Terminated PD Experimental Treatments and "Failed Trials" 2004 - present
GDNF (Neurotrophic factor) – recombinant GDNf delivered by pump infusion method
Sponsor: Amgen, Inc.
Phase II trials terminated in September 2004.
Comments: Amgen announced in June 2004 that, “Six months of treatment with GDNF delivered to the putamen failed to improve UPDRS scores compared to placebo. There was “evidence of alteration of brain function,” a likely reference to changes on neuroimaging, but improvement on UPDRS scores did not meet the primary endpoint of the trial.
Initially, Amgen announced that all subjects were entered in an open label extension study to resolve differing trial results. But in Sept. 2004, Amgen sent letter to clinical investigators halting further clinical studies, due to safety concerns – development of lesions in the cerebellum of 4 test monkeys and "anti-r-metHuGDNF neutralizing antibodies found in two of the study participants to date.”
CEP-1347 (Kinases Inhibitor)
Sponsor: Cephalon, Inc.
Phase II / III Trial discontinued in May 2005
Comments: “The study was concluded early, after an average of 21.4 months of follow-up, when a planned interim analysis demonstrated that it would be futile to continue experimental treatment. In contrast to research in animal models that predicted favorable disease-modifying outcomes, we found CEP-1347 to be an ineffective treatment in early Parkinson disease. "
NS2330 (Monoamine Uptake Inhibitor)
Sponsor: Neurosearch, Inc.
Phase III canceled Jan. 2006
Comments: "Results from three comprehensive Phase II studies in Alzheimer’s and Parkinson’s diseases with tesofensine (NS2330) did not meet the criteria we had defined together with our partner Boehringer Ingelheim for starting up Phase III clinical studies. Boehringer Ingelheim terminated the tesofensine partnership in January 2006." Further development for PD has been halted.
GPI 1485 (Neuroimmunophilin Ligand))
Sponsor: Symphony Neuro Development Company
Phase III terminated in March 2006
Comments: In March 2006 citing a lack of evidence of clinical benefit, Symphony Neuro Development Company stopped further drug treatment in its open-label study of GPI 1485 in Parkinson’s disease patients who had previously participated in the completed 2 year double blind efficacy study .
Phase III was not initiated..
"While the treatment was well tolerated and posed no significant safety issues, the treatment group failed to show an improvement in the primary endpoint of the trial which was percent change of baseline of brain uptake of [123I}Beta-CIT as measured by SPECT Scanning, a measure of the brain dopamine system that degenerates in Parkinson’s disease.... In addition, none of the exploratory clinical endpoints showed clinically meaningful benefit after 24 months of therapy....”
E2007 (perampanel ) (AMPA receptor antagonist)
Sponsor: Eisai Inc.
Phase III trials terminated in Oct. 2007 and April 2008.
Comments: “In Oct. 2007, Eisai announced one of its Phase III studies (#301) "did not meet its primary endpoint comparing perampanel (E2007) to placebo as an add-on to levodopa therapy for 764 idiopathic Parkinson's disease patients over 30 weeks. The primary endpoint was reduction in "off" time - defined as the length of time that Parkinson's symptoms return as the effect of levodopa wears off. Perampanel was well tolerated with no significant safety issues... Two additional Phase III studies (#302 and #309) will proceed as planned."
“ In April 2008, following the completion of two Phase III Studies , Eisai decided to discontinue their PD research program for E2007. The sponsor reported the studies "did not show a significant difference in the primary endpoint of reduction of "off" time ...the third Parkinson's disease Phase III study and open label treatment extension studies" were also terminated. “
Sarizotan (EMD 128130) - (Dopamine Agonist)
Sponsor: Merck KGaA
Phase III terminated in June 2006.
Comments: “Double-blind Phase III studies did not confirm Phase II results or results from preclinical studies. In June 2006, "Merck KGaA decided, after analysis of data from Phase III clinical trials not to file for approval and not to pursue further development of the compound. Merck said a statistically significant difference between sarizotan and placebo could not be demonstrated in the late-stage clinical studies."
