The second drug, cabotegravir, with a similar structure as dolutegravir, is still under development by ViiV. Drug resistance and integrase inhibitors: potential impact of HIV subtype. Overall, few discontinuations were due to intolerance or adverse events in either group. Cabotegravir is an HIV integrase strand transfer inhibitor (INSTI) injected twice monthly. Long-acting injectable formulations, namely cabotegravir, have shown superiority when compared with traditional PrEP regimens. •CAB is an investigational HIV INSTI and analogue of dolutegravir •Low solubility crystalline drug suspended in aqueous vehicle •Wet bead nanomilled; terminal sterilization by gamma irradiation •Storage: 3-year shelf life at room temp; excursions permitted 2-30˚C Cabotegravir Long-Acting Nanosuspension R H. Müller, et al. One thing of interest was weight, which really did not differ amongst those who switched vs those who continued dolutegravir/3TC. saturated or unsaturated fatty acids such as but not limited. Dolutegravir, sold under the brand name Tivicay, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. Resistance to injectable LA-cabotegravir was rare in Phase 2 and 3 clinical trials (8 cases total), but: Always seen in subtype A virus, mostly A1 (East Africa and Eastern Europe). Dolutegravir and Cabotegravir M. Aboud from ViiV Healthcare presented findings from a study looking at the most recently approved single-tablet regimen, and the only one without TDF: Triumeq, which contains the integrase inhibitor dolutegravir, abacavir, and lamivudine. bictegravir + TAF + FTC + placebo. 2020;382:1124-1135. Clinical trials are on-going to evaluate this compound, which is being developed as an oral tablet but also as a long-acting injectable formulation, which could make new treatment options available for people living with HIV. Talk to CAB about advantages/disadvantages of TDF vs TAF If on open label Truvada, discussed PCP change to Descovy Cabotegravir and pregnancy Concern for neural tube defects in pregnant women receiving dolutegravir Required hold and revision of HPTN 084 Cabotegravir … These include dolutegravir (DTG) that was approved in 2013, bictegravir (BIC) that was approved in the US in February 2018 and cabotegravir (CAB) that is in phase III clinical development with anticipated release in 2019 [ 13, 14, 15 ]. Diarrhoea (48% vs 16%) and headache (13% vs 16%) occurred in similar proportions in both groups. A long-acting (LA) cabotegravir (CAB) and rilpivirine (RPV) injectable, administered every 2 months to treatment-experienced patients with HIV-1 infection, demonstrated durable virologic suppression and high levels of patient satisfaction over the first 12 months of the phase 2b POLAR study. bictegravir + TAF + FTC + placebo. One participants had emergence of 3TC and INSTI resistance (on … At Week 96, significantly greater improvement from baseline in total treatment satisfaction score was observed in the CAB + RPV LA vs DTG/ABC/3TC treatment group (adjusted mean difference, 2.3 [95% CI, 1.1-3.5]; P< 0.001), further increasing from Weeks 24 (2.1 [0.9-3.3]) and 44 (0.7 [−0.4, 1.9]). Structure of cabotegravir (left) and dolutegravir (right). Similar treatment effects on rates of HIV-1 RNA ≥ 50 copies/mL (long acting injectable medications vs CAR) were seen across subgroups, thereby supporting the overall conclusion. When administered every two months, cabotegravir is 89% more effective than daily pills in preventing HIV acquisition in women. Cabotegravir Injectable Phase III/NDA, Phase II/III (Px) Raltegravir Injectable Preclinical ... analog of dolutegravir ... Payment: Medical vs. Pharmacy Benefit §Medical Benefit oProviders purchase LA-ARV and bill payer for drug, administration, HPTN083 interim results: Pre-exposure prophylaxis (PrEP) containing long-acting injectable cabotegravir (CAB-LA) is safe and highly effective for cisgender men and transgender women who have sex with men (MSM,TGW) Oral Presentation: Plasma exposure-viral load response analysis for dolutegravir in children with HIV-1: Results from IMPAACT P1093 cabotegravir + rilpivirine* Prevention cabotegravir long-acting* Search for Remission and Cure Legacy ARV Drug Portfolio abacavir/lamivudine, ... DNA complexes slower vs RAL or EVG DOLUTEGRAVIR 9 9 9 9 9 Breadth and depth of clinical trial data DTG superior vs … Rilpivirine (RPV) is a cytochrome P450 … Cabotegravir is a potent integrase strand transfer inhibitor with a chemical structure similar to dolutegravir that is under clinical evaluation both as oral and long-acting injectable (LAI) formulations for both the prevention or treatment of HIV infection. Cabotegravir oral tablets and a long-acting injectable two-drug regimen consisting of cabotegravir and rilpivirine for HIV treatment has been approved for use in Canada and is currently under review by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). 