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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Janssen signs licensing agreement with PATH for development of HIV-1 drug
rilpivirine.
Janssen R&D Ireland has signed a licensing agreement with PATH for the early development of a long-acting depot formulation of the human immunodeficiency virus type 1 (HIV-1) drug rilpivirine.
Rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is being developed as potential pre-exposure prophylaxis against HIV infection
read all at
Rilpivirine (TMC278, trade name Edurant) is a pharmaceutical drug, developed by Tibotec, for the treatment of HIVinfection.[1][2] It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-lifeand reduced side-effect profile compared with older NNRTIs, such as efavirenz.[3][4]
Rilpivirine entered phase III clinical trials in April 2008,[5][6] and was approved for use in the United States in May 2011.[7] A fixed-dose drug combining rilpivirine with emtricitabine and tenofovir, was approved by the U.S. Food and Drug Administration in August 2011 under the brand name Complera.[8]
Like etravirine, a second-generation NNRTI approved in 2008, rilpivirine is a diarylpyrimidine (DAPY). Rilpivirine in combination with emtricitabine and tenofovir has been shown to have higher rates of virologic failure than Atripla in patients with baseline HIV viral loads greater than 100,000 copies.
- Rilpivirine bound to proteins in the PDB
- “TMC278 – A new NNRTI”. Tibotec. Retrieved 2010-03-07.
- Stellbrink HJ (2007). “Antiviral drugs in the treatment of AIDS: what is in the pipeline ?”. Eur. J. Med. Res. 12 (9): 483–95.PMID 17933730.
- Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, de Béthune MP, Peeters M, Woodfall B (2006).“Short-term antiviral activity of TMC278–a novel NNRTI–in treatment-naive HIV-1-infected subjects”. AIDS 20 (13): 1721–6.doi:10.1097/01.aids.0000242818.65215.bd. PMID 16931936.
- Pozniak A, Morales-Ramirez J, Mohap L et al. 48-Week Primary Analysis of Trial TMC278-C204: TMC278 Demonstrates Potent and Sustained Efficacy in ART-naïve Patients. Oral abstract 144LB.
- ClinicalTrials.gov A Clinical Trial in Treatment naïve HIV-1 Patients Comparing TMC278 to Efavirenz in Combination With Tenofovir + Emtricitabine
- ClinicalTrials.gov A Clinical Trial in Treatment naïve HIV-Subjects Patients Comparing TMC278 to Efavirenz in Combination With 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
- “FDA approves new HIV treatment”. FDA. Retrieved 2011-05-20.
- “Approval of Complera: emtricitabine/rilpivirine/tenofovir DF fixed dose combination”. FDA. August 10, 2011.
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Rilpivirine hydrochloride, 4-[[4-[[4-(2-Cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) and indicated for the treatment of HIV-1 infection in treatment-naïve adult patients in combination with other antiretroviral agents. The product received marketing approval in the US (brand name Edurant) and is represented by the following general formula (I):
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[0003]EP1419152 B1 claims amongst others Rilpivirine base and Rilpivirinehydrochloride per se as well as pharmaceutical compositions comprising the same. However, only concrete examples for preparingRilpivirine base are given in said patent but no concrete examples describing the production of the hydrochloride salt are provided.
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[0004]EP1632232 B1 claims amongst others a solid pharmaceutical composition comprising crystalline forms A, B, C or D of Rilpivirinehydrochloride. In addition said patent claims a process for the production of Rilpivirine hydrochloride by reacting Rilpivirine base with hydrochloric acid in the presence of a suitable acid, such as acetic acid.
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[0005]Polymorphism is a phenomenon relating to the occurrence of different crystal forms for one molecule. There may be several different crystalline forms for the same molecule with distinct crystal structures and varying in physical properties like melting point, XRPD pattern and FTIR spectrum. These polymorphs are thus distinct solid forms which share the molecular formula of the compound from which the crystals are made up, however they may have distinct advantageous physical properties such as e.g. chemical stability, physical stability, hygroscopicity, solubility, dissolution rate, bioavailability, etc.
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[0006]The bioavailability of a compound intended to be administered orally, is dependent on the compounds solubility in aqueous systems as well as the compounds permeability as mentioned in EP1632232 B1 . Hydrates are known to be less soluble in aqueous systems than anhydrous forms of the same compound. Hence anhydrous forms of Rilpivirinehydrochloride are preferred over hydrated forms. Rilpivirinehydrochloride form D of EP1632232 B1 is a hydrate and thus no suitable candidate for the preparation of an orally administered medicament, whereas form E of the present invention is an anhydrate.
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[0007]The novel polymorph E of Rilpivirine hydrochloride of the present invention shows high solubility in aqueous systems e.g. a higher solubility than forms A and C of EP1632232 B1 and is thus especially suitable for the preparation of an orally administered medicament.