Vadova (IPX054) -Levodopa
Sponsor: IMPAX Laboratories, Inc.
Received “non-approvable letter from FDA in March 2006, and Jan. 2008. Sponsor terminated development in April 2008
Comments: The FDA issued IMPAX a "Non-approvable letter in March 2006, but Impax filed more papers to answer regulators' concerns. The FDA rejected the drug again in January 2008, saying this time the drug could be confused with other marketed versions of carbidopa/levodopa and could lead to medication errors."
Istradefylline (KW- 6002) - (Adenosine Receptor Antagonist)
Sponsor: Kyowa Pharmaceutical, Inc.
Phase III development suspended in North America in June 2008.
Comments: On June 3, 2008, Kyowa Pharmaceutical, suspended the development of istradfeylline in North America. A letter from the company President stated, "On February 25, 2008, Kyowa received a “Not Approvable” letter from the U.S. Food and Drug Administration (FDA) for istradefylline and subsequently had discussions with the FDA about options for further development. After reviewing these options, Kyowa has decided to suspend development of istradefylline in North America at this time. This decision was not related to any safety issues concerning istradefylline." "According to Dr. Mark Stacy, the trial may not have been optimally designed to reflect istradefylline's true efficacy. While at first glance the 12% to 14% reduction in "off" time from baseline appears "disappointing," Dr. Stacy said it must be kept in mind that the vast majority of these patients had advanced motor scores and were being treated with 2 or more drugs. In addition, although the trial's enrollment criteria required that patients have a minimum of 2 hours of "off" time per day, Dr. Stacy said once the data were analyzed, the researchers found that the average amount of "off" time in study subjects was 6 hours every day….Furthermore, he said, the measurement tool used to determine "off" and "on" time was likely not sensitive enough. "If we'd used a more precise tool we'd probably have bubbled up better data," he said.
Source: Medscape News, June 5, 2008
Spheramine (Retinal Pigmented Epithelial (RPE) Cells)
Sponsor: Bayer-Schering / Titan
Bayer discontinued development of Spheramine in July 2008.
Comments: Titan announced in July 2008 that its "potential cell-based treatment for Parkinson's Disease failed to meet its primary and secondary endpoints in a Phase IIb study, and likely won't be continued by partner Bayer Schering Pharma... Initial analysis of results from the 71-patient study of Spheramine -- designed to test the safety, tolerability and efficacy of the treatment -- found that it had no significant differences from sham surgery arms after 12 months of follow up." (Company press release 7/2/08)
CERE-120 (neurturin) – Gene therapy
Sponsor: Ceregene
Phase II trial failure announced in Nov. 2008.
Comments: Ceregene announced the phase II trial did not demonstrate an appreciable difference between patients treated with CERE-120 versus those in the control group. Both groups showed an approximate 7 point improvement in the protocol-defined primary endpoint (Unified Parkinson’s Disease Rating Scale- motor off score at 12 months), relative to a mean at baseline of approximately 39 points. Both groups had a substantial number of patients who demonstrated a meaningful clinical improvement from baseline. CERE-120 appeared to be safe and well tolerated."
…A company spokesman stated "...we are stunned by the results of this trial and will continue to analyze the data in order to gain greater insight into the factors that may have contributed to this negative outcome, not only to build upon this insight for our Parkinson’s program, but also to help assure continued successful development of our product candidates for other diseases.” (company press release 11/28/08)
PD Drugs approved by FDA 2004 - present
Azilect (Rasagiline) (MAO –B inhibitor) - approved for early PD.
Neupro Rotigiotine transdermal system (patch) – reformulation of dopamine agonist. All patches recalled indefinitely in North America due to manufacturing problem.
Parcopa – reformulation - orally disintegrating carbidopa/levodopap tablets
Requip XL (once-a-day) – Reformulation of dopamine agonist
Zelapar – dissolving tabs – reformulation of seligiline
Source: Parkinson Pipeline Project, Treatments in Development database
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