One of the most important stages in the development of a drug is the evaluation of how it should be administered. Adequate administration has a direct effect on the drug's efficacy, as it influences factors such as its pharmacokinetics, pharmacodynamics, safety, immunogenicity, bio-recognition of the drug, among others. On the other hand, investigation in this field allows minimization of such factors as degradation of the active substance, prevention of side effects or increases in the bio-availability of the drug in the body.
ROVI has developed a leading-edge research line in the field of drug delivery or depot systems. This is generally a subcutaneous or intramuscular injection of a pharmacologically active agent that releases the active substance in a constant flow over a long time period. The technology developed by ROVI, ISM® technology, is based in the formation of in situ implants for extended release of drugs.
In situ forming systems (ISM®) have emerged as a very attractive possibility for the extended release of bioactive macromolecules.
Over the last few years, the fast development of the ISM® technology has made possible that the depot formulations to become in science fact. ISM® technology is based on a solid and stable polymeric matrix system that contains a drug. The product is reconstituted to an injectable fluid that precipitates in situ (inside the body) after the injection, resulting in the formation of solid or semisolid implants, by solvent diffusion to body fluids.
ISM® technology overcomes most of the current difficulties related with the oral and parenteral extended release formulation combining the advantages of existing technologies such as preformed microparticles and implants. Our technology allows the extended delivery of compounds administered by parenteral route with the following key advantages: less variability, enhanced stability, rapid reconstitution and easier injection, making easier for the patient to follow the prescribed treatment.
ISM® systems have the following advantages over other marketed technologies: (I) ease administration as it is less painful, (II) zero-order kinetics, (III) reduction of the burst effect in drug release and greater reproducibility in the release profiles, (IV) highly effective encapsulation, (V) high performing process and, finally, (VI) active substance´s stability improvement.
This field of research comes up from the ROVI´s interest in the development of formulations based on ISM® technology. This technology would allow periodic administration of drugs which are administered daily in chronic and prolonged treatments, in order to improve the treatment compliance and the patient quality of life. This novel approach allows ROVI to be introduced and compete in new therapeutic areas. Extended release formulations based on ISM® technology are currently being developed for psychiatric and oncologic drugs due to their industrial potential, commercial and health interest.
In September 2010, the experimental stage for the first Phase I trial of Risperidone- ISM® began on healthy volunteers. The aim of this trial was to evaluate the pharmacokinetics and tolerability of a single intramuscular administration of Risperidone ISM®, the first candidate for the new delivery system. This trial has served, not only to confirm the pharmacokinetic profile of this depot formulation for the monthly administration of risperidone, but it has served as proof of concept for validating ISM® technology for future developments. In this regard, a new quarterly formulation of letrozole is in advanced preclinical development. This drug is a well-established aromatase inhibitor for the treatment of dependent-hormone breast cancer.
During 2012 ROVI built in Madrid a manufacturing plant of investigational Medicine Products with the ISM® release system technology, equipped with innovative and unique machinery for the filling of solid compounds in syringes under the guidelines of good manufacturing practices. Also, is building a factory which will let to produce the new drugs with ISM technology that contain high strength active principles, as letrozole, which is planned to start clinical development phase soon. The first human clinical trial of letrozol ISM® is expected for 2016, and the medication used there will be manufactured at this factory.
The extracellular matrix in animal tissues is a medium in which there is intense intercellular communication. This communication takes place through recognition phenomena between biomolecules which, unlike the intracellular interactions, takes place in an unconfined medium implying notable requirements in terms of selectivity and specificity. In this context, it is important to highlight the essential role played by carbohydrates as this is the type of biomolecule with the greatest capacity for structural diversity and therefore for transmitting information. For this reason, the new term of glycomics has recently been coined as an innovative solution for seeking out carbohydrates with new activities. Glycomics comprise the study and characterization of the sugars making up a cell.
Glycosaminoglycans (GAGs) constitute the main component in the proteoglycans present in the extracellular matrix. These polysaccharides, apart from their well-known role in the regulation of blood clotting, are involved in the control of a large number of cell signaling processes, including particular processes for cell growth, differentiation, proliferation, immune response and inflammation. In order to exercise these functions, GAGs have to interact, more or less specifically, with numerous proteins taking part in the activation or inhibition of the corresponding signaling cascade. Glycomics studies provide very valuable information in this sense, as they allow determination of the receptors taking part in the interaction with each type of GAG.
ROVI's research in the field of GAGs and, in particular, into heparins has traditionally focused on their pharmacological activity as anti-coagulants. Bemiparin (INN), our second-generation low molecular weight heparin (LMWH) is the LMWH with the lowest mean molecular weight (3,600 D), the longest half-life (5.3 h) and the best ratio on the market (8:1) between anti-factor Xa/anti-factor IIa activity. It is marketed (as Hibor®, Ivor®, Zivor®, Badyket®, Ivormax®, Ivorat®) in 52 countries and is the second most sold in Spain.
The degree of specialization and knowledge achieved by ROVI at this field, allows considering the expansion of applications, indications and alternative mechanisms of action for the heparin derived products and other glycosaminoglycans, based both anticoagulant and non-anticoagulant activity. ROVI is investigating, mainly through cooperation agreements with national and international research groups. In this sense ROVI convenes annually an International Scholarship Competition for Biomedical Research related with bemiparin, which has been already launched its fourth edition.
