Of the HIV medications in development with potential activity against highly resistant HIV (i.e., patients with GSS=0), two may become available within the next year: ibalizumab (formerly TNX-355), a monoclonal antibody currently under development by TaiMed Biologics, and dolutegravir (formerly GSK1349572), a second-generation integrase inhibitor made by ViiV Healthcare).
Ibalizumab has a completely new mode of action, so most patients should respond to it when using it with at least one other active agent. It is different from the entry inhibitor maraviroc (Selzentry, Celsentri) in that it blocks the CD4 receptor on T cells rather than blocking the CCR5 co-receptor. This means it could be effective against virus that uses either the CCR5 or CXCR4 co-receptor. It is a genetically engineered monoclonal antibody administered once every two weeks intravenously. TaiMed has finished its dosing phase 2b study and will be presenting the data in the near future. TaiMed is also developing a subcutaneous administration of ibalizumab; phase 3 studies should take place involving HIV-infected patients in eight to 12 months.
Dolutegravir has shown activity against many raltegravir (Isentress)-resistant viruses at a dose of 50 mg twice a day. Dolutegravir’s phase 3 study, which is seeking patients with raltegravir resistance, is now enrolling nationwide. However, patients are required to have a GSS=1 to join the study. For those who do not meet the entry criteria, but need help, there may be another option: The company is planning to open an expanded access program for its drug by year’s end.
However, “year’s end” is not near enough for patients who are in dire need of new, active antiretrovirals. There are many patients who cannot join the phase 3 studies, and who cannot wait eight to 12 months for both drugs to become available through their respective expanded access programs.
In these extreme cases, physicians can apply for “single patient Investigational New Drug (IND)” access to either or both of these antiretrovirals. Both TaiMed and ViiV/GlaxoSmithKline have shown good faith in helping patients in deep salvage, and they are willing to provide their drugs for patients with declining health and high mortality risk.
The following steps must be followed by physicians for each drug they want to access on behalf of one of their patients.
How to Apply for Single Patient IND Access to an Investigational Drug
If the patient’s HIV has evidence of resistance to all commercially available antiretrovirals and his/her viral load suggests that his/her HIV is not responding to the current drug regimen, a phenotypic resistance test needs to be performed along with a tropism test. It is important to also know if phenotypic resistance to enfuvirtide (T-20, Fuzeon) is present. Additionally, genotypic integrase mutations need to be characterized to assess the patient’s potential response to dolutegravir.
Once the test results have confirmed that the patient has developed resistance to all commercially available or expanded access HIV medications, and provided the patient’s health is at risk (i.e., CD4+ cell count under 100 cells/mL and declining clinical outlook), physicians can follow this procedure required by the U.S. Food and Drug Administration (FDA). (Note that the FDA has also changed its regulations to accept patient access for small groups of patients, which could save a lot of paperwork.)
- The treating physician should call the company that is developing the investigational antiretroviral to find out if it is willing to provide the drug for free before it has been approved. (Drugs have to have gone through dosing and safety studies before they can be made available in this manner. Also, antiretroviral interaction data are valuable, although ViiV and TaiMed do not expect negative drug-drug interactions from the combination of dolutegravir and ibalizumab.)
- After each manufacturer agrees to provide its respective investigational drug via single patient IND, the doctor should follow the procedure described on this FDA Web page to fill the required forms and get institutional review board (IRB) approval.
This procedure is hardly used by doctors in HIV care due to lack of information or concerns about its complexity. But in actuality, it’s very straightforward: three simple forms, a signed patient consent form and IRB approval are needed. Many local IRBs will even expedite approval of this kind of request due to its urgency.
Also, single patient IND can be approved verbally by the FDA if the patient has an expected survival of less than 30 days (this is called emergency IND). This will allow the drug company to ship the drug in an expedited manner, but the forms I mention above will still need to be processed while drug shipment is taking place.
If you need a sample patient consent form and cover letter for IRB submission, I recommend using these, which were used in the past for access to darunavir (TMC114, Prezista) and etravirine (TMC125, Intelence) while they both were investigational drugs:
ViiV and TaiMed can also make copies of consent forms for their drugs available if requested by the physician applying for access on behalf of his/her patient.
I welcome e-mails from physicians who need more information or would like additional help gaining access to investigational drugs for their HIV-infected patients whose virus is resistant to all currently available drugs. Please send e-mails to email@example.com.
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