番茄社区

BOSTON -- Late-breaker presentations at the American Academy of Neurology's annual meeting included promising results with several very different approaches to the problem of reducing "off" time in Parkinson's disease without compromising "on" time offered by dopamine-enhancing drugs.

Among them:

• A gene therapy to provide replacement of aromatic amino acid decarboxylase (AADC), the enzyme that converts levodopa into active dopamine
• An ultra-extended release form of carbidopa-levodopa
• Subcutaneous apomorphine infusion

Investigators reported results from early studies of the first two of these treatments; the apomorphine trial was a phase III study, with details released prior to the meeting and the subject of a previous 番茄社区 story.

The three studies were included in the AAN's "Emerging Science" program during which investigators gave 3-minute platform talks with more information available in posters.

Gene Therapy

One of the problems with current Parkinson's disease therapies is that dopaminergic neurons gradually become unresponsive to levodopa, which is a prodrug for dopamine. Lab studies have traced the phenomenon to loss of AADC activity within the target neurons -- suggesting that if AADC activity could be restored, so too could levodopa's effectiveness.

Chadwick Christine, MD, of the University of California San Francisco, presented results of a small trial involving packaging an AADC gene into an adeno-associated virus vector (a standard gene therapy tool), using real-time MRI to guide delivery into the putamen. This was a phase Ib trial testing three dosing regimens of the agent, dubbed . The study is still ongoing and Christine presented data only for the two of the regimens, delivering 450 and 900 μL per putamen in five patients each. (A third cohort is also receiving 900 μL but in a larger bolus.)

PET scans showed that the cohort receiving 900 μL had 50% increase in dopaminergic activity 6 months after treatment, indicating that the AADC gene had been delivered successfully and was working as intended. Moreover, that group has shown a clear and positive clinical response, with a 35% reduction in the level of dopamine-boosting medication needed to control symptoms at 6 months.

At 12 months, Christine said, patients in that group showed a whopping 4-hour increase in mean "on" time (i.e., daily time with symptoms controlled) and a nearly 2-hour reduction in mean "off" time, as reported in patient-kept diaries.

The treatment was well tolerated with no serious adverse effects related to the AAV vector, he said.

Long-Release Carbidopa-Levodopa

Another issue with conventional dopaminergic therapy is the "off" time just mentioned -- the fact that, as the disease progresses, the desired clinical effects of current dopamine-enhancing drugs do not last an entire day, and simply increasing the dosing frequency may not be a viable strategy.

Several formulations of carbidopa-levodopa aimed at attacking the problem are on the market or in development. One such product, an extended-release version sold as Rytary, was approved in 2015, but manufacturer Impax Laboratories hopes to improve on it with a new carbidopa-levodopa formulation called IPX203.

At the late-breaker session, Mark Stacy, MD, of Duke University in Durham, N.C., presented results from a single-dose phase II study involving 75 patients randomized to Rytary, an immediate-release carbidopa-levodopa, and IPX203. Outcome measures included total "off" time, good "on" time, "on" time without dyskinesia, "on" time with slight dyskinesia, and "on" time with troublesome dyskinesia.

For most of these -- including "off" time, good "on" time, and "on" time without troublesome dyskinesia -- IPX203 significantly outperformed the other two treatments. The differences from the immediate-release agent were very marked; the new formulation was incrementally better than Rytary but still achieving statistical significance. IPX203 was not worse than the other drugs in any measure.

In addition, said Stacy, IPX203 was superior for the overall duration of effect, need for rescue medications, and in responder rates according to standard criteria involving Unified Parkinson's Disease Rating Scale score improvements.

Stacy also said there were no serious or severe adverse events in the trial. Impax is now recruiting study sites for a phase IIb multiple-dose trial, the firm said.