|Provectus Biopharmaceuticals Concludes FDA Meeting for PV-10 Phase 3; Successful Completion of AB Science's Futility Test For Masitinib|
|Provectus Biopharmaceuticals Concludes FDA Meeting for PV-10 Phase 3; Successful Completion of AB Science's Futility Test For Masitinib|
|By Marilyn Mullen|
|Monday, 09 February 2015 20:48|
Provectus Biopharmaceuticals (NYSE: PVCT) announced it has held a Type C meeting with the U.S. Food and Drug Administration to review certain operational aspects of the protocol for its planned phase 3 clinical trial of intralesional PV-10, its novel investigational drug for cancer, as a treatment for melanoma. The meeting was held by teleconference on January 29, 2015.
Eric Wachter, PhD, CTO of Provectus, stated, “As noted in our press release of December 22, 2014, when we submitted the protocol to the Agency in November 2014, we included a brief list of questions about certain operational aspects of the protocol. The FDA subsequently indicated that a formal meeting was appropriate to assure that these questions were addressed in a timely and comprehensive manner. As is typical for such meetings, we provided a more extensive list of questions in the formal meeting package. This led to a very thorough and helpful review of the protocol as a result of the meeting.”
Topics formally reviewed included subject eligibility requirements, primary and secondary study end points, and study lesion definitions and conventions for defining disease progression.
Dr. Wachter noted, “We are extremely grateful for the careful review conducted by the Agency. The outcome of the review does not affect the fundamental design of the study nor the patient population, but does affect certain details concerning some secondary end points and statistical analysis matters, such as the treatment of missing data. We are making a number of small changes to the protocol in light of this review, and will issue a final version later this month.”
Dr. Wachter added, “We have eight sites, four in the U.S. and four in Australia, in our expanded access program currently using PV-10 for melanoma and other cutaneous malignancies. We expect that they will provide a path to quickly starting enrollment upon completion of the review period. In addition, we have been qualifying additional sites that will join the study pending action by their respective Institutional Review Boards.”
AB Science SA (NYSE Euronext - FR0010557264 - AB), a pharmaceutical company specialized in research, development and marketing of protein kinase inhibitors (PKIs), today announced the successful completion of a futility analysis related to the masitinib phase 3 trial for the treatment of mild to moderate Alzheimer's disease. Based on these results, the Independent Data Safety Monitoring Committee (IDMC) has recommended the continuation of the study.
Phase 3 status -- The ongoing phase 3 trial is a double-blind, randomized, placebo-controlled study (AB09004) designed to assess the safety and efficacy of masitinib in patients with confirmed mild to moderate Alzheimer's disease. The treatment period is 24 weeks and masitinib is being given as an add-on therapy to cholinesterase inhibitor (donepezil, rivastigmine or galantamine and/or memantine). The main measures are the change in two commonly used clinical assessments: the effect on ADCS-ADL, which measures self-care and activities of daily living assessed, and the effect on ADAS-Cog, which measures the effect on cognition and memory. The study is intended to enroll about 600 patients.
The study was recently assessed as non-futile by the IDMC. A futility analysis tests the inability of a clinical study to achieve its efficacy objective. Therefore, a conclusion that a study is not futile suggests that a clinical study has the potential to achieve its stated efficacy objective. The IDMC analysis was performed after about one third of the patients were enrolled into the study and had reached the 24 week treatment duration period.
The study previously successfully passed all safety data reviews by the IDMC, indicating that there is no major or unexpected safety concern with masitinib in this patient population.
Previous establishment proof of concept -- As a reminder, proof of concept for the evaluation of masitinib in Alzheimer's disease was established through a 35 patient double-blind, placebo-controlled phase 2 study. In this study, the rate of clinically relevant cognitive decline, according to the primary endpoint, ADAS-Cog response (increase >4 points), was significantly lower with masitinib treatment compared with placebo after 12 and 24 weeks (6% versus 50% for both; p=0.040 and p=0.046, respectively). Moreover, while the placebo treatment-arm demonstrated worsening mean ADAS-Cog, ADCS-ADL and MMSE scores, the masitinib treatment-arm reported improvements with statistical significance between treatment-arms at weeks 12 and/or 24 (respectively, p=0.016 and 0.030; p=0.035 and 0.128; and p=0.047 and 0.031). Adverse events occurred more frequently with masitinib treatment (65% versus 38% of patients); however, the majority of events were mild or moderate and transient. The phase 2 results were published in Alzheimers Res Ther. 2011 Apr 19;3(2):16. doi: 10.1186/alzrt75.
Scientific rationale -- The potential therapeutic benefit of masitinib in Alzheimer's disease is linked to two possible mechanisms of action: the role of mast cells in neuroinflammation and regulation of the blood-brain-barrier (BBB) permeability; and the inhibition of the protein kinase Fyn, which is involved in A-beta signaling and Tau phosphorylation.
Neuroinflammation is thought to be a major contributor in the pathogenesis of Alzheimer's disease1,2,3. Mast cells release large amounts of proinflammatory mediators and therefore play an important role in sustaining the inflammatory network of the central nervous system. Furthermore; mast cells are found on both sides of the BBB and also have the ability to rapidly cross the BBB, thereby increasing their numbers in response to physiological stimuli. Given that the neural pool of mast cells is influenced by their ability to rapidly cross the BBB, inhibition of mast cells peripheral to the BBB could impact upon neurodegenerative disease outcome. Therefore, masitinib could be an effective drug in Alzheimer's disease because it blocks mast cells through the inhibition of the tyrosine kinases c-Kit and Lyn.
In addition to blocking mast cell activity, masitinib may exert an effect through its inhibition of the tyrosine kinase Fyn4,5,6. Alzheimer's disease is associated with the pathological aggregation of amyloid-beta (A-beta) plaques and tau-positive neurofibrillary tangles. Several lines of evidence implicate Fyn in the pathogenesis of Alzheimer's disease through its dual role in A-beta signaling and Tau phosphorylation. Masitinib, by inhibiting Fyn, could possibly disrupt the A-beta signaling cascade and modulate the phosphorylation of tau protein, thus and preventing neurofibrillary tangles.
Targeted population -- The meta-analysis of epidemiologic studies indicates that between 5 and 10 million people suffer from Alzheimer's disease in the USA and Europe. Alzheimer's disease is the most common type of dementia among western countries, corresponding to about 60% of cases. Alzheimer's disease is already the sixth leading cause of all deaths in USA and the fifth leading cause among Americans over 65 years of age.7,8,9 Worldwide, it is thought that there are more than 15 million people affected by Alzheimer's disease.8
Currently, there are only five products approved for the treatment of Alzheimer's disease, four of which belong to the pharmacological class of anticholinesterases, the fifth being an NMDA inhibitor. Therefore, this remains an area of significant unmet medical need. Accordingly, the FDA recently issued new guidance (21 CFR 149 314.510) that allows for the potential of conditional approval.
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