Praziquantel for young children
The launch of praziquantel in 1980 was a milestone in the treatment of the parasitic worm disease schistosomiasis. Millions have been treated with this medicine — but this group has excluded children under six, for whom praziquantel in its present form is not suitable. Strong international partners are now cooperating to change that.
Jutta Reinhard-Rupp is the head of EMD's innovation platform Global Health
The pill tastes fairly bitter and is almost a centimeter long. No young child would want to swallow it. However, this is the only effective medicine against the parasitic worm infection schistosomiasis. According to some estimates, more than 240 million people suffer from this disease, especially in the poor nations of Africa, South America, and Asia.
Recent investigations have yielded even higher estimates of between 400 and 600 million sufferers. Approximately 280,000 people die annually from the long-term consequences of this disease.
Until a few years ago, it was not clearly known whether young children could contract schistosomiasis. As a result, not much attention was paid to developing a medicine suitable for them. However, extensive research done by Jutta Reinhard-Rupp, who heads the Global Health innovation platform at EMD, got the ball rolling. Together with experts from the Liverpool School of Tropical Medicine, she discovered that young children could in fact contract this disease, but that it was in many cases misdiagnosed.
“It’s not possible to simply divide up the big tablets. The metabolism of young children is completely different from that of grownups.“
Head of EMD's innovation platform Global Health
A hiding spot for the worm
Schistosomiasis is caused by a parasitic worm of the genus Schistosoma. In its larval stage, it enters the body of its human host by boring through the skin. Once inside the host, the larva develops into a worm that lays its eggs in the host’s body; the eggs are excreted in feces and urine. They then develop into larvae inside an intermediate host — a freshwater snail, for instance — and these larvae in turn infect other human beings. Then the cycle begins anew.
Since 1980, it has been possible to treat the disease with tablets containing the active ingredient praziquantel, which kills the worms. This medicine has been a blessing for the many millions of people who were treated with it. But the disease itself can be eliminated only if the parasites’ development cycle is interrupted and the larvae can no longer enter the bodies of human hosts.
In spite of tremendous international efforts and a EMD program in which millions of praziquantel tablets have been donated to patients, the Schistosoma parasite has been able to continue multiplying in a demographic group that has thus far been untreatable. “Praziquantel tablets are not approved as a treatment for children under the age of six,” explains Reinhard-Rupp. “However, even infants can be infected and then excrete the parasites’ eggs. In the general population, young children offer the worm a hiding spot — a protected area in which it cannot be attacked.”
Together with several partners, EMD is working on a formulation of the medicine Praziquantel that is also suitable for children under six years of age
Young children need special tablets
The long-term consequences of a schistosomiasis infection can be devastating for young children. “If children are treated for the first time only at the age of six, it’s possible that they have already been infected for several years,” Reinhard-Rupp says.
“In many cases, the parents don’t notice anything, but the children fall to grow taller, are often fatigued, and have difficulties in learning. But the worst aspect is that after all these years, the worms have entered the children’s tissues and are laying their eggs there. These eggs can cause chronic damage to the children’s organs.” Even if treatment is begun at that point, the damaged organs can no longer be healed and can cause health problems that last a lifetime.
Treatment must therefore begin during early childhood. But how should the dosage of the active ingredient be adapted? And how can the medicine be administered so that it no longer tastes bitter? “There have been no studies to determine the correct dosage for young children,” says Reinhard-Rupp. “And it’s not possible to simply divide up the big tablets, because children are not small adults, and the metabolism of young children is completely different from that of grownups.”
As a result, the task is now to develop a pediatric tablet with a type of praziquantel that works even in small doses and tastes better than the original. That’s a huge challenge for chemists and pharmacologists.
The chemist Andreas Wächtler, who joined EMD 30 years ago, is an expert on Praziquantel
Selecting the right molecule
The chemist Andreas Wächtler is an expert when it comes to praziquantel. He started working at EMD 30 years ago, just after praziquantel had been launched. Now, toward the end of his professional life, the full extent of his expertise is once again required.
How can this medicine successfully achieve the same effect in spite of a lower dosage of the active ingredient? Wächtler points out that a certain attribute of this active ingredient has been very helpful: “Praziquantel is a mixture of two molecules that have the same chemical composition, but mirror each other in their physical structure. They are not identical; they are reflections of each other like the right and the left hands.”
The two molecules’ different structures also act differently inside the human body. Fortunately, only one of the two structures is responsible for the medicinal effect, whereas the other one is disproportionately responsible for the bitter taste. According to the chemist, “Previously, only this mixture was available as an active ingredient, but we can now produce the molecule’s active form separately. When the inactive, primarily bitter form of the molecule is dispensed with, the size of the tablet can automatically be halved.”
Preparations for the initial clinical tests using this new form of praziquantel started in 2013. But these efforts have not yet exhausted all the various possibilities. The pharmacologists are also looking for the best way to administer this medicine. Sonja Skopp is the Head of the praziquantel team, which deals with issues related to the medicine’s pharmaceutical development. She explains, “In addition to optimizing the active ingredient itself, we are currently developing a form of administration that dissolves more quickly and masks the bitter taste.” Another possible option would be to cover the active ingredient with a sweet coating.
Schistosomiasis is caused by a parasitic worm of the genus Schistosoma, which lives in standing water
© Getty Images
Strong partners for an important goal
Since 2012, the various development tasks have been divided among the six partners of a consortium. “EMD’s contribution is the development of the molecule and the expertise it has accumulated over decades of working with praziquantel,” says Reinhard-Rupp.
“The Japanese company Astellas is a specialist in the technological development of new formulations; the Swiss Tropical and Public Health Institute in Basel is conducting the preclinical experiments and the subsequent clinical studies; and the Top Institute Pharma in Leiden, the Netherlands, is a nonprofit organization coordinating the collaboration of the entire consortium.”
Ultimately, however, the responsibility for the technical know-how and for supplying the medicine to the public will be transferred to the countries involved. “The first country to join the project was Brazil. Our partner there is Farmanguinhos, the country’s largest pharmaceutical research laboratory, which operates under the Brazilian Ministry of Health,” she adds. Jutta Reinhardt-Rupp has a vision: She would like to eliminate the parasitic worm disease schistosomiasis. Tablets alone will not suffice. However, the ability to treat young children will represent a major step toward this important goal.