Adefovir Dipivoxil

Adefovir dipivoxil [GS 840, bis-POM PMEA, Piv2PMEA] is an ester prodrug of the nucleoside reverse transcriptase inhibitor adefovir, the prototype compound of the acyclic nucleosides phosphonates (ANP) class.1 Unlike other ANP analogues, unmodified adefovir displays poor oral bioavailability, whereas adefovir dipivoxil is rapidly and completely converted to adefovir after oral administration. Gilead Sciences licensed the rights to develop adefovir dipivoxil from the Institute of Organic Chemistry and Biochemistry (IOCB) in the Czech Republic and the REGA Stichting Research Institute (REGA) in Belgium. The licensing agreement was amended in December 2000, and the royalty rate on future sales of adefovir dipivoxil, tenofovir disoproxil fumarate and cidofovir was reduced in return for an upfront payment of $US11.0 million from Gilead.

Accelerated approval for adefovir dipivoxil as therapy for HIV infections was granted by the FDA in November 1998; however, nephrotoxicity developing around week 32 of a 48-week Phase II/III pivotal trial delayed completion of an NDA application. Gilead conducted most of the development of adefovir dipivoxil at 120mg but decided to pursue 60mg for marketing when nephrotoxicity was discovered during what was intended to be a pivotal trial. Gilead submitted an NDA for adefovir dipivoxil, the first anti-HIV nucleotide analogue to be reviewed by the FDA, for a recommended dose of 60mg once daily with the advice to reduce to 30mg if toxicity occurred. An additional NDA for an oral suspension formulation of the drug for a paediatric indication was also submitted. In November 1999, concerns about safety at the proposed 60mg dose led an FDA advisory committee to recommend the full agency not grant Gilead Sciences permission to market adefovir dipivoxil. Following this decision, Gilead decided to terminate development of adefovir dipivoxil 60mg for HIV infections stating that resources would be better utilised by being allocated to other development programs in the company pipeline. A Marketing Authorisation Application under the centralised licensing procedure had been made in the EU with Spain and the UK to act as rapporteur and co-rapporteur, respectively.

Adefovir dipivoxil was distributed through an expanded access programme in the USA for patients with advanced HIV disease who had failed treatment with at least one protease inhibitor and two nucleosides. Entry criteria were expanded to provide adefovir dipivoxil to HIV-infected patients in need, regardless of CD4 count or HIV RNA level. Following the results of clinical trials demonstrating the effectiveness of 60mg administration, Gilead amended the expanded access protocol so all patients receiving a 120mg dose have their dose reduced to 60mg and all patients subsequently entering the programme started treatment with 60mg. This US-expanded access programme was extended to Europe, Canada and Australia. Following termination of the development programme of adefovir dipivoxil for HIV infections, Gilead stopped new enrolment in its US clinical trials and the expanded access programme. Patients receiving adefovir dipivoxil in US clinical trials have been given the opportunity to enrol in the expanded access programme.

A multicentre Phase III trial (CPCRA 039) designed to assess adefovir dipivoxil (120mg once daily) in prolonging the survival of patients with CD4 counts ≥100 cells/mm³, was terminated early on a recommendation from the National Institutes of Health's National Institute of Allergy and Infectious Diseases (NIAID) Data and Safety Monitoring Board. Enrolment would have had to be increased from 2200 to 4000 patients to adequately study the primary endpoints due to the impact of new antiretroviral treatments on survival and disease progression.

Gilead is continuing the development of adefovir dipivoxil for the treatment of hepatitis B for which the drug is administered at lower doses compared with HIV infection. Two pivotal Phase III trials are underway to evaluate adefovir dipivoxil monotherapy for this indication. Enrolment of patients has been completed for the study (GS437) investigating adefovir dipivoxil 10mg and 30mg once-daily doses over 48 weeks of treatment and 1 year of follow-up. 515 patients are participating in this study at centres in North America, Australia, Europe and Southeast Asia. The second pivotal Phase III trial (GS438), investigating adefovir dipivoxil 10mg, is being conducted at sites in Australia, France, Israel, Italy, Canada, Greece and South East Asia. The study is evaluating adefovir dipivoxil 10mg for the treatment of patients diagnosed with precore mutant chronic hepatitis B virus (HBV) infection, a strain of the virus that has evolved without the hallmark HBV ‘e’ antigen. Enrolment of 186 patients in this study was completed in June 2000. Due to the growing importance of lamivudine-resistant hepatitis B virus in liver transplant patients, Gilead is conducting an open-label study (GS435) to evaluate adefovir dipivoxil in this patient population in North America, Asia, Australia and Europe. GlaxoSmithKline (formerly Glaxo Wellcome), in collaboration with Gilead, is conducting a study evaluating once daily adefovir dipivoxil 10mg as combination therapy with lamivudine 100mg in chronic hepatitis B patients who have experienced diminished therapeutic response to lamivudine monotherapy. This 52-week trial will enrol 130 patients and is being conducted in the USA, Australia, Canada, France, Hong Kong, Singapore, Spain and the UK. Smaller clinical studies are planned to evaluate adefovir dipivoxil in patients who are beginning therapy compared with those who have received prior treatment for chronic hepatitis B infection. In March 2002, Gilead announced the initiation of an Early Access Programme to provide adefovir dipivoxil 10mg to patients ≥16 years of age with chronic HBV resistant to lamivudine and who are at risk for disease progression. The programme will initially open in the USA, followed by Canada, Australia and Europe as regulatory approval is obtained.[1] On 21 March 2002 Gilead announced the submission of a New Drug Application to the US FDA for marketing approval of adefovir dipivoxil 10mg for the treatment of patients with chronic hepatitis B, including treatment-naïve and treatment-experienced patients. An application for marketing approval of adefovir dipivoxil 10mg in Europe is expected to be filed shortly.

In December 2000, Gilead announced that it had received approval for initiation of clinical trials of adefovir dipivoxil in patients with chronic hepatitis B infections in China. A ’class 1’ designation was granted for the agent in China in December 1999, giving 12 years' market exclusivity after approval. Gilead initiated a Phase I trial of adeforvir dipivoxil in China in June 2001. Three Phase I trials will be conducted there (sequentially), as data from overseas studies are not valid under the ‘class 1’ designation. After completion of these studies, the safety and pharmacokinetics of the drug will be evaluated and a report submitted to the Chinese State Drug Administration (SDA) for expedited review. Subject to SDA aproval, a single Phase II/III trial will then be required.

Gilead has merged with NeXstar, which was to be responsible for marketing adefovir dipivoxil outside the USA. Gilead is seeking a partner to co-market the drug for hepatitis B in the Asian market while intending to retain commercial rights to the drug in the USA and certain countries in Europe. Gilead dropped the planned trade name, Preveon™, after being informed by the FDA it was in conflict with another approved pharmaceutical product.

The antirheumatic efficacy of adefovir dipivoxil was being investigated in the Czech Republic at the preclinical stage; however, no recent development has been reported.

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