番茄社区

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SEATTLE -- The experimental monoclonal antibody ibalizumab, which works differently than other HIV drugs, lowered viral load in vulnerable patients with multidrug-resistant virus, researchers reported here.

When ibalizumab was given with at least one other active drug, 43% of heavily treatment-experienced patients reached an undetectable viral load, according to of Yale University in New Haven, Conn.

The results come from a phase III study of 40 patients presented at the annual .

Ibalizumab targets the CD4 receptor protein to prevent HIV entry into T cells and is the first monoclonal antibody to be tested for HIV treatment. It's not as potent as other antiretrovirals, but it may provide the added activity needed to suppress HIV in people with few or no other treatment options.

Ibalizumab currently must be administered by infusion, but TaiMed Biologics is working on an injectable formulation.

"I think ibalizumab has the potential to be quite useful for people who have resistance to other agents," , of the University of North Carolina at Chapel Hill, told 番茄社区.

"This is a new class of drug with a new mechanism," the first since integrase inhibitors made their debut about 10 years ago," Emu said.

Early studies showed that ibalizumab is active against HIV that is resistant to other types of antiretroviral drugs. After it demonstrated modest efficacy in a phase II trial, the FDA granted it orphan drug status and a breakthrough therapy designation.

was conducted in patients who were not able to maintain viral suppression on their current HIV therapy.

The study enrolled 40 heavily treatment-experienced patients. Most were men and the average age was 51 years. At study entry they had a mean viral load of approximately 100,000 copies of HIV RNA per mL. The mean CD4 count was only 150 cells/mm³ and a third had less than 10 cells/mm³, indicating advanced immune suppression.

Study participants had been infected with HIV for 20 years on average and about a quarter had previously used 10 or more antiretrovirals. They had to have documented resistance to at least one drug from three antiretroviral classes, "but in reality they had much more resistant virus," Emu said.

Nearly 90% had exhausted all available drugs in at least one class, a third had exhausted four or more classes, and 15% were resistant to all approved antiretrovirals.

However, the patients had to have at least one active drug available to construct an optimized background regimen. To do so, more than 40% had to use a second experimental agent, the HIV attachment inhibitor fostemsavir.

"These were highly treatment-experienced, highly drug-resistant patients with very limited options," Emu said.

After a seven-day monitoring period, all patients in this open-label study received a 2,000-mg IV infusion of ibalizumab along with their current failing regimen or no therapy, meaning the antibody was used as functional monotherapy for seven days.

The primary study endpoint was the proportion of patients with at least a 0.5 log decrease in viral load by day 14. As reported at a conference last October, 83% had at least a 0.5 log drop and 60% had a 1 log decrease or more.

Participants then switched to an optimized background regimen determined by resistance testing, adding new drugs if needed, and continued to receive ibalizumab infusions at doses of 800 mg every other week through week 24.

At 24 weeks 55% of patients had at least a 1 log decrease in HIV RNA and 48% had at least a 2 log reduction. The average viral load decrease from baseline was 1.6 log.

Overall, half of the participants achieved viral suppression below 200 copies per mL and 43% had less than 50 copies per mL. While 60% of patients with a baseline CD4 count of 50 cells/mm³ or higher achieved undetectable viral load, this fell to less than 20% for those with less than 50 cells/mm³.

The overall average CD4 cell gain was 48 cells/mm³, but this differed substantially according to baseline level. People who started with 50 cells/mm³ or more saw gains of about 75 cells/mm³. Those with lower baseline levels had smaller gains, averaging 9 cells/mm³. Emu told 番茄社区 that even these modest increases are important for people starting with such low levels.

Ibalizumab was generally well tolerated and most adverse events were mild or moderate. One person stopped the study early due to a treatment-related serious adverse event (immune reconstitution inflammatory syndrome), five discontinued for other reasons, and four people with advanced immune suppression died.

In another poster presentation at the conference researchers reported findings from a phase I/II trial evaluating a new formulation of ibalizumab administered by intramuscular injection. Both tested doses -- 800 mg given two weeks apart and 2,000 mg given four weeks apart -- were well tolerated and reduced viral load by up to 1.2 log in this seven-day monotherapy study.

"Ibalizumab is really exciting because it represents a shift toward long-acting antiretroviral therapy," Emu told 番茄社区, predicting that it would be the first long-acting agent to complete phase III studies.

Other researchers at the conference described another long-acting monoclonal antibody in development, PRO-140, which targets the CCR5 co-receptor on CD4 cells.

"PRO-140 has potentially greater potency," and it is given as a subcutaneous injection rather than an infusion, allowing patients to administer it at home, Eron said. "An advantage of ibalizumab is that it acts against both CCR5 and CXCR4, whereas PRO-140 only acts against CCR5-using [HIV] variants. Both would be quite useful for people who don't have treatment options."