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[0008]In addition the crystalline forms A and C of EP1632232 B1 are difficult to make in a reliable manner as these forms are obtained from the same solvent system. As the polymorphs A and C of Rilpivirinehydrochloride are obtainable from the same solvent system acetic acid/water, the production processes are especially critical and sensitive because the single crystalline forms are only obtainable in pure form in a quite narrow range of temperature as described in the concrete examples A.a) and A.c) of EP1632232 B1 . In contrast form E of the present invention is reliably obtained by crystallization from ethanol as form E is the only polymorph of Rilpivirine hydrochloride obtained from this solvent system.
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[0009]According to example A.b) of EP1632232 B1 form B is obtained by recrystallizing Rilpivirine hydrochloride from propanone using an initial Rilpivirine hydrochloride concentration of 0.3 g/L. However, this concentration is not suitable for up-scaling as larger amounts of Rilpivirine hydrochloride would ask for tremendous solvent volumina and hence the usage of tremendously large reaction vessels. In contrast form E of the present invention is also obtained by applying higher initial Rilpivirine hydrochloride concentrations such as e.g. ≥10 g/L and is thus suitable for large scale production.
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[0010]Hence, aim of the present invention is to circumvent the drawbacks of the known forms A, B, C and D ofEP1632232 B1 by providing an anhydrous polymorph of Rilpivirine hydrochloride, which is obtainable in an easy and reliable manner also in large scale. In addition the novel polymorph shows high solubility in aqueous systems making it especially suitable for the preparation of an orally administered medicament.
Quad Pill for HIV Appears Safe in Renal Disease
Published: Jul 7, 2013
KUALA LUMPUR — HIV patients with mild to moderate renal impairment appear to tolerate treatment with a combination tablet that contains drugs known to impact kidney function, a phase III, open-label, two-cohort study found.
The treatment group receiving the four-drug combination of elvitegravir, cobicistat, tenofovir DF, and emtricitabine, branded as Stribild
Ranbaxy Laboratories gets tentative approval for HIV combination therapy
pic credit-www.pharmaceutical-technology.com
or
The US Food and Drug Administration has granted tentative approval for a fixed dose formulation of two generic drugs for use in combination with antiretrovirals.
Lamivudine and tenofovir disoproxil fumarate tablets, manufactured by India’s Ranbaxy Laboratories, will not be available for marketing in the US because of existing patent protections, but will be eligible for purchase elsewhere under the President’s Emergency Plan for Aids Relief programme.
lamuvudine
Lamivudine (2′,3′-dideoxy-3′-thiacytidine, commonly called 3TC) is a potent nucleoside analog reverse transcriptase inhibitor (nRTI).
It is marketed by GlaxoSmithKline with the brand names Zeffix, Heptovir, Epivir, and Epivir-HBV.
Lamivudine has been used for treatment of chronic hepatitis B at a lower dose than for treatment of HIV. It improves the seroconversion of e-antigen positive hepatitis B and also improves histology staging of the liver. Long term use of lamivudine unfortunately leads to emergence of a resistant hepatitis B virus (YMDD) mutant. Despite this, lamivudine is still used widely as it is well tolerated.
tenofovir disoproxil fumarate
Tenofovir disoproxil fumarate (TDF or PMPA), marketed by Gilead Sciences under the trade name Viread, belongs to a class of antiretroviral drugs known as nucleotide analogue reverse transcriptase inhibitors (NRTIs), which block reverse transcriptase, a crucial virus enzyme in human immunodeficiency virus 1 (HIV-1) and hepatitis B virus infections.
ViiV Healthcare presents phase III SAILING study data of dolutegravir vs raltegravir in treatment-experienced adults with HIV-1
Dolutegravir
| Identifiers | |
|---|---|
| CAS number | 1051375-16-6 |
8 TH MATCH 2013
ViiV Healthcare, a global specialist HIV company established in November 2009 by GSK and Pfizer dedicated to delivering advances in treatment and care for people living with HIV, has announced 24-week data from the phase III SAILING (ING111762) study evaluating the investigational integrase inhibitor dolutegravir in patients with HIV-1 who are failing on current therapy, but had not been treated with an integrase inhibitor.
At 24 weeks, 79% of study participants receiving the once-daily dolutegravir regimen were virologically suppressed (HIV-1 RNA <50 c/mL) vs. 70% of participants on the twice-daily raltegravir regimen. This difference in response was statistically significant with a 95% confidence interval for the difference of 3.4% to 15.9% (p=0.003).
The SAILING study was designed to demonstrate non-inferiority of a regimen containing dolutegravir versus raltegravir (both with up to two background agents) and the analysis met this criterion; statistical superiority was concluded as part of a pre-specified testing procedure. These data were presented at the 20th Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta, Georgia.
