LAR Isn't Too Onerous, Amylin Says" - Pink Sheet, 15 March, 2010.. Also, the company says none of its pre-clinical or clinical Bydureon studies indicated any signal that might cause concerns about cardiovascular problems.

During an Oct. 19 call with investors to break the news, Amylin CEO Daniel Bradbury expressed disappointment and said that the company was aware QT assessment was an issue for the review, but not that FDA had major concerns.

"The 'complete response' letter was the first indication that this was an approvability issue," Bradbury asserted during the call.

But the data supporting the Bydureon NDA do not appear to meet FDA’s strict guidance for all new drugs when it comes to testing for QT prolongation.

Nor did the company do a by-the-book study about this risk for Byetta, the twice-weekly version of Bydureon's active ingredient exenatide, which has been on the market since April 2005.

FDA’s strict guidance on testing for risk of the potentially fatal torsades de pointes does not appear to have been followed.

Unfortunately for Amylin, its partners and its shareholders, “thorough” isn’t just another general adjective when it comes to QT. The term “thorough” implies a set of standardized protocols recommended by the ICH-E14 guidance.

FDA spells out its standards clearly in a guidance document issued in October 2005, which requires manufacturers to undertake a specific QT prolongation study for every new drug, ideally in healthy volunteers. The "thorough" part of the study refers to the need for an active control that is known to prolong the QT interval.

Testing Very High Drug Doses Is Required

Developed jointly with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, the FDA guidance was issued following the withdrawal of several drugs – including Janssen’s antihistamine Hismenal (astemizole) and GlaxoSmithKline’s antibiotic Raxar (grepafloxacin) – in light of fatal and non-fatal cases of TdP.

The guidance requires, where possible, testing at “substantial multiples of the anticipated maximum exposure,” rather than the known or expected therapeutic dose. It also calls for a placebo and a positive control – a 400 mg dose of moxifloxacin is a commonly used comparator.

In addition to being mandated for new drugs, the recommendations also apply to some "approved drugs when a new dose or route of administration is being developed that results in significantly higher exposure.”

After the guidance was first issued, as sponsors were getting accustomed to the new requirements, NDA delays related to questions over tQT trial design were common, but they are rare nowadays.

Resubmission Expected At End Of 2011

Amylin executives said they need to meet with FDA to discuss exactly what the agency wants and devise a satisfactory clinical study design, which will determine the timing of the resubmission. The company has estimated conservatively that it may be ready to resubmit at the end of 2011. If, as expected, the response is categorized as Class 2, the review would take another six months, pushing a decision and possible launch out to mid-2012. FDA is also asking for results of Amylin's recently completed clinical trial, known as DURATION-5, but the company believes it can pull that information together rapidly.

FDA's concerns center on exenatide's pharmacokinetic profile. The drug is cleared through the kidneys, so patients with renal impairment – common in the diabetes population – may have abnormally high levels of exenatide in their blood. Byetta's half-life is shorter, so the levels don't accumulate as much, but because Bydureon is long-acting, its accumulation may be problematic. Higher levels of drug exposure are more likely to cause QT prolongation.

The company says its trial data show no signals of problems, but it hasn't conducted studies in patients taking ultra-high doses.

The agency has requested that the new tQT study include patients with PK concentrations consistent with levels seen in patients with renal impairment. During the Oct. 19 call, Bradbury said it was possible that the companies could test higher doses of Byetta, rather than Bydureon, to satisfy the regulatory demands, though that needs to be negotiated and confirmed with FDA. That would be important because Bydureon takes longer than Byetta to achieve stable levels in the blood, which could draw out the trial, analysts noted.

Typically, with Byetta, the steady state plasma concentrations of exenatide are about 211 pg/ml. In patients with severe renal impairment, blood levels might be increased several-fold beyond the normal levels. Bydureon’s pharmacokinetic profile suggests a higher steady-state plasma concentration of 300 pg/ml. And the elevation is even higher in patients with renal impairment, raising a potential concern in theory for clinically relevant prolonged QT, explained Sanjay Kaul, a Cedars-Sinai cardiologist. Kaul, also a member of the agency’s Cardiovascular and Renal Drugs Advisory Committee, stressed that he was commenting generally on cardiovascular safety and was not privy to the Bydureon "complete response" letter.

Why Did QT Work Fall Short?

The short-acting Byetta was cleared at a time in 2005 before guidance on QT prolongation had been issued, so a tQT study was not part of its original NDA.

Amylin has been taking what it terms a "line extension" strategy with the Bydureon application, relying in part on some evidence it had already collected for the initial exenatide review for Byetta. The Bydureon NDA included the DURATION-1 head-to-head study of Bydureon vs. Byetta, safety data from the DURATION-2 trial, and more than seven years' of clinical data for Byetta. DURATION-1 enrolled 295 patients who did not achieve adequate glucose control either with use of diet and exercise or with oral glucose-lowering drugs.

Amylin says plans for testing therapeutic doses of exenatide for QT prolongation had been deemed “adequate” by FDA.

