On the tip of your tongue…

Malaria kills an African child every 30 seconds, many of whom die because they are unable to reach medical help in time. A new sublingual spray developed by Norwich Research Park company LondonPharma, could help cut deaths by helping children recover sufficiently to survive the journey to hospital

Severe malaria is a medical emergency. The disease can progress quickly, leading to severe anaemia, respiratory distress and neurological symptoms including seizures and coma.

In 2010, severe malaria is believed to have caused approximately 660,000 deaths worldwide, the vast majority of these in Africa and amongst the under-fives. The precise number of children killed annually by malaria is impossible to calculate, as each year thousands will die on their way to hospital and these deaths will never be officially recorded.

For those fortunate enough to reach a medical centre for specialist care, treatment is likely to take the form of quinine or artesunate via an intravenous drip. For obvious reasons, this form of therapy can only be provided by a trained medical professional in a hospital setting and is expensive for developing countries. As it stands, there is no effective alternative for treating children with severe malaria closer to home, but this may be about to change.

A sublingual (beneath the tongue) spray is now close to completing Phase III clinical trials for the treatment of children with severe malaria. The fast-acting nature of this spray means that within 24 hours, children should have recovered enough to eat and take on fluids. It has even been shown to bring children out of a coma within six hours of administration.

Once approved for use outside of a hospital setting, the spray (which does not require refrigeration) can be applied by anyone with minimal training. Children should therefore be able to access the treatment locally.

The administration of drugs sublingually (beneath the tongue) is not a new concept. For example, sublingual nitroglycerin (a potent vasodilator) is commonly prescribed for the treatment of angina. In this scenario, the administration of the drug beneath the tongue offers significant advantages due to the speed of action. The blood vessels in the mouth are both plentiful and close to the surface, meaning the active ingredient is absorbed and can act on blood vessels throughout the body in a matter of minutes.

LondonPharma specialises in identifying already registered compounds which can potentially have their efficacy enhanced through a sublingual delivery system. Drugs that have a poor bioavailability when taken orally or those that cause gastrointestinal side effects are perfect examples of this.

The spray for childhood malaria contains artemether, an extremely effective antimalarial agent which is already commonly used in the treatment of ‘uncomplicated’ (non-severe) cases of the disease. Derived from artemisinin (which is itself isolated from a Chinese medicinal herb), artemether is generally used in tablet form combined with a second antimalarial agent (lumefantrine).

Artemether is rapidly metabolised by the liver and converted to the derivative dihydroartemisinin (DHA), which reaches its maximum concentration in the body around two to three hours after dosing1. Both artemether itself and DHA have strong antimalarial properties, reducing the parasite biomass by about 10,000-fold per asexual life cycle (around two days).2

One problem with artemether is that repeated oral dosing actually leads to a relative decrease in the drug’s plasma concentration. The compound has the ability to induce the enzymes responsible for its own metabolism, so over time its bioavailability is decreased3,4.

LondonPharma recognised that if artemether could be administered sublingually, it could potentially be used in cases of severe childhood malaria. As in the case of nitroglycerin, sublingual application allows the drug to by-pass the digestive system. Not only does this increase the speed at which the drug can act, but absorption directly into the systemic blood circulation means that ‘first-pass’ metabolism by the liver is avoided entirely. This increases artemether bioavailability up to threefold in the first instance, but up to 7-fold with repeated dosing compared to oral formulations.

Trials to date have taken place in hospitals, but it is envisaged that in the future the spray will be used locally to the child’s family home. It is important to point out that children with severe malaria will still need to travel to hospital for further treatment, even after successful treatment with the spray. However, children who receive sublingual artemether will be in a far better state of health to travel and should therefore stand a significantly better chance of surviving.

Clinicians in Africa do an incredible amount with few resources, but by the time children are admitted to hospital they are often so severely dehydrated it is near impossible to insert an intravenous drip. If sublingual application of artemether can help a child recover enough to drink, this would help clinicians considerably.

