White Paper Issue 14: Utility to Futility: Zilucoplan fails in human ALS trial

Updated: Mar 31


Thomas Edison famously said, “I haven’t failed—I’ve just found 10,000 that won’t work.” Unfortunately, that is the state of the art for ALS therapies.


Some believe that testing more potentially useful drugs will reveal the magic compound, or perhaps even combining therapies, will prove to be the elixir to slow or reverse the progression of ALS. Human trials are expensive and consume valuable resources, including burdening the very patients suffering from disease.


Efforts to expedite human clinical trials using potential treatments was conceived at Mass General Hospital, led by Merit Cudkowicz, clinician and principal investigator. The Platform approach accelerates therapy development by testing multiple compounds in a parallel trial design, saving time and reducing costs. There are 160 companies with novel treatments for ALS, all at different stages of pre-clinical development. This approach works for developing anti-cancer drugs, perhaps it will work for ALS.


Weblink: Utility Feb 2021

The science behind Zilucoplan


Zilucoplan is a drug that inhibits complement. Complement is part of the innate immune system that is activated by disease causing organisms, so named because it complemented the antibodies that killed pathogens. Complement is a system of plasma proteins that can be activated directly by a pathogen or indirectly by pathogen-bound antibody that leads to a cascade of reactions that generate active components with various functions. Novel complement control proteins are still being discovered. In addition to dealing with pathogenes, the complement system is involved in some housekeeping events in host cells. Complement can be dysregulated and lead to tissue damage and then the system can drive disease.


The classical pathway of complement activation is by antibody-antigen complexes. Disease causing organisms initiate an adaptive or antibody response. The antibody binds parts of the pathogen forming a complex. A second pathway is the lectin pathway. It is activated by some surface proteins, lectins, found on some organisms. There is a third pathway, the alternative pathway, whereby complement is activated by non-host cells as part of a danger response. In the alternative pathway, complement proteins are activated by factors that split the initial molecule into C5a and C5b, this is important because C5a is a proinflammatory cytokine.


Some scientists believe that complement is important in the pathology of ALS and inhibiting some components of the system may be useful to treat ALS. Zilucoplan is effective when complement causes disease and treatment may be life-saving when the disease is complement-dependent.

There are diseases in which complement plays a major role (although not the whole role) in the pathophysiology. In some diseases, complement activation might be involved as a smaller part of the pathophysiology and in these complex conditions, it will be challenging to determine the extent of the contribution to disease activity.


Myasthenia gravis is a disease in which autoantibodies attack the neuromuscular junction through activation of the classical complement pathway. The complement activated membrane attack complex is found at the post-synaptic membrane and affects nerve transmission. Zilucoplan blocks the membrane attack complex pathway and positively affects disease outcome.

ALS is a disease with upper and lower motor neuron loss. Muscle weakness is a clinical sign of ALS that is associated with neuron loss. Scientists used the mSOD1G93a to explore the effects of molecules in disease, this model is todays Gold Standard for ALS investigations.


The mouse model was developed because some humans with SOD1 gene abnormalities, mutations, develop ALS. The position of the mutation in SOD1 is directly related to the survival of the person carrying the defect.

mSOD1G93a mice develop some aspects of ALS due to the overexpression of SOD1 proteins. This model can be reversed using small molecules that prevent the over expression of SOD1. Another aspect of SOD1 misfolding is inability to bind copper. Copper is necessary for the proper function of SOD1 in cells. Not surprisingly, supplying copper to mice can slow the progression of disease in mSOD1 mice.


When complement-studying scientists looked at the tissues from mSOD1G93a they saw C5 activation in the mice and found membrane attack complex at the neuromuscular junction. They saw some changes in the C5a receptor, it was upregulated in untreated mice. Researchers administered C5aR1 antagonists to the mice investigating the pathway and found they had extended the animals survival and slowed disease progression. Next, they genetically deleted the C5a receptor from the mSOD1G93a mice and found that denervation at the neuromuscular junctions was reversed, the motor deficits improved, and the mice lived longer. Inhibiting complement suggested that terminal complement components are important in ALS pathology. Published studies showed that the membrane attack complex was present in human ALS patients, but not in control tissues.


A soluble form of the membrane attack complex is associated with activation of the complement pathway and it is found in the serum of patients with ALS.


Weblink: Futility


After 13 months, Healey ALS platform announces that Zilucoplan is stopped early for futility. The interim analysis conducted by an independent Data and Safety Monitoring Board found the pre-specified criteria for early stopping indicated that Zilucoplan had a low probability of meaningfully slowing disease progression. The PI, Merit Cudkowicz, said she is disappointed by the results and is quickly refocusing her efforts on other investigational products.


State of the art


So far, treatment success in any animal model hasn’t translated to success in people. The lack of predictability of models may be that the spectrum of diseases shown by people with ALS are not stratified to a disease process or a stage of progression, so case selection is not possible. Biomarkers to stratify patients may be the light needed to match the right treatment to the right patient.

The cause of a disease is different from a pathology that exists in a disease, but in itself isn’t causal. There are several criteria used to establish causation. The simplest is to show three things--that X came before Y, that the observed relationship between X and Y didn’t happen by chance alone, and that there is nothing else that accounts for the X Y relationship. Single point mutations on genes that are identified in sALS patients are the abyss for demonstrating a relationship to show disease didn’t happen by chance alone. Models are made to recapitulate the mutations and often the models don’t show any disease.


All of the investigated markers to show that Zilucoplan positively affects disease in the mSOD1 model were encouraging. However, the results of the human trial indicate that hALS is not a C5 complement-dependent disease. The contribution of complement in hALS may be housekeeping.

Complement encompasses a system of proteins and perhaps several cause neuromuscular pathology. It is possible upstream components, C3 and C1q, play a role in pathology at motor end plates in skeletal muscle from human ALS patients and the G93a mouse. Therefore, in people it may be necessary to target other factors in the complement cascade. As mentioned above, regulators of complement activation can play a part in Zilucoplan failure, new complement regulatory molecules are being discovered for this complicated system. Possibly the target for the C5 peptide was unavailable due to an inability to cross the blood brain barrier. It is also possible that the target for effectiveness is peripheral as well as central.


The immune system is complex and redundant, other players include macrophages and primed T cells, these complexities may have masked the effects in study participants. Patient selection is of course an issue, until precision medicine is available that includes specific biomarkers other drugs will fail.


ALS is a very complicated spectrum of pathologies. It is the general consensus that targeting one pathway will not be useful. There are possible pathways to illuminate the way to success, one is understanding the disease processes. Until the basic biology is understood, it is unlikely for industry to find a treatment. It is highly possible several disease presentations, with overlapping pathologies exist, and successful treatment will depend on precision medicine.


The take home message is that scientists do not know enough about the spectrum of cellular pathology that contributes to the collective syndrome of symptoms that define ALS. To improve therapeutic progress is to better understand the multi-cellular and multi-factorial processes in underlying human disease and relate the biology to mouse models. Time is a sensitive issue for those with ALS. We can investigate 10,000 pathways by consolidating our knowledge. We are working to produce an ALS Commons that will take a granular look at hundreds of ALS patients. The commons approach will provide valuable knowledge about the cellular pathology, and connections between processes, that underly human disease.



White Paper Issue 14 Utility to Futility
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