6,9,10 Cabotegravir (GSK1265744) is an integrase strand transfer inhibitor (INSTI) of the carbamoyl pyridone class and a structural analog of dolutegravir. The 96-week results reaffirm the 48-week results, showing long-acting cabotegravir and rilpivirine continued to be non-inferior compared with continuing a standard care regimen in adults with HIV-1 for the maintenance of viral suppression. Drug Interactions (see also the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug Interaction Checker). One can expect that all Dolutegravir suppliers will extend their portfolio of antiretrovirals by offering Cabotegravir in future. Cabotegravir is an investigational integrase strand transfer inhibitor currently under study for HIV prevention (preexposure prophylaxis) and treatment (in combination with rilpivirine). Side effects were less common among bictegravir users (18%) compared to dolutegravir users (26%). It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure. Official Title A Phase III Randomized, Double-blind Trial Investigating the Activity of Dolutegravir 50 mg BID vs Placebo Over 7 Days in HIV-1-infected Subjects With RAL/ELV Resistance, Followed by an Open-label Phase With an Optimized Background Regimen. ViiV Healthcare is developing cabotegravir (first disclosed in WO2006088173), which in July 2016, was reported to be in phase 2 clinical development. Primary endpoint: proportion of patients with HIV-RNA ≥50 copies/mL at Week 48 via FDA Snapshot Algorithm. Cabotegravir (GSK1265744) is a potent integrase strand transfer inhibitor and a structural analogue of dolutegravir. drug of cabotegravir, dolutegravir or bictegravir being pro-duced with esterification of the drug substances with. There are currently five drugs in this class; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), cabotegravir (CAB), bictegravir (BIC) [1,2,3,4,5,6,7]. 1433 participants enrolled in these randomized blinded studies. Long-acting injectable therapy also bypasses the gastrointestinal tract, eliminating many first pass drug–food and drug–drug interactions. Therefore, long-acting cabotegravir and rilpivirine provides a therapeutic alternative to daily oral therapy, which might be preferable to oral therapy for some people living with HIV-1. Severe side effects may include allergic … One new LAP is cabotegravir (CAB), a highly potent integrase inhibitor, with a half-life of up to 54 days, allowing for every other month parenteral administrations. HIV Prevention Investigational Therapy Superior Vs Standard of Care. Dolutegravir is the first integrase inhibitor available as a dispersible tablet for oral suspension for children weighing at least 3kg and from four weeks of age. An HIV/AIDS vaccine is the ultimate silver bullet. Dolutegravir was also associated with greater BMI gains in black and Latino/a people vs white. It is taken by mouth. Objectives: In the HIV-1-positive population, a paradigm shift from three-drug regimens (3DRs) to dolutegravir-based two-drug regimens (2DRs) both as initial and switch treatment is beginning to take place, supported virologically by the availability of new potent drugs with high genetic barrier to overcome, at least in certain conditions, the dogma of 3DRs in effective HIV-1 therapy. ClinicalTrials.gov NCT01568892. The present invention relates to processes for preparing substances with antiviral activity, in particular the integrase inhibitors dolutegravir and cabotegravir and analogues thereof, as well as intermediates useful in the processes. 6, 7 Cabotegravir is a potent HIV integrase strand transfer inhibitor (INSTI), 8 while rilpivirine is non‐nucleoside HIV reverse transcriptase inhibitor (NNRTI). It is a common RM for Dolutegravir. It is an interesting drug substance that has slightly different pharmacological properties in comparison to dolutegravir (long systemic half-life, high antiviral potency and low aqueous solubility). In the cabotegravir and rilpivirine group, 246 of 278 individuals (88%) reported an injection site reaction (ISR) at some point; however, of the … Cabotegravir, sold by itself as a tablet under the brand name Vocabria and as an injection in combination with rilpivirine as Cabenuva, is a medication used for the treatment of HIV/AIDS in adults. 