information: Presentation of results at a congress
Announcement: presentation of results at HIV Drug Therapy Glasgow 2018
Company: TaiMed Biologics (Taiwan) - Theratechnologies (Canada)
Product: Trogarzo™ (ibalizumab)
- monoclonal antibody. Ibalizumab is a CD4-directed HIV entry-inhibitor and is the first humanized monoclonal antibody in clinical trials for the treatment of HIV. Ibalizumab was designated a Breakthrough Therapy by the FDA based on preliminary clinical evidence indicating that it may represent a substantial improvement over existing therapies on one or more clinically significant endpoints. In a Phase IIb clinical trial, conducted on 113 patients, the product significantly reduced viral load in multi-drug resistant HIV-infected patients. The FDA has also granted ibalizumab Orphan Drug designation.
Disease: HIV-1 infection
area: Infectious diseases
- TMB-301 is a single arm, 24-week study of ibalizumab plus optimized background regimen in treatment experienced patients infected with multi-drug resistant HIV-1. The primary objective of the study is to demonstrate the antiviral activity of ibalizumab 7 days after the first dose of ibalizumab. Patients receiving their current failing ART regimens were monitored during a 7 day control period. Thereafter, a loading dose of 2000 mg of intravenous ibalizumab was the only ART added to their regimen. The primary efficacy endpoint is the proportion of patients achieving a ? 0.5 log10 decrease in HIV-1 RNA 7 days after initiating Ibalizumab therapy, day 14 of the study. Ibalizumab is continued at doses of 800mg IV every two weeks through 24 weeks on study treatment. Safety and additional efficacy endpoints are evaluated during the study. (NCT02475629)
- • On October 31, 2018, Theratechnologies announced that additional analysis of phase III clinical trial data of Trogarzo® (ibalizumab-uiyk) injection was presented today during a late-breaking clinical trial session at HIV Drug Therapy Glasgow 2018. The analysis compares the results of the patients who completed the study with the Intent-to-treat-Missing-Equals-Failure (ITT-MEF) method, used in the pivotal phase III clinical trial. The ITT-MEF tends to generate much more conservative results as all patients not completing a trial are considered a treatment failure notwithstanding the reason for not completing the study.
- Among patients still on treatment at week 25 (31/40), the median viral load reduction was 2.5 log10 with 55% (17/31) achieving a viral load below 50 copies/ml compared to a 1.8 log10 viral load reduction and 43% of patients with a viral load suppression below 50 copies/ml using the ITT-MEF analysis method.
- At week 48, the median viral load reduction was 2.9 log10 among the 24 who were still on treatment. Among those 24 patients, 67% (16/24) had a viral load under 50 copies/ml compared to a 2.8 log10 reduction and 59% of patients with a viral load suppression below 50 copies/ml with the ITT-MEF analysis method.
- • On October 3, 2018 – Theratechnologies announced that pharmacokinetic data from the pivotal phase III clinical trial for Trogarzo™ (ibalizumab-uiyk) injection have been presented tomorrow at IDWeek™ in San Francisco. These data conclude that the FDA-approved dosing regimen of 2,000 mg loading dose followed by an 800 mg maintenance dose every two weeks is enough to support high levels of CD4 receptor occupancy and drug concentration above therapeutic level. The data is derived from the pivotal TMB-301 study.
- • On August 15, 2018 – Theratechnologies announced that results from the phase III clinical trial used to obtain FDA approval for Trogarzo™ (ibalizumab-uiyk) injection in the United States were published in The New England Journal of Medicine (NEJM). Furthermore, the NEJM published an article, authored by the Office of the Antimicrobial Products of the FDA, giving rationale for the design of the phase III trial of Trogarzo™ that led to its approval.
- The phase III, open-label study, enrolled 40 patients with multidrug-resistant (MDR) HIV-1 in whom multiple antiretroviral therapies had failed. All patients at baseline were experiencing viral failure. After a seven-day control period, patients received an intravenous 2000 mg loading dose of Trogarzo™ which was the only change made to their antiretroviral regimen. Through the 24-week treatment period of the study, patients were given a maintenance dose of 800 mg of Trogarzo™ every two weeks along with an optimized background regimen that included at least one additional fully active agent.
- The primary endpoint of the study was the proportion of patients with a viral load reduction of at least 0.5 log10 from baseline, 7 day after the loading dose. The mean baseline viral load was 4.5 log10 while the mean CD4 cell count was 150 per microliter. Of the 40 patients, 33 (83%) had a decrease in viral load of at least 0.5 log10 from baseline. At the end of the 24-week treatment period, 43% of patients had a viral load lower than 50 copies per milliliter (considered below detection level) and 50% had a viral load of less than 200 copies per milliliter.
- • On March 7, 2018, Theratechnologies presented new results from additional analyses based on studies conducted with Trogarzo™ and Egrifta®. The study conclusions were unveiled during the 25th Conference on Retroviruses and Opportunistic Infections (CROI). The goal was to determine the in vitro activity of ibalizumab in treatment-experienced HIV-infected patients who are resistant to a significant number or all drugs approved for the treatment of HIV, namely nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), enfuvirtide (ENF) and maraviroc (MVC).
