Ibalizumab, a long-acting monoclonal antibody that prevents HIV from entering cells, maintained viral suppression for a year in people with highly resistant HIV and limited treatment options, according to a presentation at the IDWeek 2017 conference last week in San Diego.

Study participants who received ibalizumab infusions every two weeks along with an optimised background antiretroviral regimen had a median viral load reduction of at least 2.5 log 10 after 12 months of treatment.

Ibalizumab targets a protein on human cells rather than attacking HIV directly. It binds to the CD4 receptor on the surface of T-cells, but instead of preventing HIV from attaching to these cells, it blocks a shape change that is necessary for the virus to enter them.

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. treatment-experienced A person who has previously taken treatment for a condition. Treatment-experienced people may have taken several different regimens before and may have a strain of HIV that is resistant to multiple drug classes. Food and Drug Administration (FDA) Regulatory agency that evaluates and approves medicines and medical devices for safety and efficacy in the United States. The FDA regulates over-the-counter and prescription drugs, including generic drugs. The European Medicines Agency performs a similar role in the European Union. 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. drug resistance A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

Ibalizumab (TMB-355, previously known as TNX-355) has been in development for more than ten years. Early studies showed that it was active against multiple types of HIV and had no cross-resistance or interactions with existing antiretrovirals. After it demonstrated modest efficacy in a phase 2 study, the US Food and Drug Administration (FDA) granted it orphan drug status and a breakthrough therapy designation.

At this year's Conference on Retroviruses and Opportunistic Infections (CROI), Brinda Emu of Yale University presented 24-week findings from a phase 3 trial evaluating ibalizumab for people who were not able to maintain viral suppression on their current antiretroviral regimen. At IDWeek, she presented 48-week follow-up results.

Study TMB-301 enrolled 40 highly treatment-experienced participants who were on a failing regimen with resistance to at least three antiretroviral drug classes. Most (85%) were men, the median age was 53 years and they had been living with HIV for more than 20 years on average. The median CD4 cell count was about 100 cells/mm3 and 10% had a level below 10 cells/mm3, indicating very advanced immune suppression.

The group was heavily treatment-experienced with substantial drug resistance. More than a quarter had used at least 10 previous antiretrovirals, more than half had exhausted three or more drug classes and about 15% were resistant to all approved antiretrovirals. However, they had to have at least one active drug available to construct an optimised background regimen (to do this, about 40% had to include the investigational attachment inhibitor fostemsavir).

After a six-day observation period, all participants received a 2000mg loading dose of ibalizumab as an intravenous infusion on day 7 while remaining on their failing regimen – that is, ibalizumab was used as functional monotherapy. On day 14, they added an optimised background regimen selected on the basis of resistance testing. Starting on day 21, they began receiving 800mg ibalizumab infusions every other week through week 24. Participants who completed the first 24 weeks could then continue on ibalizumab for 24 more weeks as part of an expanded access programme (TMB-311).

As reported at last year's IDWeek, 83% of participants saw at least a 0.5 log 10 drop and 60% had at least a 1.0 log 10 drop in viral load from baseline levels at day 14, or 7 days after the first ibalizumab infusion. As Emu reported earlier this year, 55% had at least a 1.0 log 10 decrease and 48% had at least a 2.0 log 10 decrease at 24 weeks, with a mean reduction of 1.6 log 10 . At that point, 43% had achieved viral suppression below 50 copies/ml and half were below 200 copies/ml.

Among the 27 participants who entered the expanded access study, the median viral load reduction was 2.5 log at week 24, and this was sustained through week 48. All 15 participants who had undetectable HIV RNA (< 50 copies/ml) at week 24 maintained viral suppression at week 48, and an additional individual who had detectable viral load at week 24 fell below this threshold by week 48.

At week 24, the overall average CD4 cell gain was approximately 50 cells/mm3, but participants with less advanced immune suppression saw larger increases. People who started with more than 200 cells/mm3 had a mean gain of 81 cells/mm3, while those with under 50 cells/mm3 at baseline had a mean gain of 7 cells/mm3. CD4 counts were maintained through week 48.

Ibalizumab was generally safe and well-tolerated, and most adverse events were mild or moderate. At 24 weeks, one person had stopped the study due to a treatment-related serious adverse event (immune reconstitution inflammatory syndrome), four discontinued for other reasons and four people with advanced immune suppression died. The most common adverse events were diarrhoea, dizziness, nausea and rash; no infusion-related adverse events were reported. No new or unexpected drug-related serious adverse events or safety concerns emerged between weeks 24 and 48.

While ibalizumab is not as potent as many other antiretrovirals, it may provide the additional activity needed to suppress HIV for people with highly resistant HIV and few or no other treatment options.

"The participants enrolled in the Phase III study were highly treatment experienced with limited antiretroviral options due to drug resistance," Dr Emu said in a press release issued by Theratechnologies, which is developing ibalizumab in conjunction with TaiMed Biologics.

"As clinicians treating these patients, having access to an agent with a novel mechanism of action was critical," Dr Emu continued. "Seeing sustained virologic response out to 48 weeks is heartening and emphasizes the potential benefit that ibalizumab may bring to HIV patients in need of new treatment options."

The FDA is expected to issue a decision about ibalizumab in early January 2018, according to Theratechnologies. If approved, ibalizumab would be the first antiretroviral with a new mechanism to be introduced in a decade.