Pill of Pills, Early Stimulation & Failure to Grow
by Jon Palfreman, PhD on 4 March 2013
Pill of Pills PD patients can’t live without levodopa. Living with it is no picnic either. The drug’s short half-life (1.5-2 hours) and Parkinson’s relentless disease progression make a volatile combination. Patients eventually succumb to levodopa-induced motor complications (LIMCs). Unfortunately, efforts to minimize LIMCs with extended/sustained release formulations of levodopa-carbidopa––which seek to “smooth out” drug plasma peaks and troughs––have been disappointing; indeed, they’ve often produced worse dyskinesias than regular Sinemet. Impax Pharmaceuticals claims its new drug, IPX0666, can do better. It’s a clever concept. Patients take a pill containing multiple smaller pills. The pills dissolve on different schedules, resulting, Impax says, in a half-life of around 6 hours. Clinicians and their patients will soon be able to judge if IPX066 moves the therapeutic needle—enabling PD patients to get significantly more of the “good” (on time) and much less of the “bad” (off time and dyskinesias).
Early Stimulation Deep Brain Stimulation (DBS) has been hitherto mostly recommended for advanced PD cases suffering intractable levodopa-induced motor complications (LIMCs). A new French/German study in NEJM (February 14, 2013) presents strong evidence that DBS can benefit earlier cases as well. The EARLYSTIM trial led by Günther Deuschl, and Yves Agid, assembled a cohort of 251 PD patients ––– average characteristics: age: 52;
PD duration: 7.5 years; five years of L-dopa use and 18 months of LIMCs––and randomly assigned half to best-practices drug therapy (BPDT) and half to drug therapy plus DBS (DBS/BPDT).
After 2 years, the DBS group beat the BPDT group across the board—a 26% edge in quality of life (based on the PDQ-39 self questionnaire); a 16.4 difference on the UPDRS III motor scale (off medication), and fewer LIMCs. A final bonus: the DBS group lowered their L-dopa intake by 39% while the drug only group increased theirs by 21%. David Charles of Vanderbilt Neuroscience Institute, who is awaiting publication of his own “earlystim” study, called the European paper “transformative." "It's not as if it [the DBS] was a little bit better,” he told Scientific American, ”the numbers on quality of life and motor performance were dramatic."
Now for the bad news. The study reports that 55% of the DBS group experienced “serious adverse events,” including 26 surgically related incidents. Also, major depression was worse in the DBS group. The BPDT group, however, didn’t fair much better, with 44% suffering serious adverse events including impulse control disorder (ICD) and hallucinations. Finally, four patients in the DBS group and three in the drug group attempted suicide. Three succeeded in taking their own lives (two in the DBS group and one in the drug only group).
Notwithstanding these adverse effects, this study is a potential game changer. If this relatively young group of patients continues to do well, and survives a decade or more without motor complications, then demand for DBS can be expected to increase.
Failure to Grow Over the past decade, hopes that growth factors ––like glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and neurturin (NRTN)––might rescue weakened neurons and halt (and perhaps even reverse) PD have been dashed again and again. Despite promising animal data, controlled human studies have been a bust––from Amgen’s failed direct GDNF infusion trials to Ceregene’s disappointing NRTN gene therapy study. Now comes the latest set back. British company Phytopharm plc just announced that Cogane, an oral medicine designed to stimulate production of GDNF and BDNF, showed no efficacy in a phase II trial on early stage PD patients.
Co-chief Investigator for the study Professor C Warren Olanow called it “disappointing.” Sure is. The next best shot for this strategy depends on the outcome of Ceregene’s latest NRTN gene therapy trial––where genes have been infused both into the putamen and substantia nigra. Ceregene expects to report results in April 2013. A NIH trial using GDNF is also underway.