Ibalizumab monoclonal antibody is effective in real-world use

By | October 9, 2019

Ibalizumab (Trogarzo), a long-acting monoclonal antibody that prevents HIV from entering cells, suppressed HIV for 48 weeks in people with highly resistant virus who received the drug in an expanded access programme, according to a presentation at the IDWeek 2019 conference in Washington, DC.

Rather than attacking HIV directly, ibalizumab targets a protein on human cells. Theratechnologies, the company that developed the drug, calls it a post-attachment HIV inhibitor. It binds to the CD4 receptor on the surface of T-cells and interferes with a protein shape change that is required for viral entry. Administered by intravenous infusion every two weeks, ibalizumab is the first biologic agent approved for HIV and the first antiretroviral that does not require daily dosing.

Ibalizumab (TMB-355, previously known as TNX-355), which was in development for over a decade, was approved by the US Food and Drug Administration in March 2018 for people with limited options due to extensive prior treatment experience and multidrug-resistant virus. In July, it received a positive opinion from the European Medicines Agency.

Glossary

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

ribonucleic acid (RNA)

The chemical structure that carries genetic instructions for protein synthesis. Although DNA is the primary genetic material of cells, RNA is the genetic material for some viruses like HIV.

protocol

A detailed research plan that describes the aims and objectives of a clinical trial and how it will be conducted.

protein

A substance which forms the structure of most cells and enzymes.

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

Approval of ibalizumab was based on results from the phase 3 TMB-301 trial, which enrolled 40 heavily treatment-experienced participants who were unable to achieve viral suppression using existing antiretrovirals. Most were men, the median age was just over 50 years and they had been HIV positive for more than 20 years on average. They were all resistant to at least three drugs, over a quarter had tried ten or more agents and 15% were resistant to all approved antiretrovirals. However, they had to have at least one active drug still available to construct an optimised background regimen, which could include other experimental agents such as the investigational attachment inhibitor fostemsavir.

Participants started with a 2000mg infusion of ibalizumab as functional monotherapy along with their existing failing regimen; 60% experienced at least a 1.0 log10 decrease in HIV RNA by day 7. A week later they switched to an optimised background regimen that included the active drug, and at day 21 they began receiving 800mg ibalizumab infusions every other week.

Data presented at the 2017 Conference on Retroviruses and Opportunistic Infections and at IDWeek 2017 showed that 55% of study participants had at least a 1.0 log10 drop in viral load and 48% had at least a 2.0 log10 decrease at 24 weeks. At that point, 43% had HIV RNA below 50 copies/ml. Among the 27 participants who continued treatment in an expanded access protocol, viral suppression was maintained through week 48. The average CD4 cell gain was approximately 50 cells/mm3 at week 24, though people with less advanced immune suppression at baseline saw larger increases.

At this year’s IDWeek, Dr Brinda Emu of Yale University and colleagues reported follow-on results from a larger group of 38 people enrolled in the expanded access protocol, known as TMB-311.

Most (87%) were men and the median age was 53 years. The median CD4 count was 26 cells/mm3 and more than half had less than 50 cells/mm3, indicating advanced immune suppression. Again, they were resistant to antiretrovirals from at least three drug classes, but their virus remained fully sensitive to at least one antiretroviral agent.

Unlike participants in study TMB-301, those in the expanded access cohort started on an optimised background regimen at the same time as they received their first 2000mg infusion of ibalizumab, after which they received 800mg doses every two weeks.

In this group, 76% experienced a viral load decrease of at least 0.5 log10  and 57% had at least a 1.0 log10 drop by day 7. Among the 24 people who completed 24 weeks of treatment, 46% had HIV RNA below 50 copies/ml. Among the 17 people who continued treatment through 48 weeks, 47% had undetectable viral load. However, this figure does not include seven people who withdrew from the expanded access programme and started taking commercially available ibalizumab after its approval.

In both the phase 3 trial and the expanded access cohort, ibalizumab was generally safe and well tolerated. The most common treatment-emergent adverse events were diarrhoea, headache, nausea, cough, skin rash and fatigue, in most cases mild or moderate. No participants reported injection site reactions.

Results from the expanded access cohort – which reflects the group of people with long-term HIV infection who are likely to use ibalizumab in the real world – “demonstrate durable viral suppression in this difficult-to-treat patient population,” the researchers concluded.

References

Emu B et al. Ibalizumab efficacy and safety through 48 weeks of treatment: results of an expanded access protocol (TMB-311). IDWeek, Washington, DC, abstract 661, 2019.

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