11 Rilpivirine (RPV) is a next-generation non-NRTI (NNRTI) currently approved as a once-daily oral tablet to be used in combination with other antiretrovirals for the treatment of HIV infection. HTB. Cabotegravir is an investigational integrase strand transfer inhibitor (INSTI) and analogue of dolutegravir. Most cabotegravir + rilpivirine participants (83%) developed injection site reactions that decreased over time, but in 6 participants (1%) it led to withdrawal. (b) 50% inhibitory concentrations of inhibition of 3′-end processing of raltegravir, elvitegravir, dolutegravir, cabotegravir and … A sister study, HPTN 084, is looking at CAB-LA vs. Truvada in women and adolescent girls. Results of the phase 2 LATTE study show that after 24 weeks of induction triple therapy, maintenance therapy with cabotegravir (a long-acting dolutegravir analogue) and rilpivirine led to virological suppression in 82% of patients, compared to 71% who received efavirenz plus two NRTIs. Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Adverse events reported for cabotegravir included the headache and insomnia common with dolutegravir use. Virological failure occurred earlier and more frequently in the raltegravir group (12% vs 6%) by week 48, and four of 354 patients in the dolutegravir group had integrase inhibitor resistance by week 48 compared to 17/361 in the raltegravir group (adjusted difference -3.7%, 95% CI -6.1 to … The international medical humanitarian organization Médecins Sans Frontières (MSF) has expressed solidarity with the people living with HIV who are opposing the patent applications in India for two important HIV medicines, dolutegravir and cabotegravir. ISR reporting decreased with time in both groups and, by week 48, the proportion of participants reporting ISR was similar in the two groups (20% in every 8 weeks, 19% in every 4 weeks group). Thinking about AEs, there really weren't any major differences, looking at most of the AEs. Suboptimal adherence results in reduced treatment effectiveness, increased costs, and greater risk of resistance and onwards transmission. In this clinical trial, both regimens were highly effective and tolerated over the course of one year. CABOTEGRAVIR: GSK126744 Long Acting ( 744 LA) Muller et al, European Journal of Pharmaceutics and Biopharaceutics,2011 Spreen, 7th IAS, 2013; Min, ICAAC, 2009 Taoda, International Congress on Drug Therapy in HIV Infection, 2012 Favorable attributes for PrEP: • High genetic barrier to resistance N Engl J Med . Early studies have shown that cabotegravir protected monkeys against infection with an HIV-like virus and it appears an injection every 12 weeks can maintain protective levels in humans . (a) 50% inhibitory concentrations of strand transfer activity of raltegravir, elvitegravir, dolutegravir, cabotegravir and bictegravir. Cabotegravir is a structural analogue of dolutegravir and, like dolutegravir, it is dosed once … 5 Cabotegravir is also being studied as an investigational drug to prevent HIV infection. Common side effects include trouble sleeping, feeling tired, diarrhea, high blood sugar, and headache. Mean weight gain 3.7 vs. 2.4 kg DTG+3TC vs. DTG + TDF/FTC. Process for preparing integrase inhibitors such as dolutegravir and cabotegravir and their analogs, useful for treating viral infections eg HIV infection. Cabotegravir and raltegravir appeared to be relatively low-affinity substrates for UGTs, as represented by high K m values (167–560 µM) , whereas the K m values for dolutegravir were between 32 and 96 µM. European Journal of Pharmaceutics To address these issues, long-acting (LA) injectable regimens of the INSTI cabotegravir (CAB) and the NNRTI rilpivirine (RPV) are under evaluation. Cabotegravir (CAB) (GSK1265744) is an investigational INSTI and structural analog of dolutegravir. Of the three current FDA-approved INSTIs, Dolutegravir (DTG), has been the most effective, in part because treatment does not readily select for resistant mutants. However, recent studies showed that when INSTI-experienced patients are put on a DTG-salvage therapy, they have reduced response rates. Cabotegravir and rilpivirine are the first two drugs of LAI formulation, currently in final phase of clinical development. Cabotegravir