- Blood samples were collected at study entry from all 40 participants in the phase III clinical trial using ibalizumab (TMB-301). The analysis was conducted to determine susceptibility to ibalizumab and to all other antiretrovirals. The study results confirm that ibalizumab is a potent new tool for the treatment of HIV-1 as it is equally active in HIV isolates notwithstanding if those are sensitive or resistant to all other antiretrovirals.
- Phase III clinical trial results show that, seven days after the initial infusion of ibalizumab, 83% of patients had a viral load decrease of ? 0.5 log10 (p < 0.0001) while the mean viral load decrease was 1.1 log10.
- • On January 17, 2017, Theratechnologies announced that the abstract submitted by its partner, TaiMed Biologics, for the 24-week study results of the ibalizumab (IBA) phase III study (TMB-301) has been selected for a late breaker presentation, Tuesday, February 14th, 2017, at the Conference on Retroviruses and Opportunistic Infections (CROI) to be held in Seattle, WA, from February 13 to 16, 2017. These results were first announced in November 10, 2016 (see below). Dr. Brinda Emu, Assistant Professor of Medicine, Infectious Diseases, Yale School of Medicine, CT, will be presenting additional efficacy and safety data related to the 24-week study. In addition, an abstract presenting the preliminary pharmacokinetics (PK) and pharmacodynamics (PD) data of a study comparing the intramuscular (IM) to the intravenous (IV) administration of ibalizumab has also been accepted for a presentation, Wednesday, February 15, 2017. The results of this study demonstrate that the PK profile of 800 mg IBA bi-weekly IM administration was comparable to the 800 mg IV bi-weekly administration while maintaining effective concentration during the dosing period.
- • On November 10, 2016, Theratechnologies announced that it has been notified by its partner, TaiMed Biologics, of the preliminary results for the safety and efficacy secondary endpoints of the 24-week Phase III trial with ibalizumab in patients with multi-drug resistant (MDR) HIV-1 (TMB-301).
This Phase III trial confirms the safety and efficacy results of ibalizumab observed in the previously completed Phase IIb study, despite the fact that the patient population in the Phase III trial had higher levels of MDR HIV-1 and more advanced disease at time of enrollment.
- In the Phase III trial, after 24 weeks of treatment, the mean reduction in viral load was 1.6 log10 and a total of 48% of patients had a reduction in viral load of more than 2.0 log10
during this period. At the end of the treatment period using ibalizumab with optimized background regimen, the proportion of study participants with undetectable viral
load (HIV-1 <50 copies/mL) was 43% (mean viral load reduction of 3.1 log10) and 53% of patients had a viral load lower than 400 copies/mL. The mean viral load of patients at
baseline was 100,287 copies/mL. As previously announced, the preliminary results also indicated that 83% of patients enrolled in the Phase III trial (33/40, p<0.0001) have met the
primary endpoint of a decrease of ? 0.5 log10 in viral load following a 7-day treatment period with ibalizumab.
The safety results in this Phase III trial are consistent with the ones previously observed in the Phase IIb study. Other than for one case of immune reconstitution inflammatory syndrome, an inflammatory response in HIV-infected patients that may be triggered after changing to more active antiretroviral therapy (ART), no serious adverse events (SAEs) were considered to be related to ibalizumab. Most treatment-emergent adverse events reported were mild to moderate in severity. No notable trends in laboratory abnormalities were observed.
- • On May 24, 2016, Theratechnologies announced that it has been notified by its partner, TaiMed Biologics, of the preliminary results for the primary end point of the phase III trial with ibalizumab in patients with multi-drug resistant HIV-1 (TMB-301). Preliminary results indicate that 82.5% of patients enrolled in the phase III study (33/40, p-value <0.0001) have met the primary endpoint of a decrease of ? 0.5 log10 in viral load following a 7-day treatment period with ibalizumab. This result is statistically significantly better than results observed during the control period. The administration of ibalizumab was well tolerated during the first week of treatment. TaiMed plans to submit an abstract to present these results at a major scientific conference later this year. The study should be completed before the end of October 2016.
- • On April 27, 2016, Theratechnologies announced that it has been notified by its partner, TaiMed Biologics that the enrollment for the Phase III study of ibalizumab, in combination with optimized background regimen (patients’ current therapy), for patients infected with multi-drug resistant HIV-1 has been completed as of April 27, 2016. The enrollment in the US has reached 36 patients, exceeding the minimum of 30 patients proposed by the FDA. The last patient enrolled in the study has entered the initial 7-day control period. On Day 7, ibalizumab will be administered and the primary end point will be assessed 7 days after initiation of ibalizumab on Day 14. The study will continue for a total of 24 weeks of treatment with ibalizumab. This open label, single arm Phase III study is the last clinical trial required by the FDA to complete the BLA submission. The primary end point is the proportion of patients achieving a viral load reduction of at least 0.5 log10 at Day 14. Top-line results of the primary end point should be available by the end of May 2016.