Etravirine (TMC125, Intelence) granted accelerated approval in US

Edwin J. Bernard
Published: 21 January 2008

The second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (formerly TMC125) was granted accelerated approval by the US Food and Drug Administration (FDA) last Friday, January 18th. The drug – given the trade name Intelence by its developers, Tibotec – is only approved for treatment-experienced adults, and at under US$8000 a year wholesale, significantly undercuts the price of other drugs from other classes for the treatment-experienced.

The FDA says that etravirine should be used in combination with other antiretrovirals, and is only indicated for treatment-experienced adults who have evidence of viral replication and HIV strains resistant to an NNRTI and other antiretrovirals.

The drug's approval is based on Week 24 analyses from the DUET 1 and DUET 2, studies, which included individuals with both NNRTI resistance and at least three primary protease inhibitor mutations. Longer-term data will be required before the FDA can consider traditional approval for etravirine.

The DUET study results, published last July in The Lancet, suggest that an undetectable viral load can be achieved in this highly treatment-experienced population if they receive both etravirine and Tibotec’s darunavir (Prezista), and have only a modest level of NNRTI resistance.

A press release from Tibotec’s parent company, Johnson & Johnson, highlights the following:

  • A patient's full treatment history and, when available, resistance testing, should be considered when initiating therapy with etravirine
  • The use of other active antiretroviral agents alongside etravirine is associated with an increased likelihood of treatment response
  • Individuals who have experienced virologic failure on an NNRTI-containing regimen, should not combine etravirine with currently approved N[t]RTIs alone, due to the risk of virologic failure.
  • The risks and benefits of etravirine have not been established in children, in pregnant women, and in treatment-naïve adults.

Etravirine’s most commonly reported side-effects are rash and nausea. However, rare cases of serious skin reactions such as Stevens-Johnson syndrome and erythema multiforme have been reported during etravirine’s development.

Resistance data

The press release also contains updated information on resistance mutations and etravirine susceptibility. It confirms that the presence of the most common NNRTI mutation, K103N, did not affect the treatment response in the individuals on etravirine in the DUET studies.

However, the presence at baseline of V179D, V179F, V179T, Y181V, or G190S was associated with a decreased virologic response to etravirine.

In addition, the presence at baseline of three or more NNRTI mutations, as defined by the 2007 IAS-USA guidelines (V90I, A98G, L100I, K101E/P, K103N, V106A/I/M, V108I, V179D/F, Y181C/I/V, Y188C/H/L, G190A/S, P225H) resulted in a decreased virologic response to etravirine.

Virologic failure on an etravirine-containing regimen most commonly led to the folowing NNRTI-resistance associated mutations: V179F, V179I, Y181C, and Y181I. Less common emerging NNRTI-resistance associated mutations included: K101E, K103N, V106I/M, V108I, Y188L, V189I, G190S/C and R356K.

The company notes, therefore, that, “cross-resistance to delavirdine, efavirenz, and/or nevirapine is expected after virologic failure with an [etravirine]-containing regimen.”

Dr Martin Fisher, a consultant in HIV/GU medicine at Brighton & Sussex University Hospital, told this month’s HIV Treatment Update that cross-resistance to current (and possibly future) NNRTIs may be etravirine's most limiting factor. “When using etravirine one has to look very carefully at the degree of underlying non-nucleoside resistance,” he said.

“What’s become very apparent is that the more non-nucleoside mutations one has, broadly speaking, the less likely etravirine is to work. So, the critical message there is that if anybody is taking either nevirapine or efavirenz and is experiencing virological failure, you need to get off that non-nucleoside as soon as possible because otherwise you’re scuppering your chances of etravirine working in the future.”

Drug interactions

The press release also includes an updated list of drug interactions. Tibotec says that etravirine should not be co-administered with: ritonavir-boosted tipranavir, ritonavir-boosted fosamprenavir, ritonavir-boosted atazanavir, full-dose ritonavir (i.e. 600mg bid), non-ritonavir-boosted protease inhibitors, or other NNRTIs. Combining etravirine with Kaletra (lopinavir/ritonavir) is possible, but should be done “with caution.”

Pfizer has previously announced that dose adjustments are required when combining etravirine with its CCR5 antagonist maraviroc (Celsentri). Data from the University of Liverpool’s drug interaction website suggests that co-administering etravirine with Merck’s integrase inhibitor raltegravir (Isentress) requires no dose adjustments.

In addition, etravirine should not be co-administered with carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, rifabutin (when part of a regimen containing protease inhibitor/ritonavir) or products containing St. John's wort.

It also warns that “this not a complete list of potential drug interactions” and that co-administration of etravirine “with other agents such as substrates, inhibitors, or inducers of CYP3A4, CYP2C9, and/or CYP2C19 may alter the therapeutic effect or adverse events profile of [etravirine] or the co-administered drug(s).”

Availability and pricing

Etravirine is expected to become available in the United States this week. Tibotec has also submitted applications for approval of etravirine to the European Agency for the Evaluation of Medicinal Products (EMEA) as well as to regulatory authorities in Canada, Switzerland, Russia and Australia. Etravirine has been available in an expanded access programme since the end of 2006.

A Tibotec spokeswoman told Reuters that etravirine’s wholesale cost will be US$5.45 per tablet. Since the approved dosing is two tablets twice per day, that means its annual wholesale cost (US$7,957) is well below that of other oral drugs approved for treatment-experienced individuals, including Tibotec’s own darunavir (at around US$9,000), Merck’s raltegravir (at around US$10,000) and Pfizer’s maraviroc (at around US$10,585) .

Outspoken treatment advocate, Martin Delaney of the Fair Pricing Coalition, was quoted in the Johnson & Johnson press release thus: "Tibotec Therapeutics continues to demonstrate real leadership in the pharmaceutical industry by pricing [etravirine] fairly and responsibly,” he said. “We applaud Tibotec's responsible corporate behaviour and expect to see the drug quickly accepted on all formularies."