Tenofovir: Gilead applies for approval, expanded access relaxed

30 June 2001. Related: Antiretrovirals.

Tenofovir, Gilead Sciences’ candidate reverse transcriptase inhibitor, could be approved in about six months.

In an unexpected move, the company announced May 1 that it had filed a New Drug Application with the FDA. After approval, tenofovir could be prescribed for any adult with HIV, according to the company’s proposed labelling. Gilead will soon proceed with similar marketing applications in Europe.

Tenofovir, or PMPA, stops the infection of new cells by halting the gene-building activity of HIV’s reverse transcriptase enzyme. The drug is similar to nucleoside analogues such as ddI but requires less intracellular processing to reach its active state. Tenofovir is distinguished by its long intracellular half-life, which allows once-a-day dosing. It also has a somewhat different resistance profile than the standard nucleoside analogues, so it may be active against many HIV isolates that have mutated to resist the approved nucleoside analogues. In trials so far, resistance to tenofovir has been slow to develop – although it has been found.

Tenofovir’s safety profile is considerably improved over adefovir, a closely related compound developed by Gilead. Adefovir was rejected by the FDA because of severe kidney toxicities coupled with modest efficacy.

Gilead’s new drug may be helpful in a salvage regimen, but it does not represent any dramatic breakthrough. In a 189-person phase II treatment-intensification trial,(1) tenofovir was added to volunteers’ previous regimens at doses of 0 mg (placebo), 75 mg, 150 mg or 300 mg per day. The trial participants had a mean 4.6 years prior anti-HIV therapy and a mean baseline viral load of 5,000. At study entry, 94% of the enrolees also had HIV with mutations conferring resistance to various nucleoside analogues, principally AZT and 3TC. HIV in more than half of the participants also had resistance to protease inhibitors. The trial participants on 300 mg/day – the preferred dose – recorded viral load reductions averaging about 0.6 log (75%) through both weeks 24 and 48. The presence or absence of AZT or 3TC resistance was not associated with a major difference in the response. The modest, stable viral load reduction was not accompanied by any appreciable change in CD4 count, either.

Gilead scientists are reporting almost identical preliminary results from a similar 552-person phase III treatment-intensification trial. Both these trials make it clear that tenofovir requires concomitant active antiretrovirals from other drug classes to form a regimen that can successfully suppress HIV. This is true in treatment-naive individuals, who appear to have a better response to tenofovir, as it is in those with a history of treatment failure. In its 600-person phase III trial for those without prior treatment, Gilead is comparing tenofovir directly to the nucleoside analogue d4T, each combined with the nucleoside analogue 3TC and the NNRTI efavirenz.

Expanded access: Gilead drops CD4, viral load exclusions

Since last February, an expanded-access program has been open to people whose advanced disease state and treatment history mandate immediate use of new drugs to suppress their HIV (see AIDS TREATMENT NEWS #360, February 23, 2001). Gilead always intended that this program would be very small. It at first restricted entry to persons with viral loads over 10,000 and CD4 counts under 100 – plus documented treatment failure with at least two protease inhibitors or one PI and one non-nucleoside reverse transcriptase inhibitor (NNRTI). (Those with a CD4 count between 100 and 200 could also apply if they had had an AIDS-defining opportunistic infection within the last 90 days.)

Expanded-access enrolment has been even slower than anticipated. Public dissatisfaction over the paltry enrolment figures led Gilead to abandon its viral load and CD4 count entry criteria. As to speeding up the enrolment process, Debbie Fletcher of Gilead said in an interview, “About 20% of the doctors have submitted incomplete registration materials and had their applications returned. The paper work can go back and forth and back and forth. Our field representatives will follow up with the physicians who don’t finish filling out the forms.”

One HIV specialist summed up his frustrating experience with Gilead: “Paperwork did go back and forth. It took them weeks to turn it around and tell you they needed something more. Then you would send that, and they would come up with something else.”

The Coalition for Salvage Therapy has asked the company for a full and regular accounting of the program’s enrolment. In a strongly worded letter, this national activist network said that applicants to the program “are not only patients with few or no remaining options for treatment, but also patients whose disease has been allowed to progress to the point where ‘waiting for things to get sorted out’ with the program is simply not an option.” The Coalition had long pressured Gilead for a much broader expanded-access distribution before finally settling for the present restricted effort.

For the expanded-access program, Gilead advises doctors to prescribe at least one new anti-HIV agent in addition to tenofovir. Tenofovir naturally substitutes for other nucleoside analogues, not for protease inhibitors or NNRTIs. Some treatment activists have argued that Gilead should abandon the requirement that enrolees have past failure with PIs or NNRTIs. The program should be open to anyone lacking new nucleoside analogues to create a viable treatment combination.

This is the way tenofovir expanded access works in France, where the drug is recommended for patients with nucleoside analogue intolerance or with nucleoside resistant-resistant HIV, as demonstrated by resistance assays. In the United Kingdom, tenofovir is available to any patient who, in the judgment of his or her doctor, could not otherwise construct an effective anti-HIV regimen. Regulations in both countries preclude strict entry criteria, including CD4 count or viral load limits.

When tenofovir is approved, the issues around expanded access will be largely academic. At least the program is growing. Enrolment has picked up dramatically in the U.S., where about 150 people are now signed up. Also, Gilead has asked Germany, Italy and Spain for permission to extend the program beyond the U.S., UK and France. Further information can be obtained from Gilead at 1-800-Gilead-5 in the US and 33-1-44-90-34-46 in Europe.

Reference:

1. Miller MD et al. Baseline and Final Phenotypic Analysis of HIV-1 from Patients Adding Tenofovir Disoproxil Fumarate (TDF) Therapy to Background ART. 8th Conference on Retroviruses and Opportunistic Infections. February 4-8, 2001. Poster 441. Source: AIDS TREATMENT NEWS Issue #364, May 11, 2001. Copyright © 2001 – AIDS Treatment News. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used. Subscription lists are kept confidential. AIDS Treatment News, Subscription and Editorial Office: 1233 Locust St., 5th floor Philadelphia, PA 19107 800/TREAT-1-2 toll-free email: aidsnews@critpath.org
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Comment

European activists have been asking Gilead for expanded access in Europe for well over a year. Companies developing new agents with an indication for people who are resistant to current therapies benefit from a faster regulation process and should therefore plan for compassionate use earlier in the development programme. In this case the EAP was delayed by the company until it was confident that approval would be likely within six months.

The EAP for TDF is now enrolling in the US, France and the UK. Spain, Italy and Germany are expected to follow shortly. European clinicians with patients in need of TDF should contact Gilead directly on: + 33-1-44-90-34-46

An EAP for adefovir, for use in treating hepatitis B in people resistant to current treatment is still not available despite repeated community requests and sufficient efficacy and safety data.

Gilead have now given an indication that this may now be forthcoming in Europe based on an estimated limited demand and European clinicians with patients in need of ADV for HBV are also encouraged to contact Gilead on the above number.