Introduction and Background of the Project

Introduction

Malaria remains a major health threat as more than three billions of the world’s population are currently at risk and half a million deaths, mostly young children, are reported each year. Over the last decade, a combined effort has generated a broad portfolio of new generation antimalarial drug candidates, amongst them are the Plasmodia specific dihydroorotate dehydrogenase (DHODH) inhibitors (lead DSM265 and back-up DSM421).

DSM265 has entered clinical Phase I in 2014 and its potency as a single dose treatment for P. falciparum malaria has recently been demonstrated in patients. Comparable clearance of P. vivax could not be achieved with a similar or even higher dose of DSM265. The strategy for the back-up molecule of DSM265 includes the objective to improve two features:

- Comparable potency against P. falciparum and P. vivax;

- Reduced cost of goods by increasing solubility and simplifying drug product formulation.

The candidate DSM421 is a potent plasmodial DHODH inhibitor and shows excellent anti-parasitic activity in vitro and in vivo. In contrast to DSM265, DSM421 showed equal potency against P. falciparum and P. vivax isolates in ex-vivo assays. The solubility of DSM421 is much improved compared to DSM265 which should allow a simple and inexpensive formulation.

Project objective

DSM421 has the potential of being a back-up to DSM265, which is currently in Phase IIa clinical trials. DSM421 is a pre-clinical candidate in the MMV portfolio with the potential to be part of a Single Encounter Radical Cure (SERC) against P. falciparum and P. vivax or for chemoprevention. DSM421 is predicted to be a slowly eliminated, long acting drug in humans.

The overall objective presented in this proposal is to develop DSM421 up to Phase Ib challenge studies with a GO / GO NO decision for development as SERC or chemopretective agent.

Project design

The overall goal of this proposal is the assessment of safety of DSM421 in phase I clinical studies and efficacy in phase Ib challenge studies, as well as supporting pre-clinical toxicology studies to advance into phase IIa clinical trials. The project design is divided into 6 parts:

1. Document the safety, tolerability and pharmacokinetics of DSM421 when administered to healthy volunteers (First in Human study (FIH).

2. Assess the blood stage activity of DSM421 against P. falciparum and P. vivax in an

Induced Blood Stage Malaria challenge study (IBSM).

3. Assess the activity of DSM421 against P. falciparum liver stages in a Controlled Human Malaria Infection study (CHMI). This model allows confirming the activity of DSM421 as a chemoprotective agent.

4. Based on the outcome of points 2 and 3, decide whether to pursue treatment of blood stage infection or a chemoprotection indication in a Phase IIa study

5. Manufacture the clinical supplies to support the above phase I studies.

6. Complete the required non-clinical safety studies to support Phase IIa clinical trials (treatment or chemoprevention) and assess the embryofetal safety of DSM421 in light of potential use in pregnant women.

How can your partnership (project) address global health challenges?

More than 200 million cases and 438,000 deaths caused by malaria were reported in 2015^*; these remain unacceptably high numbers for a preventable and treatable disease. 88% of all malaria deaths occur in sub-Saharan Africa mediated majority by P. falciparum, killing globally over 300,000 children under five years of age¹.

P. vivax infection represents a major health issue as well. More than 13.8 million cases of P. vivax malariawere reported in 2015 causing more than 50% of all deaths attributed to malaria outside Africa¹.

Furthermore, the emergence of resistance against existing antimalarials and insecticides threatens the rapid progress in malaria control and elimination. Parasite resistance to artemisinin – the core compound of ACTs – has been detected in five countries in South-East Asia: in Cambodia, the Lao People’s Democratic Republic, Myanmar, Thailand and Vietnam.

The top priorities for the development of novel malaria treatments are to provide the next generation of medicines as a single exposure radical cure (abbreviated to SERC) in order to overcome growing resistance issues and improve treatment compliance.

What sort of innovation are you bringing in your project?

DSM421 is a potent and highly specific inhibitor of the Plasmodium DHODH, which is a new mode of action for the treatment or chemoprotection against malaria. DSM421 has the potential of being a back-up to DSM265. DSM421 has several features that differentiate it from DSM265 and from other antimalarials:

1) DSM421 showed equal activity on P. vivax and P. falciparum ex-vivo field isolates providing strong indication to overcome the liabilities of DSM265 in curing P. vivax infections.

2) DSM421 is simple to synthesize and its improved drug like properties (e.g. increased solubility) compared to DSM265 allows simpler and more cost effective formulation.

