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PPL-100 Phase I Report: New PI from Merck
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Ambrilia Announces that Phase 1 Study Results Support Continued Development of PPL-100, an Investigational HIV/AIDS Protease Inhibitor
DECEMBER 8, 2006
MONTREAL, QUEBEC--(CCNMatthews - Dec. 8, 2006) - Ambrilia Biopharma Inc. (TSX:AMB), a biopharmaceutical company developing innovative therapeutics in the fields of cancer and infectious diseases, announced today the outcome from the Phase 1 repeat dose study with PPL-100, its lead investigational protease inhibitor (PI) for the treatment of HIV/AIDS.
The study showed that PPL-100 has a good safety profile, with only mild (grade 1) adverse events observed in the treatment groups. No moderate or severe cardiovascular and hepatic adverse effects, characteristic of the class of compounds, were observed and no clinically significant abnormalities were observed in laboratory safety tests.
The pharmacokinetic (PK) data from the current repeat dose study support the potential for PPL-100 either as an un-boosted once-daily or twice-daily treatment for PI-naive and treatment-experienced HIV/AIDS patients.
In October, Merck & Co., Inc. signed an exclusive licensing agreement with Ambrilia granting Merck, through an affiliate, worldwide rights to Ambrilia's protease inhibitor program, including PPL-100. Based upon the results of the repeat dose study, Merck has commenced an active formulation program to further improve the pharmacokinetic profile of the compound and move the program forward. To date, PPL-100 has been administered as capsules with neat unformulated compound. Because of this formulation development at Merck, the $US 3 million milestone expected by Ambrilia with the Phase 1 repeat dose results will not be received. Nevertheless, all subsequent milestones will not be affected.
"We are pleased with the results from our Phase 1 repeat dose study that confirm our original expectations and belief in PPL-100," said Hans J. Mader, President and Chief Executive Officer of Ambrilia. "We look forward to following the progress made by Merck as it moves the compound through improved formulation and further clinical development," he added.
Ambrilia's PPL-100 is a promising protease inhibitor (PI) which binds specifically to HIV-1 protease, the enzyme that allows the virus to finalize its maturation, and therefore results in the formation of immature and non-infectious viral particles.
Contrary to most commercially available Protease Inhibitors (PI) that cause serious side effects, PPL-100 was shown to be well tolerated and non-toxic. More importantly, a recent study demonstrated that PPL-100 has a high genetic barrier, therefore making it more difficult for the HIV virus to develop resistant strains.
The resistance to PIs is mainly due to the appearance of mutations in the virus, particularly in the protease gene. The resistant mutations to marketed PIs most likely result from the prolonged use of these drugs in HIV positive patients. For this reason, new antiviral drugs with a high genetic barrier need to be developed to fight the emergence of resistant HIV viruses. The high genetic barrier of PPL-100 differentiates significantly this drug candidate from commercially available PIs. In addition, PPL-100 confers to the virus hypersensitivity to some existing PIs.
Single-dose study data as well as population PK modeling results suggest that PPL-100 is a potential first-line, once-daily without ritonavir boosting PI to treat a large spectrum of HIV/AIDS patients.
HIV/AIDS - Integrase inhibitor program
Ambrilia's integrase inhibitor program is based on a family of molecules containing hydroxyphenyl derivatives, aromatic derivatives and pyridoxal phosphate derivatives several of which have shown activity in enzymatic assays on HIV replication in cell culture.
Integrase is an essential enzyme for HIV to integrate its proviral DNA into host cell DNA. Inhibiting the integrase enzyme could be a decisive key to interrupt the replication cycle, and at the same time address viral mutation in order to control newer, drug-resistant strains. As to the prevalence of resistance to existing HIV therapies increases, other therapeutic options become indispensable. To date, few integrase inhibitors have been described and even fewer have shown sufficient antiviral activity to be pursued further as therapeutic agents.
Development status
Ambrilia's medicinal chemists and biologists are currently designing and testing new molecules in order to increase the efficacy of the drug to low nanomolar range while at the same time retaining an excellent safety profile and activity in both wild-type and multi-drug resistant viral strains.
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