is being studied in both an oral form (half-life 40 hours) and … In this study, dolutegravir/3TC really gained the most weight noninferiority than a 3- or 4-drug TAF-continuing regimen. Simon Collins, HIV i-Base. This section contains a selection of key portals curated by our global team. Introduction Combination antiretroviral therapy (cART) improves outcomes for people living with HIV (PLWH) but requires adherence to daily dosing. WO-2016113372. Proportion of patients with HIV-RNA ≥50 copies/mL at Week 48 in pooled analysis was 2% for CABENUVA vs 2% for daily oral comparator (non-inferior treatment difference: 0.2% [95% CI: -1.4, 1.7]) Dolutegravir @ time of conception 1,683 5 0.30% Non-dolutegravir @ time of conception 14,792 15 0.10% Dolutegravir initiated during pregnancy 3,840 1 0.03% HIV-uninfected mothers 89,372 70 0.08% 2018 Regimen N # Events Percentage Dolutegravir @ time of conception 426 4 0.94% Non-dolutegravir @ time of conception 11,300 14 0.12% The single death (in the oral therapy arm) was an overdose from methamphetamine and judged unrelated to study drugs. Chronic daily oral ART can be lifesaving but also inconvenient, increasing the risks of non-adherence and treatment failure. risks of taking the medicine must be weighed against the good it will do. The second drug, cabotegravir, with a similar structure as dolutegravir, is still under development by ViiV. ViiV Healthcare and Janssen Pharmaceutical announced positive 48-week data from the phase 3 ATLAS (N=616) and FLAIR (N=566) studies evaluating a long-acting injectable formulation of cabotegravir (ViiV) + rilpivirine (Janssen) in patients with HIV-1 infection.The full data were presented at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle. No participant discontinued bictegravir, emtricitabine, and tenofovir alafenamide compared with five (2%) who discontinued dolutegravir, abacavir, and lamivudine. Cabotegravir Another research team reported on cabotegravir (GSK1265744), an experimental integrase inhibitor related to dolutegravir. Of the participants without data at week 48, 3.6% vs 1.3% (n=11 vs 4) in the CAB/RPV vs oral therapy arms discontinued due to side effects. [2] Contents. Rilpivirine : Orally, there is a decrease in total rilpivirine exposure during pregnancy in the 2nd and 3rd trimesters compared to the postpartum period, representing a 21%, 29% and 35% decrease in Cmax, AUC and Cmin respectively. LA Cabotegravir and Rilpivirine –Phase 3 Results LA-CBT and LA-RPV given q monthly were non-inferior to standard of care ART in 2 Phase 3 clinical trials. Vivian, Mylan, Styrax and Honour are importing Methyl 4-methoxyacetoacetate in huge quantities (maybe for Dolutegravir) and these could be potential suppliers of Cabotegravir. Cabotegravir is an investigational integrase strand transfer inhibitor (INSTI) and analogue of dolutegravir. Metabolism: Cabotegravir (CAB) is metabolized primarily by uridine diphosphate-glucuronosyl transferase (UGT)1A1.Drugs that are strong inducers of UGT1A1 may decrease CAB concentrations and decrease effectiveness. CAB LA is composed of cabotegravir free acid, polysorbate 20, polyethylene glycol 3350, mannitol, and water for injection Drug: Rilpivirine - Injectable Suspension (RPV LA) It is a sterile white suspension containing 300 mg/mL of RPV as the free base. Research teams enrolled 822 volunteers who had never previously been exposed to anti-HIV drugs and randomly assigned them to receive one of the following regimens: 1. Dolutegravir and raltegravir were associated with greater BMI gains in women than men: 0.44 vs 0.12/year, p<0.01; and 0.3 vs 0.08/year, p=0.03, respectively. IDWeek™ 2020; Virtual. Phase Phase III. IDWeek™ 2020; October 21–25, 2020; Virtual Mills A, et al. Cabotegravir : There are no pharmacokinetic data for cabotegravir during pregnancy. Treatment with long-acting (LA), injection-based ART administered by healthcare professionals … Dolutegravir plus 3TC for initial therapy: Gemini Studies 144 wks. January 2021: Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results ... (34% vs. 70%). ViiV Healthcare announced positive 48-week data from the phase 3 ATLAS (N=616) and FLAIR (N=566) studies evaluating a long-acting injectable formulation of cabotegravir + … Pair-wise comparisons were done using t test. It is available in the form of tablets and as an intramuscular injection, as well as in an injectable combination with rilpivirine under the brand name