Globally more than three billion people are at risk of contracting malaria. In 2015 alone, an estimated 214 million new cases were recorded. Of these 88% occurred in Africa, which shoulders the heaviest malaria burden. And of the 438,000 malaria deaths worldwide in the same year, 90% were in Africa. One of the most difficult challenges in malaria control is antimalarial drug resistance. It also has substantial implications for global public health. To tackle drug resistance, the only solution is for new drugs to be developed that are able to resist and/or circumvent antimalarial drug resistance. Scientists at the University of Cape Town’s drug discovery and development centre, H3D, have taken a critical step here, discovering a second new compound that could eventually be developed into an antimalarial medicine. The centre’s founder and director, Professor Kelly Chibale, explains the significance of their discovery.
What effect have large drug breakthroughs had on trends in malaria infection and death rates?
Drug breakthroughs provide hope for the future and contribute to the global malaria drug pipeline, given the constant threat of antimalarial drug resistance. When a drug breakthrough successfully makes it all the way to the market for patients to take, a reduction in both malaria infections and death rates can be expected.
But the challenge is that only some drug breakthroughs lead to the successful development and launch of a medicine onto the market for patients to take.
Drugs kill a disease-causing organism like the malaria parasite by, for example, inhibiting a biological target such as a certain key enzyme or biochemical process that is important for the parasite to survive. The drug works because of specific interactions with the biological target. Among other factors, drug resistance emerges when changes or mutations occur in the biological target in such a way that the drug molecule cannot interact in a specific way with the target.
In some cases resistance has emerged within one year; with other drugs it can take longer. How soon resistance emerges depends on various factors, including the type of biological target, patient compliance and improper use.
Resistance means that we cannot use the drug at the same safe dose as was determined during clinical trials. When a drug target has undergone a mutation, the drug is no longer effective at killing the parasite at the safe dose. To increase the dose might lead to toxicity and side-effects.
What impact has drug resistance had on malaria infection and deaths?
Even when resistance is confined in a certain area, if that drug-resistant strain gets transmitted to another area, it will spread drug resistance. Drug resistance has rendered some drugs useless and malaria impossible to treat (using such drugs) in certain parts of the world. There are different drug-resistant strains in different parts of the world.
Resistance to antimalarial medicines has significantly increased the global cost of controlling malaria over time. This is due to the fact that new drugs must continually be developed to replace medicines that have become ineffective. Patients for whom the treatment is not working require repeated consultations at health facilities. This often results in lost work days, absences from school and increased costs to the health system.
Malaria infections and deaths will easily increase if transmission of the infectious parasite strains go unabated. Untreated malaria leads to death.
A new candidate for a drug (MMV048) was found in 2012. What has happened since?
MMV048 is still in clinical development undergoing human trials. Human clinical trials are extremely expensive and take a long time. They involve at least three phases.
Assuming funding is readily available it can take at least a minimum of six to eight years and even longer if a drug has to be tested in combination with other drugs during human clinical trials. This would require a phase four study. If funding is not available for each phase, the process can be significantly delayed.
Then there is an average of two years to seek regulatory approval and five to 10 years for post marketing-surveillance.
The are other factors, such as delays in recruiting patients for the trials or not having enough human subjects for the trials.
MMV048 has finished its first phase of human trials. One of the major obstacles to taking MMV048 forward to the next phase, phase two human trials, is a lack of funding. Until and unless we are successful with fundraising, the phase two trials will be delayed.
You have found a new candidate – UCT943. What is the significance of this?
This candidate is significant on several levels. First, we have a promising molecule that has been added to the global antimalarial drug pipeline with the potential to contribute to malaria prevention, control and eradication.
Second, our data so far shows that UCT943 has promise to be more potent against the parasite. It also promises to be easier to formulate. This means that the active pharmaceutical ingredient has good chemical properties to formulate it into a capsule or tablet.
Third, UCT943 strengthens the inhibitor programme of the biological target parasite enzyme phosphoinositide 4-kinase. This enzyme is important for the parasite to survive. What this means is when UCT943 gets into the parasite, it blocks this enzyme’s natural function, resulting in parasite death.
And finally, the candidate was discovered by an international team led by H3D, the first integrated drug discovery and development centre in Africa. Being the first of its kind on the continent, this centre and this discovery have put South Africa on the drug discovery map internationally. It is a unique opportunity for South Africa and Africa to provide a portal of collaboration to major global companies. Internationally, pharmaceutical companies are lining up to partner with top-level universities in science and medicine. Through H3D this is already happening at the University of Cape Town.
What happens next?
Pre-clinical development before phase one human trials may commence. Pre-clinical development will include extensive long-term safety and/or toxicology testing, and large-scale manufacture of UCT943 to manufacture enough material for clinical trials. The pre-clinical development is expected to take 18 months.
Kelly Chibale receives funding from Medicines for Malaria Venture (Switzerland), South African Technology Innovation Agency (TIA), Department of Science and Technology (DST) and Strategic Innovation Partnerships unit of the South African Medical Research Council.
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