The publication of the ADAGIO study results has given further weight to the suggestion that Teva Pharmaceutucals' Azilect (rasagiline) may be able to slow the progression of Parkinson’s disease as well as treat its symptoms.

The report in the 24 September issue of The New England Journal of Medicinewill heighten expectations that Teva and its Danish partner Lundbeck can eventually expand the labelling of Azilect (rasagiline), a mainstay of Teva’s branded medicines business, to include disease modification.

However, Teva is still in discussions with the Food and Drug Administration about the ADAGIO results and a US application to widen the indications for Azilect is not likely until next year.

Described as one of the largest trials ever conducted in Parkinson’s disease, the 18-month ADAGIO (Attenuation of Disease Progression with Azilect Given Once Daily) study was sponsored by Teva and included 1,176 patients with very early-stage Parkinson’s in 14 countries.

The ADAGIO trial was the first to use a ‘delayed start’ as its primary design, noted researchers led by Dr C Warren Olanow, professor in the Department of Neurology at Mount Sinai School of Medicine in New York, US.

Patients were randomised to either rasagiline 1mg or 2mg per day for 72 weeks (early start) or placebo for 36 weeks followed by rasagiline 1mg or 2mg per day for 36 weeks (delayed start). This meant the researchers could assess whether early treatment influenced the outcome at the final visit, when patients in both groups were on the same therapy.

The three primary endpoints were based on the Unified Parkinson’s Disease Rating Scale (UPDRS), which is used to track PD progression according to criteria such as mental state, daily activities and motor skills.

The endpoints were: 1) the rate of UPDRS deterioration between weeks 12 and 36 in the early-start versus placebo group; 2) the change in UPDRS score between baseline and final visit (week 72) in the early-start group compared with the delayed-start group; 3) demonstrating non-inferiority of the early- versus the delayed-start group in terms of how much the UPDRS score deteriorated between weeks 48 and 72 (i.e., whether the treatment benefit was sustained).

The 1mg dose of rasagiline met all three of the primary endpoints in the ADAGIO trial while the 2mg dose met none of them, the researchers reported. The previously untreated Parkinson’s disease patients randomised to initiate therapy with rasagiline 1mg per day showed benefits at 18 months that were not achieved with the same dose at nine months, they said.

Specifically, early-start treatment with 1mg rasagiline produced:

- A smaller mean increase (i.e., rate of worsening) than placebo in the UPDRS score between weeks 12 and 36 (0.09±0.02 points per week in the early-start group versus 0.14±0.01 points per week in the placebo group: p=0.01).

- Less deterioration in the score between baseline and week 72 (2.82±0.53 points in the early-start group versus 4.52±0.56 points in the delayed-start group: p=0.02).

- Non-inferiority between the two groups with respect to the rate of change in the UPDRS score between weeks 48 and 72 (0.085±0.02 points per week in the early-start group versus 0.085±0.02 points per week in the delayed-start group: p=<0.001).

“The finding that early treatment with rasagiline 1mg per day provides benefits that cannot be achieved with later administration of the same drug indicates that these benefits are not simply due to a symptomatic effect of the drug and are consistent with the possibility that the drug is disease-modifying,” Dr Olanow commented.

“If this can be confirmed, this would be the first drug determined to have a disease-modifying effect in PD, and that is exciting news for the PD community.”

The delayed-start trial design was an attempt to get around the problem of detecting disease-modifying effects in Parkinson’s that may be confounded by symptomatic improvement, Dr Olanow explained.

In the ADAGIO trial, he suggested, the failure of rasagiline 2mg to achieve similar results to the 1mg dose may have been due to the more pronounced symptomatic impact of the higher dose masking an underlying disease-modifying effect.

Data from the Phase III trial were presented at the Congress of the European Federation of Neurological Societies in Madrid, Spain in August 2008.

William Marth, president and chief executive officer of Teva North America, said the company had been "working to respond to questions raised by the FDA regarding ADAGIO and anticipates further discussions with the FDA to review and interpret the findings from this landmark study".

The company expects to file a supplemental New Drug Application for Azilect in 2010, "with the scope of any modification to the AZILECT 1mg/day label remaining subject to the conclusion of those discussions", Marth noted.