Awarded Amount$1,589,999DiseaseMalariaInterventionDrugDevelopment StageClinical Phase2Collaboration PartnersTakeda Pharmaceutical Company Limited , Medicines for Malaria Venture (MMV)Past Project
Introduction and Background of the Project
DSM265 is an approved clinical candidate in MMV’s portfolio and is a novel, selective inhibitor of Plasmodium DHODH, which kills the malaria parasite through the inhibition of an essential enzyme. This is a compound with a long duration of action that could potentially be part of a new treatment for malaria as a single dose cure, or for chemoprophylaxis.
For development of a single dose cure, an oral solid dosage form is in development to support future clinical studies and eventually commercial use. The dosage form is also required to be suitable for pediatric use since majority of the population affected by malaria are children under five years of age. DSM265 is a low solubility, high permeability drug (BSC Class II) and therefore requires relatively complex formulation techniques to improve its bioavailability. The projected cost of the drug substance is also high.
This proposal to optimize the current clinical formulation builds on previous development work that was supported by GHIT by reducing the cost of goods and lowering the administration volume for pediatric use while providing desired bioavailability in the target population.
To successfully optimize the current DSM265 oral formulation by maximizing the drug loading and minimizing the dose administration volume to be suitable for pediatric use. To aid in the testing of the formulation prototypes, a discriminatory dissolution method and/or a physiologically based pharmacokinetic (PBPK) model will be developed to predict human exposure. Upon successful optimization, it is proposed to manufacture clinical supplies to be tested in a confirmatory human bioavailability study.
DSM265 is a drug with low aqueous solubility and high permeability (BCS Class II). In order to improve its bioavailability, spray dried dispersion (SDD) formulations were developed wherein the drug is present in a stable amorphous form. The drug to excipient ratio is critical in stabilizing the amorphous form thus affecting its bioavailability. Higher levels of excipients (lower drug loading) tend to improve API stability and solubility. Typical drug loading for SDD formulations is between 15-30%. The current formulation that was used in previous clinical studies is a 25% drug loaded SDD powder formulation. During future development work, drug loading between 30-50% will be studied to determine optimal drug loading.
The current formulation also has poor flow properties which poses packaging challenges. Furthermore, for administration purposes, it was dispersed using an aqueous solution containing solubilizing agents and sweetener. The need for this dosing vehicle poses commercially logistical problems and stability challenges, and increases the cost of goods. The relatively high dosing volume is also an issue for pediatric patient population. A granulation process that incorporates the solubilizing and sweetening agents in the granule can potentially have better flow properties and require only water for reconstitution. Successful formulation development at higher drug loading and choice of dispersing agents can bring down the dispersion volume that is suitable for pediatric administration.
In parallel, MMV will develop prototypes with 25-50% drug loading using hot melt extrusion (HME) process as it is a cheaper technology than spray drying.
In order to carry out the above optimization work MMV will need to develop a discriminating dissolution method and/or a PBPK model to test the formulation prototypes in order to predict their human exposure.
Upon successful prototype development and testing, MMV will manufacture clinical supplies of the selected prototypes for a definitive human bioavailability study.
How can your partnership (project) address global health challenges?
Despite being an entirely preventable and treatable disease, malaria still places half the world's population at risk in 97 countries, with more than 200 million cases each year. In 2016, an estimated 429,000 people have died. The WHO estimates that 90% of all malaria deaths occur in sub-Saharan Africa, 70% of whom were children under five years of age in 2016. That is one child almost every two minutes.
Furthermore, the emergence of resistance to insecticides and malaria medicines currently being used in endemic countries is a growing concern. The imperative, therefore, is to develop and implement approaches that will eradicate the parasite. In line with this, MMV’s strategy looks both at the short-term goals, that we can deliver to the market within the next 5 years to support elimination efforts, and projects that lay the groundwork for ‘game-changing’ next-generation medicines to support eradication.
The top priorities for the development of novel malaria treatments are to provide the next generation of medicines – for a single exposure radical cure and prophylaxis (abbreviated to SERCaP). A SERCaP product would transform malaria treatment and could form the base of an eradication agenda based on mass drug administration.