The company says that in 2006 it proactively presented its plan to assess QT prolongation during the Bydureon end of Phase II and pre-NDA meetings with FDA. “FDA responded that our plan to assess this as part of the DURATION-1 Phase III study was adequate,” Amylin said in an e-mailed statement.

The company formally assessed any relationship between QT/QTc intervals and exenatide concentrations in Bydureon-treated patients in the DURATION-1 study. Electrocardiograms and steady-state plasma exenatide concentrations were analyzed in the 148 patients with type 2 diabetes receiving the therapeutic dose of Bydureon 2 mg subcutaneously once weekly. No clinically meaningful QT prolongation or positive correlation between plasma exenatide concentrations and changes in QTc interval were seen over a wide range of exenatide concentrations in this population, which included 56 patients with mild and 10 patients with moderate impairment in renal function. Moreover, chronic dosing with Bydureon (2 mg SC weekly) in patients with type 2 diabetes did not result in clinically meaningful changes in QTc interval, Amylin explained.

The Bydureon application was also supported by a tQT study of Byetta in healthy volunteers. Results were released publicly in a poster presentation at the American Diabetes Association meeting in 2009. That study did have a placebo control as well as a positive moxifloxacin control, in accordance with FDA guidance. And it was negative for QT prolongation. But only a single 10 mcg dose – the therapeutic dose indicated on the label – was administered.

Looking ahead, a conservative approach to tQT design may be most appropriate. In an Oct. 21 note, Deutsche Bank’s Robin Karnauskas noted that management has suggested the possibility of using infused Bydureon to quickly achieve high dose levels representative of Bydureon in renally impaired patients as a shorter option, but that this possibility is looking unlikely.

“We remain conservative and assume the company must use injectable Bydureon. Under this scenario, dosing could take 7-8 weeks (as dosing too fast could induce nausea and it could take time to reach peak levels), which would account for the longer time frame for a QT study (versus other oral pill QT studies the Street is accustomed to),” Karnauskas wrote.

QT Signal Wouldn’t Spell The End

Even if the drug was shown to cause QT prolongation, it might survive. Many drugs associated with QT prolongation issues have got on the market since FDA issued its guidance, and some are doing exceptionally well.

Atypical antipsychotics are a case in point, as several agents in the class are known to prolong QT. Bristol-Myers Squibb’s Abilify (aripiprazole) is a blockbuster, although FDA has issued several warnings on this drug in light of adverse event reports of TdP. Vanda’s Fanapt (iloperidone) gained approval as a late entrant to the class, albeit with a label that explicitly warns of the QT risks and advises first considering other alternatives. Association with QT prolongation didn’t keep Theravance’s novel antibiotic Vibativ (televancin) from getting approved. More recently, on Oct. 20 FDA announced a change in the labeling for Roche/Genentech’s HIV antiviral medication Invirase (saquinavir) to warn of life-threatening arrhythmia effects when used in combination with Norvir (ritonavir), but let the drug stay on the market.

Many factors would come into play regarding an assessment of risk in the case of a signal, including the severity of the signal and interactions with other drugs. Regulators would look at the totality of the data to make an assessment of the drug’s safety, Kaul commented.

And implications could vary across therapeutic areas, depending on how serious diseases are and the availability of alternative therapies – FDA tends to take a more severe stance, for example, with drugs that are in crowded therapeutic areas and/or used in chronic diseases that are non-life threatening on an acute basis.

In diabetes, other drugs within the GLP-1 class are available. Byetta was the first GLP-1 approved and Novo Nordisk’s once-daily Victoza is now on the market and selling well. Victoza is not cleared by the kidneys and does not appear to have any QT prolongation issues.

Some industry observers have criticized FDA after the Bydureon decision, arguing that regulatory scrutiny is getting too intense following the controversy over potential cardiac safety problems with GlaxoSmithKline's Avandia (rosiglitazone). Others, however, take the opposite view, pointing out that the decision on Bydureon seemed reasonable, given ongoing concerns about cardiovascular risks of long-term use of Avandia and the risks associated with bringing a new drug into a large patient population.

Many safe older therapies are available that work well for blood-sugar lowering, commented Suneil Koliwad, president of the San Francisco chapter of the American Diabetes Association. Koliwad acknowledges that given the poor compliance of diabetes patients with existing medications, a once-weekly could have great clinical value, but doesn’t see that benefit as outweighing an unknown risk for QT prolongation.

“We do have a lot of other effective drugs and there are no data to say this particular new drug is head-and-shoulders above other drugs in the marketplace. It’s not a wonder drug in that sense,” he said.

After Avandia, Koliwad said that some practitioners are asking whether new drugs really offer what manufacturers claim or whether in fact they offer only incremental advances in managing patients and with the downside of unknown rare adverse events.

“Practitioners now are much more interested in ensuring new drugs are exceptionally safe,” Koliwad said.

By Emily Hayes

Amylin Plans Cardiac Safety Study By The Book After Bydureon Rejection

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