The second small molecule drug pridopidine (CAS RN: 346688-38-8), also a regimen in the HEALEY ALS Platform trial (NCT04297683), was investigated in a completed Phase II/III clinical trial (NCT04615923). While there were no significant improvements in the primary outcome measures of disease progression and mortality rate, there were positive results reported for secondary outcome measures such as improved respiratory and speech measurements. Improvement in disease progression and neurofilament light levels (biomarker for neuronal injury) for rapidly declining ALS participants who were early in the disease were also seen. Pridopidine is also available through an expanded access clinical trial (NCT06069934) for up to 200 patients with ALS who are ineligible for other clinical trials. Pridopidine is a highly selective sigma-1 agonist. Sigma-1 receptor is highly expressed in the brain and CNS and activation by pridopidine stimulates multiple cellular pathways, including autophagy, which are essential to neuronal function and survival, and may lead to neuroprotective effects. Prilenia Therapeutics was granted orphan drug designation for pridopidine in 2021 from the US FDA for treating ALS. Highlighted therapies in clinical development for the treatment of HD include antisense oligonucleotides, cell-based, and monoclonal antibody therapies along with computer based cognitive stimulation and small molecule agents. One such antisense oligonucleotide (ASO) therapeutic is Wave Life Sciences' gene silencing therapeutic, WVE-003. Interim results for Phase I/Phase II clinical trial NCT05032196, reveals that a single dose of WVE-003 (30 or 60 mg) led to a mean 35% reduction in mHTT in the cerebrospinal fluid compared to a placebo. More upcoming trial findings are expected by June 2024. Phase I and Phase II/Phase III clinical trials (NCT02728115 and NCT04219241) assessing the safety and efficacy of Cellavita's NestaCell, a stem cell therapy derived from immature human dental pulp, are currently active for the treatment of HD. Another Phase III clinical trial (NCT06097780) researching NestaCell is not yet recruiting but has an estimated start date of June 2024 and will also investigate the efficacy and safety of NestaCell. A previous Phase I clinical trial revealed no serious adverse events and improved HD motor symptoms with the use of NestaCell in the treatment of HD. Another treatment of HD utilizing a computer based cognitive rehabilitation program is being researched by the Santa Cre Hospital in Spain. Researchers are currently recruiting for their study (NCT05769972) to examine the use of this method in patients with HD with expectations that the program will have a greater beneficial effect on the cognitive status of HD patients compared to control modalities such as music therapy. Monoclonal antibody therapeutic Pepinemab, a semaphorin 4D blocking antibody developed by Vaccinex, was researched in a Phase II clinical trial (NCT02481674) to determine safety, tolerability, pharmacokinetics, and efficacy. While this trial did not meet its primary endpoints, it did have a favorable safety profile, showed a reduction in brain atrophy, and improvement in decline in brain metabolic activity that is typically seen in HD progression. Lastly for the treatment of HD, Sage Therapeutics' small molecule drug SAGE-718 is currently recruiting for their Phase II/Phase III clinical trials. These trials (NCT05107128, NCT05358821, and NCT05655520) will investigate the safety, tolerability, and efficacy of these drugs for the treatment of HD. SAGE-718, a NMDA receptor positive allosteric modulator has completed initial single and multiple ascending dose clinical studies, where it demonstrated efficacy in disease-relevant populations. In addition, SAGE-718 was granted both FDA Fast track designation 440 in 2022 and FDA Orphan Drug Designation in 2023. Therapy types in clinical development highlighted for the treatment of MG include antigen, cell, and fusion protein therapies along small molecule drugs. COUR Pharmaceutical is developing CNP-106, an antigen specific therapeutic designed to prevent immune mediated neuromuscular destruction and aims to reprogram the immune system to address the immunological root cause of myasthenia gravis. The not yet recruiting Phase I/II clinical trial (NCT06106672) will enroll up to 54 adult patients and assess the treatment's safety, tolerability, pharmacological properties, and efficacy. Descartes-08, a mRNA CAR T-cell therapy expressing a chimeric antigen receptor directed to B-cell maturation antigen is currently recruiting for an ongoing Phase II clinical trial (NCT04146051). Results from the Phase IIa portion of the study revealed that Descartes-08 is well tolerated and participants saw meaningful improvement in MG disease scorings. Descartes-08 was granted Orphan Drug Designation by the US FDA for the treatment of MG in 2024. RemeGene is currently recruiting for its Phase III clinical trial (NCT05737160) investigating fusion protein Telitacicept for the treatment of MG. Telitacicept is constructed with the extracellular domain of the transmembrane activator and calcium modulator and cyclophilin ligand interactor receptor and the fragment crystallizable domain of immunoglobulin G. Telitacicept targets two cell-signaling molecules critical for B-lymphocyte development: B-cell lymphocyte stimulator and a proliferation inducing ligand, which allows it to effectively reduce B-cell mediated autoimmune responses. Results from a previous Phase II study showed that Telitacicpet improved MG symptoms and had a good safety profile. Lastly, we look at a small molecule factor D inhibitor developed by Alexion Pharmaceuticals. ALXN2050 is currently being investigated in an active Phase II clinical trial (NCT05218096) for its ability to improve the disease symptoms and the daily life of people with MG along with its safety. Seventy patients are enrolled with a study completion date of late 2025, results with be forthcoming soon.