Other malaria risk groups may also benefit from sublingual artemether, including pregnant women. It is estimated that malaria causes around 10,000 maternal deaths each year in Africa, as well as many new-borns dying due to complications associated with low birth weight.

Treatment of malaria in pregnant women is more complex than in other groups and some anti-malarial drugs are not advised for women in the first trimester of pregnancy.5,6 However, the increased efficacy of sublingual artemether means it is a good candidate for treatment of this group.

The drug may also prove to be an effective treatment for other clinical indications, including some early stage cancers. LondonPhama is currently running an exploratory Phase I/II clinical study on cervical and breast cancer which will complete in 2014. Use of the treatment in other cancers will be explored subsequently. LondonPharma is optimistic that sublingual artemether has significant potential in this field.

Essentially any drug can be developed for sublingual application, providing it can be absorbed quickly (preventing it from trickling down the throat) and that it is not locally irritant. LondonPharma is looking at all areas and trying to find interesting molecules that may benefit from a sublingual method of application.

For example, the poor patient compliance figures for individuals taking statins to help prevent against coronary and vascular disease is currently a major concern in preventive cardiology. Reasons for non-adherence are varied; however the frequency of side-effects is known to be key contributing factor. In addition to this, disillusionment with ‘too many pills’ is thought to play a role, particularly amongst elderly patients.7

Re-formulating these drugs for a sublingual method of delivery may help diminish the problem of associated side-effects. This could help increase patient adherence over the long-term and hopefully reduce the associated cases of cardiovascular morbidity.

Newly discovered molecules seem to be all-too-frequently developed as tablets, intramuscular injection (IM) etc; however, drug development is not an easy industry and it is important for companies to really think ahead. The optimum method of administration should be carefully considered early on in the development process.

LondonPharma has recently relocated from the Norwich BioIncubator to the Norwich Research Park Innovation Centre, providing the company with the additional laboratory space and business resources required for growth. One of the major advantages of the Park is the opportunity for collaboration between businesses and academia, with the University of East Anglia (UEA), the Norfolk and Norwich University Hospital and the Clinical Research and Trials Unit all located on-site.

All across the Norwich Research Park, scientists are carrying out some incredibly interesting research with some newly discovered molecules. As in the case of artemether, many of these are derivatives from plant extracts which are thought to have medicinal properties. Looking to the future, collaborating with some of these research groups and providing a helping hand with the development of a newly discovered molecule is an exciting prospect for LondonPharma

Author: Clive Booles is a respiratory and sublingual drug delivery specialist who helped to establish LondonPharma in 2007. He is now Research and Development Director of the Norwich-based company.

References:

1. White NJ, van Vugt M, Ezzet F: Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet 1999, 37:105-125. 2. N.J. White: Preventing antimalarial drug resistance through combinations. Drug Resist Updat.1998 Mar;1(1):3-9. 3. Gordi T, Xie R, Huong NV, Huong DX, Karlsson MO, Ashton M. A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction. Br J Clin Pharmacol. 2005;59:189–198 4. Zhu F, Du F, Li X, Xing J: An investigation of the auto-induction of and gender-related variability in the pharmacokinetics of dihydroartemisinin in the rat. Malar J. 2012 Nov 21;11:379 5. World Health Organization. Guidelines for the treatment of malaria. Second Edition: World Health Organization, 2010. 6. Manyando C, Mkandawire R, Puma L, Sinkala M, Mpabalwani E, Njunju E, Gomes M, Ribeiro I, Walter V, Virtanen M, et al.: Safety of artemether-lumefantrine in pregnant women with malaria: results of a prospective cohort study in Zambia. Malar J 9:249 (2010) 7. Bates TR, Connaughton VM, Watts GF. Non-adherence to statin therapy: a major challenge for preventive cardiology. Expert Opin Pharmacother 2009;10:297