**7. Future directions: Therapeutic applications**

To date, riluzole (Rilutek, Aventis Pharmaceuticals Inc) is the only approved therapeutic to treat ALS; it is known to prevent the pre-synaptic release of glutamine (Bellingham, 2011, Miller et al., 2007). In clinical trials, it has been shown to extend survival by around 2 ~ 3 months and delay the onset of ventilator dependence or tracheostomy (Bellingham, 2011, Miller et al., 2007). It is not clear that the drug improves the quality of life, however. Given this modest extension of ~2-3 months in survival there is an urgent need to develop new therapeutics which will significantly extend survival and also decrease morbidity in ALS.

Recent studies have suggested that the innate immune system is important in sensing ALS progression and its subsequent upregulation may drive the progression of this disease (Woodruff et al., 2008b). The complement system would be a logical and viable pathway to target, given the steadily accumulating clinical evidence of complement involvement in this disease. This is also supported by our findings where using specific C5a receptor antagonist improved motor symptoms and extended survival in the SOD1G93A transgenic rat (Woodruff et al., 2008a).

Our laboratories have developed a series of cyclic peptide C5a receptor antagonists which are potent inhibitors of C5a receptors on human inflammatory cells (Woodruff et al., 2011). PMX53 (AcF-[OPdChaWR] and PMX205 (hydrocinnamate-[OPdChaWR]) are orally active cyclic hexapeptides, which were derived from the linear CD88 antagonist, Me-FKPdChaWR (Konteatis et al., 1994) that were cyclised to induce structural and metabolic stability(Finch et al., 1999, March et al., 2004). These drugs have been shown to display therapeutic efficacy in numerous rodent models of inflammatory disease including rheumatoid arthritis (Woodruff et al., 2002), ischemic reperfusion injuries (Arumugam et al., 2004) and inflammatory bowel disease (Woodruff et al., 2003), as well as acute neurodegeneration (Woodruff et al., 2006). PMX205 is more lipophilic than the original CD88 antagonist PMX53, which results in increased potency in certain inflammatory models (Woodruff et al., 2005) and increased CNS penetrance (Woodruff et al., 2006). Hence, it has been used to reduce disease severity and prolong survival in animal models of neural degeneration including Huntington's disease, Alzheimer's disease and ALS (Ager et al., 2010, Fonseca et al., 2009, Woodruff et al., 2006, Woodruff et al., 2008a). As a result of this work, PMX205 would be the particular PMX series compound we would promote for any future clinical trialling in ALS.

In addition to inhibiting C5a receptors, targeting other factors of the complement system may provide viable therapeutic options to treat ALS. Several complement inhibitors have been developed over the years and compounds such as sCR1, C5 antibodies, compstatin or others could be used as potential therapies for ALS. However, due to the need to chronically administer a drug in ALS, a small, orally active and BBB permeable complement inhibitor, such as PMX205, would be required. The selectivity of PMX205 towards the classical C5a receptor leaves other components of the complement system intact, allowing for the production of complement factors including the MAC, thus reducing immune suppression -

complement pathways (Figure 1). Hence inhibiting central components of the complement system, at the C3 and C5 level, may have benefits in slowing disease progression in ALS, as opposed to inhibiting an individual activation pathway. Specifically, our studies suggest that inhibiting the pro-inflammatory C5 activation fragment, C5a, which is central to, and generated by, all complement pathways, may be a novel therapeutic strategy to treat ALS.

To date, riluzole (Rilutek, Aventis Pharmaceuticals Inc) is the only approved therapeutic to treat ALS; it is known to prevent the pre-synaptic release of glutamine (Bellingham, 2011, Miller et al., 2007). In clinical trials, it has been shown to extend survival by around 2 ~ 3 months and delay the onset of ventilator dependence or tracheostomy (Bellingham, 2011, Miller et al., 2007). It is not clear that the drug improves the quality of life, however. Given this modest extension of ~2-3 months in survival there is an urgent need to develop new therapeutics which will significantly extend survival and also decrease morbidity in ALS. Recent studies have suggested that the innate immune system is important in sensing ALS progression and its subsequent upregulation may drive the progression of this disease (Woodruff et al., 2008b). The complement system would be a logical and viable pathway to target, given the steadily accumulating clinical evidence of complement involvement in this disease. This is also supported by our findings where using specific C5a receptor antagonist improved motor symptoms and extended survival in the SOD1G93A transgenic rat (Woodruff

Our laboratories have developed a series of cyclic peptide C5a receptor antagonists which are potent inhibitors of C5a receptors on human inflammatory cells (Woodruff et al., 2011). PMX53 (AcF-[OPdChaWR] and PMX205 (hydrocinnamate-[OPdChaWR]) are orally active cyclic hexapeptides, which were derived from the linear CD88 antagonist, Me-FKPdChaWR (Konteatis et al., 1994) that were cyclised to induce structural and metabolic stability(Finch et al., 1999, March et al., 2004). These drugs have been shown to display therapeutic efficacy in numerous rodent models of inflammatory disease including rheumatoid arthritis (Woodruff et al., 2002), ischemic reperfusion injuries (Arumugam et al., 2004) and inflammatory bowel disease (Woodruff et al., 2003), as well as acute neurodegeneration (Woodruff et al., 2006). PMX205 is more lipophilic than the original CD88 antagonist PMX53, which results in increased potency in certain inflammatory models (Woodruff et al., 2005) and increased CNS penetrance (Woodruff et al., 2006). Hence, it has been used to reduce disease severity and prolong survival in animal models of neural degeneration including Huntington's disease, Alzheimer's disease and ALS (Ager et al., 2010, Fonseca et al., 2009, Woodruff et al., 2006, Woodruff et al., 2008a). As a result of this work, PMX205 would be the particular PMX series compound we would promote for any future clinical

In addition to inhibiting C5a receptors, targeting other factors of the complement system may provide viable therapeutic options to treat ALS. Several complement inhibitors have been developed over the years and compounds such as sCR1, C5 antibodies, compstatin or others could be used as potential therapies for ALS. However, due to the need to chronically administer a drug in ALS, a small, orally active and BBB permeable complement inhibitor, such as PMX205, would be required. The selectivity of PMX205 towards the classical C5a receptor leaves other components of the complement system intact, allowing for the production of complement factors including the MAC, thus reducing immune suppression -

**7. Future directions: Therapeutic applications** 

et al., 2008a).

trialling in ALS.

a likely side effect of other inhibitors of complement which act more upstream in the system, were they are to be used chronically. Finally, PMX53, an analogue to PMX205 has already been shown to be safe when administered to humans, successfully completing three Phase I/IIa clinical trials, thus promoting the safety of these classes of drugs in humans (Woodruff et al., 2011).

In addition to anti-complement agents, combined therapies targeting multiple and disparate pathways will most likely be needed to effectively treat ALS. Extensive controlled clinical trials will need to be conducted in order to ascertain any potential therapeutic benefit of a complement inhibitor to treat the devastating and intractable nature of ALS.
