At the ALS Therapy Development Institute (ALS TDI), our goal is to make sure that effective treatments for ALS make it from the lab to the clinic – whether they originated from our research or some else’s. While our major focus is on the invention of completely new ALS treatments, we also allocate some time and resources toward investigating the validity of promising results found in experiments by other researchers and companies. This is the second the series of blogs about drugs invented by others that we’ve validated at ALS TDI.

If you follow ALS research closely, you will often hear a lot about the protein superoxide dismutase-1, often abbreviated as SOD1. A mutation in the gene responsible for producing this protein, which is essential for the healthy function of human cells, is a known cause of many cases of familial ALS. There is also evidence, although it is somewhat controversial, that it may contribute to some cases of sporadic ALS as well.

AP-101 is a monoclonal antibody that targets the “misfolded” SOD1 protein produced by this mutated gene. Antibodies are proteins that are normally produced by the immune system and bind to and neutralize foreign pathogens – like disease-causing bacteria and viruses – in the body. A monoclonal antibody is an antibody produced by a cloned immune cell. They can be designed to bind to a specific protein – in the case of AP-101, misfolded SOD1 proteins in motor neurons.

A SOD1 protein.

AP-101 was developed by Neurimmune, a Swiss drug developer also behind Aducanumab, an Alzheimer’s drug currently in phase 3 trials with Biogen. Aducanumab is another monoclonal antibody that similarly targets a misfolded protein, in this case called “amyloid beta,” that is suspected to be a cause of that neurogenerative disease.

It was news of this drug’s development that attracted the attention ALS TDI’s Chief Scientific Officer, Dr. Fernando Vieira, who became interested when he discovered that the company had also performed preclinical tests with a similar monoclonal antibody drug targeting the SOD1 protein. He reached out directly to the company.

“I emailed to them and I said, this seems like a good idea,” he recalls, “I’m really interested in trying to understand misfolded SOD1. Is there something that lab can do to help your group understand whether or not this will be effective for ALS? And they said, ‘yes.’”

This led to a collaboration between ALS TDI and Neurimmune that lasted several years and helped move AP-101 from the laboratory into the clinic.

“ALS is a devastating neuromuscular disease, and there is an urgent need for new and effective therapies that can slow or stop its progression,” said Dr. Jan Grimm, the CSO of Neurimmune, in a press release at the time. “Our human antibodies are directed against pathologically misfolded SOD1 and the selected lead candidate shows marked efficacy in independent ALS animal models. We believe that there is significant potential for this therapeutic approach for ALS and are enthusiastic to jointly advancing the program towards clinical development together with ALS TDI.”

ALS TDI scientists began testing AP-101 in a SOD1 mouse model of ALS in 2013. Preclinical work conducted by Neurimmune prior to the collaboration showed evidence of a reduction in muscle atrophy, better motor function, and a longer lifespan in mice given the treatment. ALS TDI spent the next three years rigorously testing the drug in our own laboratory to confirm these results. This led to ALS TDI scientists eventually publishing two papers in collaboration with Neurimmune confirming the drug’s effectiveness in mice – we found the treatment delayed the onset of disease symptoms, extended the survival of the mice and reduced the overall aggregation of misfolded SOD1 and motor neuron degeneration.

In late 2016, Neurimmune joined with the venture capital firm TVM Life Science Ventures VII to form AL-S Pharma AG, a special purpose company to advance AP-101 into clinical trials. A phase one clinical trial enrolled its first patients in late 2019 and is continuing to recruit.

To find out more about AP-101 and see updates of the trial, click here. To learn more about other drugs we’ve validated, see our last blog about Copper ATSM.