H-PHAR SA was founded in 2002 to develop products based on Hubriphar SA “Know How”, in particular, a drug (Azodicarbonamide) inactivating the retroviral nucleocapside Protein 7 (NCp7) opening a new therapeutic route to treat mutated HIV resistant to the actual therapy combining at least three active medicinal products.H-PHAR SA has built up a network of collaboration with multiple industrial partners and universities. The principal advantage of its compact structure is flexibility and reactivity fully compliant with International Conference on Harmonisation (ICH) recommendations and Good Practices Guidelines (GMP, GLP and GCP).
Costs have are maintained as low as possible in such a manner that the drug would be affordable worldwide for all patients in need. The GMP production of a specific pharmaceutical Azodicarbonamide grade includes a particular dedicated synthesis avoiding semicarbazide (SEM) and heavy metals followed by micronization. This conducts to a new chemical entity (cGMP micronized ADA ). Therefore, the development plan of cGMP micronized ADA responds to all classical drug development steps.
H-PHAR SA is based on a research that began in 1989, when the activity of Azodicarbonamide (ADA) against HIV was discovered by Dr. Michel Vandevelde and Mrs Hélène Margery. They founded the company Hubriphar SA, whose business concept was the identification and the production of anti-HIV compounds that could be added to vaginal creams to prevent spreading of the infection (microbicides).The patent application covering all therapeutic applications of Azodicarbonamide and of a large class of analogues was filed on April 19 th, 1990 . The patents are granted on the main pharmaceutical markets, including Europe , North America and Japan .
In collaboration with the REGA Institute Leuven, the Pasteur Institute Brussels and the Free University of Brussels, ADA characterisation and preclinical toxicology data were generated (thanks to the Region of Brussels grants). The 5 years research results were presented at the 9 th International conference of antiviral research; Urabandai, Fukushima, Japan; 19 - 24 May, 1996 followed by a publication in AIDS Research Human Retroviruses established the basis of a collaboration with the National Cancer Institute (NCI) and the Food and Drug Administration (FDA) in the US.
The mechanism of action of ADA was elucidated in 1996 by Rice and co-workers at the NCI and published in Nature Medicine (1). Azodicarbonamide was found to inhibit HIV replication by targeting the nucleocapside (NCp7) CCHC zinc fingers. The modification of zinc-binding sites inside the conserved CCHC motif of retroviruses including human immunodeficiency virus NCp7 (HIV) induces a complete loss of infectivity. Moreover no resistance of the virus to the inactivation of this specific protein is expected and tests of selection failed to identify resistant mutant viruses.
During the year 1995 - 96, a sufficient amount of a pharmaceutical ADA prototype was produced at the University of Liège and authorization for human administration was obtained. In 1998, the Company completed a phase I/II dose escalation clinical study with ADA in add-on on patients failing on current antiretroviral therapy. The study showed a significant response and provided safety results allowing larger clinical trials. Results have been published in AIDS (2).From 1197 up to 1999 Hubriphar SA conducted in collaboration with the Free University of Brussels an ambitious programme of fundamental research with the goal to better understand ADA effects on human cells and enzymes.
Results were published in Nature Medicine (3) and in Biochemical Pharmacology (4)New applications patents were granted protecting these interesting discoveries.In 2002, the financial situation imposed to find new partners and in collaboration with Floridienne (one of the oldest Belgian industrial company) H-PHAR SA was created with a capital of 2.500.000 €. In April 2003, the Free University of Brussels took a participation in H-PHAR SA (15% of the shares).
A strategy was elaborated as follow :
||Nomination of a “Scientific Advisory Board”;
||Production of a cGMP micronized pharmaceutical grade Azodicarbonamide (new synthesis route, identifiable chemical characteristics “finger print”) leading to a new chemical entity;
||ICH/CGP compliant development plan will be conducted;
||An intermediate submission will be introduced with the idea to obtain an “under exceptional circumstances” market access.
In the beginning of 2004, H-PHAR SA was refinanced through private and public placement (Region of Wallonnie SRIW and the European Capital Risk Fund Objective 1), raising 2.000.000 € with the obligation to succeed in a cGMP micronized ADA production, pre-clinical and phase I clinical trials performed within a strict timeframe.
2015, H-PHAR SA capital worth 8.350.000€.( 6887 shares)
Most of the research results are unpublished and are groupes in a common technical document.
All the data are compliant with European Medicinal Evaluation Agency requirements.
Our collaboration with the US National Cancer Institute an The National Institute of Allergy and Infectious Diseases (NIAID) leads to more than 331bioactivity screening studies(reporting of 01 june 2015)
from 2007 to 2014.alowing:
(1) Rice, W.G., Turpin, J.A., Huang, M., Clanton, D., Buckheit, R.W., Covell, D.G., Wallquist, A., McDonnell, N.B., DeGuzman, R.N., Summers, M.F., Zalkow, L., Bader, J.P., Haugwitz, R.D. and Sausville, E.A .
Azodicarbonamide inhibits HIV-1 replication by targeting the nucleocapsid protein .
Nature Medicine 3, 341-345 (1997).
(2) Phase I/II dose escalation and randomized withdrawal study with add-on azodicarbonamide in patients failing on current antiretroviral therapy.
Goebel FD, Hemmer R, Schmit JC, Bogner JR, de Clercq E, Witvrouw M, Pannecouque C, Valeyev R, Vandevelde M, Margery H, Tassignon JP.
Medizinische Poliklinik, Ludwig-Maximilians-Universitat, Munich , Germany .
AIDS. 2001 Jan 5;15(1):33-45.
(3) Tassignon J, Ismaili J, Le Moine A, Van Laethem F, Leo O, Vandevelde M, Goldman M. Azodicarbonamide inhibits T-cell responses in vitro and in vivo.
Nat Med. 1999 Aug;5 (8):947-50
(4) Christine Fagny, Michel Vandevelde, Michal Svoboda and Patrick Robberecht Ribonucleotide reductase and thymidine phosphorylation: two potential targets of Azodicarbonamide Biochemical Pharmacology, Volume 64, Issue 3, 1 August 2002, Pages 451-456