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T-20: new class of drug about to enter market; fusion inhibitor
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T-20 is making a splash at the World Conference. I just attended the press conference Roche/Trimeris held in the press room at the Barcelona conference. T-20 is the first entry inhibitor to approach commercial availability for patients. The companies anounced at this press meeting that they are filing with the FDA in the 2nd half of this year; an expanded access program for T-20 is expected to begin later this year. Roche has successfully produced commercial scale of drug at their Colorado manufacturing facility. Validation batches are being made now. Roche said that as soon as these batches are validated drug can be available for expanded access of T-20. They said cost has not yet been decided. T-20 is expected to be available in the pharmacy in early 2003.
Fusion inhibitors belong to a new category of investigational anti-HIV compounds that are collectively known as "entry inhibitors". They work in various ways to block HIV before it takes over a cell where it reproduces itself. Entry inhibitors prevent HIV from entering the CD4 cell- a different step in the reproduction cycle of HIV from the currently available classes of HIV drugs. Three different classes of entry inhibitors are under development- attachment inhibitors, coreceptor inhibitors and fusion inhibitors. Each class targets a different step in the process of HIV entry:
--attachment inhibitors work by preventing the attachment of HIV to the outer membrane of the host cell (cd4)
--co-receptor inhibitors work be preventing the interaction of HIV with co-receptors on the host cell surface
--Fusion inhibitors block HIV fusion with the cell membrane and prevent HIV infecting the cell.
T-20 is the most advanced entry inhibitor in clinical development. Other companies are trying to develop entry inhibitors. Bristol Myers Squibb has a development program and BMS-806 is the prototype. They announced new information on 806 & their program at the Resistance Workshop last week. Preliminary test tube research showed no cross resistance between 806 & T-20. Also at this Workshop Merck announced they are planning to begin a study of their new integrase inhibitor in HIV-infected patients this Fall. As well, GlaxoSmithKline has an integrase inhibitor in human studies. In addition, Roche/Trimeris have T-1249 in earlier development, a secondline fusion inhibitor, which so far appears to have little cross-resistance to T-20. T-20 will be used for patients with advanced HIV because it is administered by subutaneous self-injection.
At the press conference Dani Bolognesi, CEO & Founder of Trimeris, said T-20 accomplishes a goal for treatment that no currently available drugs can do; and that is true. There is no expected cross resistance between T-20 and currently available classes of drugs. Because T-20 doesn't enter cells Dani says there is low chance for drug-drug interacterions. Because drug is injected there is low tolerability issues. They are meeting a major milestone by presenting the phase III study results for first time publicly here in Barcelona. The FDA is in the process of reviewing the application for approval for commercial availability.
TORO 1 and TORO 2 are the two large studies presented here that will be reviewed by the FDA for approval of the drug. TORO 1 was conducted at 49 sites in Canada, US, Mexico & Brazil. This is an open-label, randomized, international study. Patients were very heavily pretreated with HIV drugs. Average CD4 count was 80, viral load over 100,000 copies, over 84% had prior AIDS defining event. 84% were white and 92% were men. Onaverage patients had previously used 12 HIV drugs. Patients were randomized to receive either T-20 plus an optimized background of additional drugs vs the optimized background without T-20. 336 patients were in the T-20 group and 165 in the other group.
WEEK 24 Study Results
The viral load reduction in the T-20 group was -1.70 log vs -0.76 in the other group. The difference between the arms was 0.9 log and was significant (p<0.0001). The percent of patients achieving <400 copies was 37% in the T-20 group vs 16% in the other group (ITT). 19% vs 7% had <50 copies, also significant difference. 51% had 1 log or greater viral load reduction in the T-20 group vs 29% in the other treatment group and this difference was significant (P<0.0001), (ITT, DC=Failure). The patients receiving T-20 had an average increase in CD4 of 76 vs 32 for the other treatment group, and this difference was also significant (p=0.0001). The time to virologic failure was much less in the T-20 group than in the other group, and this difference was also significant (P<0.0001).
The side effect profile for T-20 appears pretty good so far. The side effect profile was about the same in the T-20 group as in the other group. 77% of patients in the T-20 group experienced at least 1 drug related adverse event vs 75% in the other group. About 11% discontinued from the study in the T-20 group vs 21% in the other group. 16/326 in the T-20 group (5%) discontinued due to adverse event or lab test and 9/326 (3%) discontinued due to injection site reaction, this is the most common side effect of using T-20. The study investigators commented that 3% is low but a study is a controlled environment. Patients in the study were motivated due to advanced HIV and so were good patients and received support. We need to see how the injection site reaction and self injection affects utility in real world setting. Deciding which patients will be treated with T-20 is yet to be fully characterized until it is in the market for a while, due to ISR & self-injection. Roche is designing a patient education program on how to deal with the ISRs and it's described below.
TORO 2 was conducted in Europe and Asia at 64 sites. The study design was similar. Baseline CD4 was 100 and viral load over 100,000 copies. 335 patients received T-20 and 169 did not. 75-82% had prior AIDS defining events. The side effect profile and discontinuation rates were similar.
WEEK 24 RESULTS
The viral load reduction was -1.43 log in the T-20 group vs -0.65 in the other group (P>0.0001). 28% vs 13% had <400 copies of viral load. 42% (ITT, DC-failure) vs 20% had 1 log or greater viral load reduction. 12% vs 5% had <50 copies, also significant. CD4 increase was 76 in T-20 group vs 32 in other group.
PATIENT EDUCATION
Roche is planning to launch an education program to teach patient about the injection process and to manage the injection site reactions. They are planning to teach patients what the ISR looks like and how to manage it. They are producing a video for patients. They will have a patient card, a placemat, that the patient can use during injection process. They will launch a patient website for reference to learn about this. They are considering conducting patient support groups and education forums. They will have a nurse on an 800 hotline for support. Roche plans to meet with community advocates in August to elicit ideas from them on how to outreach patients and optimize education.
This afternoon is the HCV/HIV coinfection oral session.
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