Date: 2013-07-26
Type of information: Development agreement
Compound: CHF 5074
Company: Chiesi Farmaceutici (Italy) Cerespir (USA)
Therapeutic area: Neurodegenerative diseases - CNS diseases
Type agreement: development
licensing
commercialisation
Action mechanism: CHF 5074 is a small molecule with a microglial modulating mechanism of action capable of selectively reducing pro-inflammatory activities of microglial cells while increasing their ability to remove neurotoxic amyloid beta aggregates in the brain by phagocytosis. Chronic dysfunction of microglia is increasingly believed to play an important role at the very beginnings of Alzheimer’s disease. In Alzheimer’s disease transgenic mouse models, CHF 5074 was shown to reduce neuroinflammation, inhibit brain amyloid beta plaque deposits, reduce tau pathology, and reverse associated memory deficits. These findings indicate CHF 5074 acts simultaneously on several important therapeutic targets, and this multi-target approach may translate into preventing the memory loss that is the hallmark of Alzheimer’s disease.
Disease: mild cognitive impairment (MCI)
Details: * On July 26, 2013, CereSpir and Chiesi Farmaceutici have entered into a Letter of Intent and are negotiating a Licensing Agreement, whereby CereSpir will acquire the exclusive global development and commercialization rights to CHF 5074, a novel, first-in-class small molecule microglia modulator that was discovered and developed by Chiesi researchers. Upon execution of the License Agreement, Chiesi is committed to completing the ongoing long-term extension phase of the double-blind, placebo-controlled Phase 2 study in patients with mild cognitive impairment (MCI). Forty-three patients are expected to reach the 90-week endpoint of the Phase 2 study at the end of 2013. Chiesi has demonstrated CHF 5074 improves cognition and reduced brain inflammation in patients with mild cognitive impairment (MCI), and interim results from this study have been presented on July 16 at the Alzheimer’s Association International Conference 2013 (AAIC 2013) in Boston. CereSpir will be responsible for the late-stage development of CHF 5074, regulatory filings, and commercial activities.
Interim results of a Phase 2 study have just been presented by Chiesi at the Alzheimer’s Association International Conference 2013 (AAIC 2013). This 90-week study, which included a 96-patient 14-week double-blind, placebo-controlled study and an ongoing 76-week open-label extension study, tested three titrated doses of CHF 5074 (200 mg, 400 mg, 600 mg dosed orally once daily) in MCI patients. Upon completion of the 14-week study, 74 MCI patients enrolled in the open-label extension study and continued receiving CHF5074 at the dose equal to that of their originally assigned double-blind study cohort. Interim analysis of cognitive tests of 30 patients reaching Study Week 88 showed statistically significant improvements compared to baseline on
• Digit Symbol Substitution Test (+4.3 ± 1.4 matches p < 0.003)
• Trail Making Test-A (-7.0 ± 2.4 sec, p = 0.007)
• Trail Making Test-B (-7.4 ± 6.8 sec, p = 0.291)
• Immediate Word Recall (+3.7 ± 0.9 words, p < 0.001)
• Delayed Word Recall (+1.2 ± 0.4 words, p = 0.012)
• Composite Hopkins Verbal Learning Score (5.0 ± 1.4 (0.001)
ApoE4 carriers (n=12) performed significantly better (p<0.05) than ApoE4 non-carriers on Immediate Word Recall and Trail Making Test-A with improvements representing 25-38% of baseline scores.
In the double-blind, placebo-controlled phase of the study, treatment with CHF 5074 resulted in a dose-depended reduction in inflammatory biomarkers (TNF-alpha and sCD40L) in cerebrospinal fluid collected after 12 weeks of dosing.
Seventy-four patients entered the open-label study: 26 continued on 200 mg/day, 21 continued on 400 mg/day, and 27 continued on 600 mg/day. Patients were monitored for vital signs, cardiac activity, neuropsychological performance and safety laboratory parameters. At Study Week 40, 14 patients dropped out: four, two, and eight in the 200, 400, and 600 mg/day cohorts, respectively. Three of drop-outs were for adverse events: two in the 600 mg/day group (serum creatinine elevation and worsening of cognitive function), and one in the 400 mg/day group (pneumonia). The most frequent treatment-emergent adverse events were gastrointestinal disorders, with diarrhea being reported by 1.4% of patients on 200 mg/day, 6.3% of patients on 400 mg/day, and 20.0% of patients on 600 mg/day.
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