3) DSM421 has a long predicted half-life (predicted to be ~83 h in humans). This long half-life will allow the compound to persist until parasites have been eliminated (post treatment prophylaxis).

4) DSM421 inhibits a novel target. DHODH has previously not been exploited for antimalarial chemotherapy. It represents a differentiated therapeutic mode of action, and thus is active against current drug resistant strains and is expected to have activity on resistant strains that may emerge following to use of current therapies.

Role and Responsibility of Each Partner

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.

The project will be conducted by a team comprising the project director, scientists from MMV and Takeda, and further supported in kind by AbbVie colleagues and consultants on specific subject matters. It will be this project team that is responsible for all activities. The studies will be conducted in collaboration between MMV/Takeda, the principal investigators and the clinical monitor.

Takeda’s responsibility is consulting within the project team on non-clinical and clinical science, clinical operations, regulatory, ethical approval processes, CMC and other scientific aspects.

Others (including references if necessary)

1. WHO. World Malaria Report 2015. WHO (2015)

Final Report

1. Project objective 

Malaria remains a major health threat as half a million deaths are reported each year. In the context of the emerging resistance to current treatments, a new generation of antimalarials is required to achieve Malaria eradication. DHODH inhibitors are promising candidates for this purpose.

DSM265, currently in phase IIa, is the lead compound in this category as its potency as a single dose treatment for P. falciparum malaria has recently been demonstrated in patients. As comparable clearance of P. vivax could not be achieved with DSM265, a back-up compound, with comparable potency against P. falciparum (Pf) and P. vivax (Pv), is highly desirable. 

The pre-clinical candidate DSM421 has this potential: it is a potent plasmodial DHODH inhibitor, shows excellent anti-parasitic activity, equal potency against Pf and Pv isolates in ex-vivo assays and has an improved solubility, which should allow a simple and inexpensive formulation. 

The objective of this project is to evaluate DSM421 safety and tolerability and assess its potency in an integrated First in Human and Challenge phase I study in healthy human volunteers. 

2. Project design 

The project is divided into 6 parts:

1. Document the safety, tolerability and pharmacokinetics of DSM421 in a First in Human study (FIH).

2. Assess the blood stage activity of DSM421 against Pf and Pv in an Induced Blood Stage Malaria challenge study (IBSM).

3. Assess the activity of DSM421 against Pf liver stages in a Controlled Human Malaria Infection study (CHMI). This model allows confirming activity as a chemoprotective agent.

4. Based on the outcome of points 2 and 3, decide whether to pursue treatment of blood stage infection or a chemoprotection indication in a Phase IIa study.

5. Manufacture the clinical supplies to support the above phase I studies.

6. Complete the required non-clinical safety studies to support Phase IIa clinical trials (treatment or chemoprevention) and assess the embryofetal safety of DSM421 in light of potential use in pregnant women.

3. Results, lessons learned 

In order to safely administer DSM421 for the first time to humans, the Health Authorities require the completion of a preclinical toxicology package to limit the safety risks to the healthy volunteers involved in the phase I studies. 

During this phase, it was discovered that DSM421 causes nerve degeneration of low to moderate severity to dogs. To ensure that healthy volunteers are not exposed to a similar risk during the FIH study, these damages must be shown to be reversible and monitorable in humans. Reversibility can be assessed by adding a long recovery period to a new GLP toxicology study and monitorability may be possible via nerve conduction studies. However, the new GLP toxicology study would increase project’s costs and the need for nerve conduction evaluations in human would complicate the FIH study.

Another unexpected finding increased the risk to healthy volunteers’ safety. In a preclinical study which aimed at evaluating the effect of DSM421 on the respiratory function, rats died when administered doses that were tolerated in a number of other studies. This was an isolated event limited to specific experimental conditions known to cause stress to the subjects.  It is difficult to assess the likelihood that this may occur in humans, but such risk cannot be taken. 

Because of these two issues, it was estimated that the administration of DSM421 would bear a certain level of risk to the health of the study volunteers. This risk may not be completely avoided even with extensive and expensive preventive measures. It was therefore decided to halt DSM421’s further developments before the start of phase I.

In parallel to the toxicology evaluations, attempts were made to develop a suitable and simple formulation for DSM421. This endeavor has been particularly successful and lead to the generation of tablet prototypes shown to allow high absorption of compound into the blood. While this is a very favorable outcome for DSM421which supports continued clinical development, it does not mitigate the safety risks which are responsible for halting development of DSM421.