DSM265 is a novel triazolopyrimidine inhibitor designed to target the parasite dihydroorotate dehydrogenase (DHODH) enzyme thus blocking de novo pyrimidine nucleotide biosynthesis & parasite growth. Selectivity of DSM265 to human DHODH is, however, very high. It exhibits a low IC50 value in vitro in red blood cells infected with P. falciparum parasites, one of the parasites causing malaria in humans and is equally potent on liver stage parasites. The liver stage activity combined with the long half-life, makes this drug a very exciting candidate of a new generation of chemo-preventive agents and potentially an adequate use in low transmission blocking areas of disease endemic countries.
What sort of innovation are you bringing in your project?
Due to its novel mechanism of action, DSM265 has the potential to be a slowly eliminated single dose drug to treat uncomplicated P. falciparum malaria. Its unique characteristics also make it a safe and potentially effective chemopreventive agent. The formulation under development will ultimately offer an inexpensive, child -friendly oral dosage form that is stable at tropical conditions.
Role and Responsibility of Each Partner
MMV is partnering with Takeda on the development of DSM265. MMV as designated grantee for this proposal is responsible for delivering the work plan to the agreed timeline and budget, in addition to required GHIT reporting. A joint project team comprising the project director, scientists from MMV and Takeda, will be responsible for all activities. The studies will be conducted in collaboration between MMV/Takeda, the principal investigators and monitoring CROs.
MMV’s responsibility will be to sponsor, lead and manage the project and co-ordinate the activities. Experimental work will be performed at external clinical sites or CROs and CMOs. Takeda’s responsibility is to consult within the project team on clinical science, clinical operations, regulatory and ethical approval process, CMC and scientific aspects.
Others (including references if necessary)
WHO World Malaria Report 2016
1. Project objective
The objective of the project was to develop an oral formulation of DSM265, a novel antimalarial drug which holds promise as a single dose cure for P. falciparum malaria, that is suitable for administration to children (6 months and older) and commercially viable. The pediatric formulation should provide similar drug exposure in humans as that of previous clinical powder formulation that was not commercially viable. The target administration volume for a pediatric formulation is less than 10-15 ml, and the formulation must be dispersable in potable water. The cost of the formulation should allow easy access in low-to-middle-income countries.
2. Project design
Previous efforts to develop a pediatric formulation of DSM265 focused on maximizing the drug load in the formulation in order to reduce the administration volume and formulation costs. Cheaper technologies other than spray-drying were also explored. However, drug bioavailability from these formulations (with > 70% w/w drug load) was significantly lower than that from the clinical formulation. Therefore, in the current project, optimum drug loading was investigated using spray-dried dispersion. In addition, in vitro models to predict human bioavailability were evaluated. Based on the in vitro data and confirmatory bioavailability in dogs, an optimum formulation was selected for a human bioavailability study.
3. Results, lessons learned
A pediatric formulation of DSM265 containing 34% w/w drug loading was developed by spray-drying technology. The pediatric dose of the powder formulation could be dispersed in 7 ml of water compared to that of reference clinical formulation which required a minimum volume of 30 ml for administration in children. (The reference formulation also required a complex vehicle for reconstitution which was not commercially viable.) The new formulation showed similar dissolution properties in vitro and similar oral bioavailability in dogs, to that of the reference formulation. In a human clinical study, the bioavailability of the new formulation in healthy adult volunteers (n = 14 subjects) was approximately 93% of the reference formulation. There was a small/negligible food effect with the new formulation as the bioavailability was 17% higher following a high fat breakfast compared to fasted condition. Based on the positive bioavailability results and the fact that the new formulation meets the target administration volume in children, it is nominated for future clinical studies.
The spray-drying technology is scalable and amenable to continuous processing which, at large commercial volumes, can deliver an affordable treatment in endemic countries. Outside the scope of the current project, the cost of the drug substance was also substantially reduced by identifying cheaper starting materials for synthesis and by optimizing the synthetic route. Therefore, based on the human bioavailability results, the administration volume and projected cost of goods, the pediatric formulation is deemed suitable for commercial use.
Formulation Optimization Work on DSM265