Identification of a novel oral clinical candidate superior to praziquantel to treat schistosomiasis

Schistosomiasis is a severe helminthic disease affecting over 200 million people mainly in poor countries of sub-saharan Africa and resulting in 300,000 deaths per year. Treatment relies on a single drug, praziquantel (PZQ), but this is not ideal since: (i) PZQ kills adult worms but not juvenile worms developing in the body and so cure requires patients to be retreated which adds to cost and undermines efforts to control the level of disease by mass treatment of schoolchildren or communities (ii) emergence of resistance is a major concern following several reports of treatment failure. Spread of such resistance would leave us without a single drug to treat and control this disease (iii) PZQ is sub-optimal for paediatric since the tablets are large and the drug bitter which often causes choking.

Since the development of PZQ and its implementation in the 1980s pharmaceutical companies have stopped schistosome drug discovery and there has been limited interest in development of alternative drugs, even in academic institutions. PZQ and earlier anti-schistosome drugs were discovered by testing in mouse models of the disease run by pharma which is a very slow and costly process for discovery of promising chemical structures. Our recent development of an in vitro High throughput screen (HTS) to identify drug effects using in vitro derived Schistosoma mansoni larvae allows, for the first time, screening of the large compound collections put together by pharma and academic institutions as resources for drug discovery. Our aim is to develop a clinical candidate better than PZQ notably in being active against all intra-mammalian stages. The in vitro screening sequence (larval HTS/juvenile worms/adult worms/cytotoxicity) will identify compounds active against all stages of the important human schistosome species and with promising parasite/cytotoxicity profiles.

Salvensis, our collaborator, has agreement from a large pharmaceutical company to access a refined subset of its proprietary compound file. In addition we have large collections of commercially available inhibitors, never before tested for schistosomiasis activity, available for this project. Funding is sought to bridge the translational gaps in NTD drug discovery between academia and pharma and between large compound collections and the first available HTS for schistosome drug discovery. In addition to the file, Salvensis, a not-for-profit organisation based on >50 years experience in pharma drug discovery, is able to access pharma tools and information, greatly facilitating NTD drug discovery.

LSHTM and Salvensis will use carefully selected medicinal chemists to synthesize analogues of the most promising molecules from our in vitro assays in order to identify the best series and optimise them, through a series of milestones, to an oral clinical candidate which we will aim to license for clinical development.

Schistosomiasis is a severe helminthic disease affecting an estimated 600 million people. Treatment relies on a single drug, praziquantel (PZQ), but this is not ideal since (i) PZQ kills adult worms but not juveniles so cure requires retreatment (ii) emergence of resistance is a major concern following several reports of treatment failure (iii) PZQ is sub-optimal for paediatric use often causing choking.

No good starting points for schistosomiasis drug discovery have been reported in the literature. Our recent development of an HTS using Schistosoma mansoni larvae allows, for the first time, screening of large compound collections for quality lead compounds and to optimize SAR. Our aim is to develop a clinical candidate better than PZQ notably in being active against all intra-mammalian stages. The in vitro screening sequence (larval HTS/juvenile worms/adult worms/cytotoxicity/S.haematobium and S.japonicum adults) will identify compounds active against all stages of the important species and with promising parasite/cytotoxicity profiles.

Salvensis, our collaborator, has agreement from a large pharmaceutical company to access a refined subset of its proprietary compound file. In addition we have large collections of commercially available inhibitors available. Funding is sought to bridge the translational gaps in NTD drug discovery between academia and pharma and between large compound collections and the first available HTS for schistosome drug discovery. Salvensis, a not-for-profit organisation based on >50 years experience in pharma drug discovery will also use state of the art computational methodology in selecting and designing compounds for screening.

Using our in vitro and in vivo (S. mansoni/mouse) assays, LSHTM and Salvensis will use carefully selected third parties to identify the best series and optimise them, through a series of milestones, to an oral clinical candidate which we will aim to license for clinical development.

Schistosomiasis is a severe helminthic disease of the liver, intestine and/or urinary tract. This disease affects an estimated 391-587 million people worldwide [1] mainly in poor countries of sub-saharan Africa and accounts for up to 300,000 deaths [2] and 70 million disability-adjusted life years [3] annually. Treatment and control depends on a single drug, praziquantel [PZQ], but this is not ideal [4] because:-
1. PZQ kills adult worms but not juveniles so cure requires retreatment. This undermines control programmes in high-transmission areas and elimination efforts in low-transmission areas.
2. Major concerns exist about emergence of resistance to PZQ following several reports of treatment failures [5-7] yielding isolates showing heritable lower susceptibility to PZQ experimentally [6, 8].
3. PZQ is sub-optimal for paediatric use as the dose is large.

We seek to discover a novel treatment that would address all three of these issues with PZQ in that it would kill juvenile and adult worms, would have a novel structure and therefore be unlikely to be cross resistant with PZQ and would require a lower dose and thus be more suited for paediatric use.

The major beneficiaries of this research would ultimately be the hundreds of millions of people worldwide infected with schistosomiasis and the families, communities and countries in which they live. In the best case scenario, PZQ will continue to be effective and cheap and the new drug will offer improvements as a schistosomiasis eradication tool and for paediatric use. In the worst case scenario, should resistance to PZQ become a widespread phenomenon, the new drug may become the only reliable treatment for millions of people infected with this major disease.

The development of the candidate drug we aim to discover would of course offer economic opportunities to those organisations involved in the drug development process, though it remains the case that payment for drug development will mostly be funded by governments and philanthropy.

In addition, we aim to discover the candidate drug utilising a novel model of public/private partnership, exploiting the academic excellence of years of research dedicated to understanding the disease and developing screens and animal models for schistosomiasis infection with the expertise of large pharma through the mechanism of a collaboration between LSHTM and Salvensis, a not for profit SME. There is the very real potential for this kind of public/private partnership to develop as an alternative to the current broken model of drug discovery, particularly as it applies to diseases which are uneconomic for shareholders alone, but are nevertheless compelling public health issues.