Differences in treatment outcome in favour of the dolutegravir arm were driven by greater virologic response: at Week 24, 15% of patients receiving the dolutegravir regimen had virologic non-response vs. 24% of patients receiving the raltegravir regimen. In addition, fewer subjects failed therapy with integrase inhibitor resistance on dolutegravir (n=2) than on raltegravir (n=10, p=0.016).
Overall, the tolerability of dolutegravir (DTG) was similar to that of raltegravir (RAL). At 24 weeks, 2% of subjects on the dolutegravir regimen discontinued due to adverse events (AEs) vs. 4% of subjects on the raltegravir regimen. The rate of drug-related AEs was similar for both arms (DTG 20%, RAL 23%) and commonly reported AEs (defined as events that occurred in more than 10% of subjects) were similar on both arms, namely diarrhoea (20% DTG, 17% RAL) and upper respiratory tract infection (11% DTG, 8% RAL).
“People living with HIV who have developed resistance to more than one antiretroviral drug class face increasingly narrow treatment options and clinical decisions become increasingly complex. We welcome these initial results supporting the efficacy and tolerability of dolutegravir as a potentially useful addition in the management of HIV in treatment-experienced patients.” said John Pottage, chief scientific and medical officer, ViiV Healthcare. “These encouraging data were included as part of the comprehensive clinical data package supporting recent regulatory submissions for dolutegravir and we look forward to receiving the primary analysis at 48 weeks in due course.”
The primary objective of the ongoing double-blind, double-dummy phase III SAILING study is to demonstrate the antiviral activity of once-daily dolutegravir 50mg compared to twice-daily raltegravir 400mg over 48 weeks in HIV-1 infected, antiretroviral-experienced, integrase inhibitor-naïve adults. At baseline, 715 study participants were randomised 1:1 to receive either dolutegravir or raltegravir plus investigator-selected background regimen of no more than 2 agents, one of which was fully active. All subjects had documented genotypic or phenotypic resistance to agents from at least two antiretroviral therapy drug classes, and ongoing virologic replication. Median baseline HIV-1 RNA levels were 4.18 log10 c/mL and median baseline CD4+ cell counts were 200 cells/mm3. The study population included 32% women, 42% were of African American/African heritage, and 46% of study participants were classified as CDC Class C (patients who have one or more AIDS-defining illness). The 48-week primary analysis of this study will be presented at a future scientific meeting.
S/GSK1349572 (dolutegravir, DTG) is an investigational integrase inhibitor currently in development for the treatment of HIV; it does not require an additional pharmacokinetic boosting drug to be added to the regimen. Integrase inhibitors block HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection.
SAILING is the fourth phase III dolutegravir study reporting in 2012 and 2013. Data from the two studies in treatment-naïve populations, SPRING-2 (ING113086) and SINGLE (ING114467), were announced in April and July of 2012 respectively. Data from VIKING-3 (ING112574) in integrase inhibitor-resistant patients were announced in November 2012. Dolutegravir is not yet approved as a treatment for HIV or any other indication anywhere in the world.
Dolutegravir[1] is an experimental new drug under investigation for the treatment of HIV infection. Dolutegravir is an integrase inhibitor. Also known as S/GSK1349572 or just “572”, the drug is under development by GlaxoSmithKline (GSK). Studies have shown dolutegravir to be effective in patients with resistance to the integrase inhibitor, raltegravir.[2] Clinical trials are underway to support dolutegravir in combination with abacavir and lamivudine, in a new new fixed dose combination called 572-Trii.[3] In February, 2013 the Food and Drug Administration announced that it would fast track dolutegravir’s approval process.[4]
Results from the 96-week comparison with efavirenz, SPRING-1, showed dolutegravir 50mg orally to be effective at reducing HIV viral load and raising CD4 counts in integrase-naive patients. [5]
References
- [1] American Medical Association (AMA), STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL (Dolutegravir) Accessed 3 December 2011.
- Dolutegravir (“572”) Holds Up in Heavily Raltegravir-Resistant Patients, Phase 2B Study Finds Nelson Vergel. The Body PRO. Accessed 23 April 2011.
- Shionogi-ViiV Healthcare Starts Phase 3 Trial for “572-Trii” Test positive airwave. The Body PRO. Accessed 23 April 2011.
- “GSK wins priority status for new HIV drug in U.S”. Reuters. 16 February 2013. Retrieved 18 February 2013.
- Horn, Tim. ViiV’s Dolutegravir Continues to Show Well After 96 Weeks, Versus Sustiva, for First-Time Treatment. AIDSmeds.com 7 Mar 2012. Accessed 14 Mar 2012.
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