ROVI has developed a biosimilar of enoxaparin, a low molecular weight heparin with antithrombotic effect. The Company requested the marketing authorization from the European and USA health authorities, recently. On February 2015, after the completion of the validation phase, it started the assessment process for Europe to obtain the mentioned marketing authorization.
One of the most relevant side effects of using urinary tract catheters is the high prevalence of urinary tract infections that leads to high mortality rates (E.g., due to sepsis) and causes significant costs in health care systems. Despite the extensive employment of closed systems or catheters coated with antibacterial compounds, the incidence of urinary tract infections associated to urethral catheter is still high, because the biofilm formation (figure 1) reduces the antimicrobial agents activity and then the elimination of microorganisms.
Figure 1. Biofilm formation.
ROVI has designed a multilayer technology platform that is currently under development. This technology will be initially applied to urethral catheters. It is based on the use of polymer layers that bioerode under the influence of bacterial metabolism. This erosion provides important advantages over the state of the art technologies, by reducing bacterial adhesion on the luminal surface, facilitating biofilm elimination and avoiding the formation of encrustations that lead to catheter blockage.
Therefore, the urethral catheters based on ROVI's multilayer technology platform will constitute an alternative over existing medical devices. They will increase patient's quality of life, reducing the use of antibiotics and catheter substitutions due to blockage. Then, they will reduce also morbidity and hospitalization associated to the use of these devices.
Figure 2. Catheter encrustation
ROVI has developed several polymeric compositions and many microbiological trials were performed in order to evaluate the capacity of avoiding bacterial attachment, promoting biofilm elimination and avoiding the formation of encrustations. These results were also compared over those obtained with materials commonly used in catheter fabrication such as silicone and PVC. ROVI has started also a scale-up processes study and it developed the first technological beneficial prototypes for in vivo trials.
The development of this innovative research line will provide ROVI with the ability to extend company's patents and commercial products portfolio in the medical devices field in a competitive way, as the technology can be also used as a platform for future developments.
The Clinical Research Program of ROVI is supported by its technological platform: ISM® (In Situ Microparticles system)
The ISM® technology is designed to allow the extended release of compounds administered by parenteral route with the following key advantages: less variability, enhanced stability and decrease of the number of doses of the active principle.
ROVI has already initiated the research program with this technological platform for some compounds and currently there are several projects on different development phases:
Risperidone ISM®: It is an atypical second-generation antipsychotic drug which has been formulated with ISM technology. In 2010, the clinical testing stage began for the first Phase I trial of Risperidone-ISM® on healthy volunteers and finished by the end of 1Q 2011. This trial aimed mainly to evaluate the pharmacokinetics and the tolerability of a single intramuscular administration of Risperidone in an ISM® formulation. In July 2011, ROVI disclosed the positive results obtained from this clinical trial. The analysis of the data showed that ISM® technology enables the sustained delivery of Risperidone from the first day, which will allow for once-monthly administration without oral Risperidone supplementation in the first weeks. These characteristics will facilitate the adherence with treatment of schizophrenic patients, and represent an improvement on the Risperidone formulations that are currently available. The full results were presented at the 3rd European Conference on Schizophrenia Research held in Berlin in September 2011 .
After obtaining these favourable results, in 2012 ROVI held meetings with the Spanish Agency of Medicines and the U.S. Food and Drug Administration (FDA) in order to get scientific and regulatory advice on the clinical development of Risperidone ISM®. In addition, in 2013 it was started the PRISMA-1 study, a new multicentre, international, phase I study to evaluate the pharmacokinetic profile, tolerability and safety of single doses of Risperidone ISM® at different concentrations (50 mg, 75 mg and 100 mg) administered to patients with squizophrenia or squizoafective disorders. The results of this study confirm that ISM® technology provides a sustained release of risperidone that achieve therapeutic levels from the first day of administration. Furthermore, It allows a monthly administration without oral supplementation. These results were presented at the XII Congress of the EACPT (European Association for Clinical Pharmacology and Therapeutics), held in Madrid in June 2015.
Furthermore, at the end of 2013 ROVI submitted an IND (Investigational New Drug) to the FDA, in order to start the phase II trial, PRISMA-2 . The study took place in several centres from the USA, with the aim of evaluate the pharmacokinetic profile, safe and to explore efficacy of multiple doses of Risperidona ISM® in patients with stable schizophrenia. The preliminary positive results of this study are have been announced by press release. The final results will be probably published before the end of 2015 and it will be presented in the 24th European congress of Psychiatry, which will take place in Madrid in March 2016. All these results, together with those from previous studies, will be used for the planed scientific advise with the European Medicines Agency (EMA) and FDA about the design of the phase III clinical trial, which is scheduled by the first half of 2016.
Letrozole-ISM®: ROVI is also dedicating its efforts for the development of a novel formulation for a quarterly injection of a well-recognised aromatase inhibitor, letrozole. Letrozole is currently considered as a key therapy for the treatment of the hormone-dependent breast cancer and the ISM technology may provide better compliance and additional benefits to those patients who are suffering from this type of tumor. After completing regulatory preclinical studies for letrozole ISM®, it will initiate the clinical development phase in 2016.