Telaprevir

Structural formula
General
Non-proprietary name	Telaprevir
Molecular formula	C 36 H 53 N 7 O 6
External identifiers / databases
EC number	609-814-6
ECHA InfoCard	100.129.857
PubChem	3010818
ChemSpider	2279948
DrugBank	DB05521
Wikidata	Q408557
Drug information
ATC code	J05 AE
Drug class	Antivirals
Mechanism of action	Protease inhibition
properties
Molar mass	679.9 g · mol -1
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling ; no classification available
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Telaprevir is a virus-inhibiting ( virostatic ) drug from the still new class of HCV protease inhibitors .

Telaprevir was launched in the USA in May 2011 as Incivek ^® (pharmaceutical company: Vertex Pharmaceuticals ) and in the EU in September 2011 as Incivo ^® (pharmaceutical company: Janssen-Cilag International NV ) exclusively in combination with the two antiviral agents peginterferon α and ribavirin approved for the treatment of chronic hepatitis C virus infection in adults. Vertex Pharmaceuticals stopped marketing Incivek ^{® in} late 2014. Janssen stopped marketing Incivo ^® in the EU in 2016.

Telaprevir is effective orally .

Mechanism of action

Telaprevir inhibits the viral NS3.4A protease of the hepatitis C virus (HCV) genotype 1 by reversibly binding to a serine group in the active site of the protease. The formation of the viral proteins by breaking down the viral polyprotein that is primarily formed is thereby prevented at the point of cleavage of the non-structural protein 3 and virus replication in HCV-infected host cells is blocked.

application areas

Telaprevir in combination with peginterferon alfa and ribavirin is indicated for the treatment of genotype 1 hepatitis C virus infection in adult patients with compensated liver disease (including cirrhosis ) who have either not received treatment, have not responded to treatment, or have received treatment but have relapsed. Compensated liver disease is when the liver is damaged but still functions normally.

Incivo has been shown to be effective in phase III placebo-controlled studies , with the main studies enrolling 1,095 untreated and 663 previously unsuccessful patients with chronic genotype 1 hepatitis C infection and compensated liver disease. All patients also received peginterferon α and ribavirin. Another study compared the effect of different lengths of peginterferon α / ribavirin therapy (either 6 or 12 months) in combination with a three-month telaprevir treatment. The main measure of effectiveness was the number of patients who had no viral RNA in their blood six months after the end of treatment ( sustained virologic response , SVR).

In the studies, the additional administration of telaprevir for three months in addition to the current standard therapy with peginterferon α and ribavirin resulted in a significantly higher sustained virological response (75% in patients treated for the first time, 88% in previously unsuccessful patients) compared to the use of standard therapy alone (44% in patients treated for the first time, 24% in unsuccessfully pretreated patients). The third study found that in telaprevir-treated patients, six months of peginterferon α / ribavirin therapy was as effective as twelve months.

Restrictions on use and side effects

Telaprevir is contraindicated in patients with corresponding hypersensitivity to the active ingredient, and in the case of simultaneous use of class Ia or III antiarrhythmics . Because of the mandatory simultaneous treatment with peginterferon α and ribavirin, the use of telaprevir during pregnancy is prohibited. Since telaprevir is a potent inhibitor of CYP3A , its use is also contraindicated in concomitant use of medicinal products whose clearance is highly dependent on the same enzyme system and in which elevated plasma concentrations can have serious or life-threatening consequences.

Numerous side effects can occur with the triple therapy telaprevir / peginterferon α / ribavirin, the most common of which are anemia , rash, thrombocytopenia , lymphocytopenia , pruritus , diarrhea and nausea. The skin reactions can sometimes be very severe; two cases of toxic epidermal necrolysis (TEN) are known, one of which was fatal. Even if the circumstances have not yet been fully clarified, there is a warning from the drug commission of the German medical profession.

chemical characterization

The synthetically produced substance telaprevir has six chiral centers and is optically active . The pharmacological activity is very dependent on the conformation of the molecule, as has, for example, the R - diastereomer of telaprevir called only one-thirtieth of the efficacy of telaprevir even VRT 127,394th

Telaprevir is virtually insoluble in water and moderately soluble in ethanol . An anhydrous crystalline modification, form A, is used medicinally .

Early benefit assessment (Section 35a SGB V)

A resolution regarding the additional benefit of telaprevir - based on Section 35a SGB V ( AMNOG ) ( early benefit assessment ) - by the Federal Joint Committee (G-BA) took place at the end of March 2012. According to the G-BA, the additional benefit for the active ingredient telaprevir cannot be quantified. A rather positive assessment by the Institute for Quality and Efficiency in Health Care (IQWiG) had been made beforehand.

Individual evidence

↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
↑ Information on Incivo on the European Medicines Agency website .
↑ From Riches to Rags: Vertex Discontinues Incivek as Sales Evaporate . Retrieved December 1, 2015.
^ Telaprevir discontinued in Canada . Archived from the original on December 8, 2015. Retrieved December 1, 2015.
↑ http://www.eatg.org/press/eatg-welcomes-the-removal-of-incivo-telaprevir-from-eu-markets/
↑ Specialist information Incivo , akdae.de (PDF; 274 kB) as of March 2012.
↑ Procedure in the event of severe skin reactions in connection with INCIVO therapy (PDF; 361 kB).
↑ Information archive | Early benefit assessment (§ 35a SGB V) , website of the Federal Joint Committee (G-BA).
↑ Early benefit assessment: G-BA makes six further decisions , G-BA press release of March 29, 2012.
↑ BMG: Announcement of a resolution (PDF; 388 kB), publication in the Federal Gazette BAnz AT May 10, 2012 B3 .
↑ Telaprevir: additional benefit for certain patients with hepatitis C , press release from the Institute for Quality and Efficiency in Health Care (IQWiG).

[NV-1] This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.

[2] Information on Incivo on the European Medicines Agency website .

[3] From Riches to Rags: Vertex Discontinues Incivek as Sales Evaporate . Retrieved December 1, 2015.

[4] Telaprevir discontinued in Canada . Archived from the original on December 8, 2015. Retrieved December 1, 2015.

[5] ttp://www.eatg.org/press/eatg-welcomes-the-removal-of-incivo-telaprevir-from-eu-markets/

[6] Specialist information Incivo , akdae.de (PDF; 274 kB) as of March 2012.

[7] Procedure in the event of severe skin reactions in connection with INCIVO therapy (PDF; 361 kB).

[8] Information archive | Early benefit assessment (§ 35a SGB V) , website of the Federal Joint Committee (G-BA).

[9] Early benefit assessment: G-BA makes six further decisions , G-BA press release of March 29, 2012.

[10] BMG: Announcement of a resolution (PDF; 388 kB), publication in the Federal Gazette BAnz AT May 10, 2012 B3 .

[11] Telaprevir: additional benefit for certain patients with hepatitis C , press release from the Institute for Quality and Efficiency in Health Care (IQWiG).