Cabenuva. At the time of writing, cabotegravir is still an investigational antiretroviral agent, manufactured as a once-daily oral tablet and as an intramuscular (IM) and subcutaneous (SC) injectable. dolutegravir + TAF + FTC + placebo. – Dolutegravir highly potent, effective orally for HIV treatment – Cabotegravir-LA highly effective IM for treatment – Protects vaginal & rectal SHIV challenge in macaques • Liability for PrEP – Systemic exposure (fever, fatigue, flu-like illness, headache, rash) – … Cabotegravir 3. Cabotegravir Injectable Phase III/NDA, Phase II/III (Px) Raltegravir Injectable Preclinical ... analog of dolutegravir ... Payment: Medical vs. Pharmacy Benefit §Medical Benefit oProviders purchase LA-ARV and bill payer for drug, administration, Taken together, the 96-week findings provide important evidence to support the long-term use of long-acting cabotegravir and rilpivirine in virologically suppressed people living with HIV-1. Many drugs in the HIV therapy pipeline are being developed as long-acting injections or implantable formulations. It is an integrase inhibitor with a carbamoyl pyridone structure similar to that of dolutegravir. Orkin C, Oka S, Philibert P, et al. In this clinical trial, both regimens were highly effective and tolerated over the course of one year. Conference on Retroviruses and Opportunistic Infections; March 6-10, 2021; Virtual •Weight gain and metabolic alterations have been reported with INSTI- and TAF-based antiretroviral regimens1–3 •Cabotegravir (CAB), an INSTI, and rilpivirine (RPV), an NNRTI, have been approved in the US, Canada, and Europe as the first complete long-acting (LA) injectable regimen Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. Although dolutegravir and cabotegravir have been notable for the lack of integrase resistance that in integrase-naive patients, several case studies were presented at the workshop about resistance in … Side effects were less common among bictegravir users (18%) compared to dolutegravir users (26%). These results are consistent with the dolutegravir vs efavirenz studies, 54,55 and a 30 mg dose of cabotegravir was chosen to proceed based on close review of reasons for discontinuation in each group. ViiV Healthcare announces US FDA approval of the first-ever dispersible tablet formulation of dolutegravir, Tivicay PD, a once-daily treatment for children living with HIV. Cabotegravir, however, does not have as high a barrier to resistance as dolutegravir. Cabotegravir is a drug that has been approved under the brand name Vocabria by the U.S. Food and Drug Administration (FDA) for use with oral rilpivirine (brand name: Edurant) for the short-term treatment of HIV infection. Results of the phase 2 LATTE study show that after 24 weeks of induction triple therapy, maintenance therapy with cabotegravir (a long-acting dolutegravir analogue) and rilpivirine led to virological suppression in 82% of patients, compared to 71% who received efavirenz plus two NRTIs. The present invention relates to processes for preparing substances with antiviral activity, in particular the integrase inhibitors dolutegravir and cabotegravir and analogues thereof, as well as intermediates useful in the processes. Despite this excellent profile, high volume dosing, injection site reactions and low body fluid drug concentrations affect broad use for virus infected and susceptible people. Therapy with long-acting cabotegravir plus rilpivirine was noninferior to oral therapy with dolutegravir–abacavir–lamivudine with regard to maintaining HIV-1 suppression. Explore the big challenges, opportunities, debates and frameworks for business and human rights. Cabotegravir, sold under the brand name Vocabria, is a antiretroviral medication used for the treatment of HIV/AIDS. 24 March 2015.Related: Conference reports, Resistance, idrw 24 Seattle 2015. Long-acting injectable cabotegravir is also being studied for HIV treatment with long-acting injectable rilpivirine (see Briefly). dolutegravir + TAF + FTC + placebo. Research teams enrolled 822 volunteers who had never previously been exposed to anti-HIV drugs and randomly assigned them to receive one of the following regimens: 1. Comparative efficacy and safety of a combination therapy of dolutegravir and lamivudine vs 3-drug antiretroviral regimens in treatment-naïve HIV-1 infected patients at 96 weeks: A systematic review and network meta-analysis.
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