Organization Description
Neurimmune is a biotech company focused on antibody-based therapies to remove extracellular aggregates that drive diseases of aging, including Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), cardiac TTR amyloidosis, and type 2 diabetes. Their proprietary Reverse Translational Medicine (RTM) technology platform screens the B-cells of older persons who are free of these diseases or who are progressing unusually slowly through them, looking for high-affinity antibody lead candidates that may bind and clear disease-causing aggregates. These candidates are further developed via human affinity maturation and tolerance selection to create clinical candidates.
ALXN2220/NI006
ALXN2220 (now NI006) is a recombinant human monoclonal IgG1 antibody that highly selectively (the company says “exclusively”) targets the aggregated form of transthyretin (TTR). TTR aggregates drive senile cardiac amyloidosis (SCA) and is implicated in a high percentage of heart failure with preserved ejection fraction (HFpEF) in aging persons, as well as polyneuropathy, carpal tunnel syndrome, spinal stenosis, and other conditions in persons carrying disease-driving mutations. Aggregated TTR deposits in the heart muscle, making the ventricular wall thicker and less flexible, which impairs the heart’s pumping capacity and leads to death. SCA from TTR amyloidosis and other extracellular aggregates appear to be responsible for a high percentage of deaths in supercentenarians. It is believed that no more than 1% of patients with SCA are diagnosed, and its likely involvement in many HFpEF cases further increases the number of aging persons who could benefit from a TTR amyloid-clearing immunotherapy.
Neurimmune developed ALXN2220 by applying its RTM platform to B-cell memory in older persons free of SCA. Because it is selective for conformation rather than sequence, ALXN2220 targets aggregates formed by either wild-type TTR or disease-associated mutations.
In January 2022, Neurimmune entered an exclusive collaboration and license agreement with Alexion, AstraZeneca’s rare disease group, under which Neurimmune would be responsible for completing a then-ongoing Phase Ib clinical trial on ALXN2220, following which Alexion would be responsible for further clinical development and would receive an exclusive worldwide licence to develop, manufacture and commercialize it.
The results of the Phase Ib trial were published in The New England Journal of Medicine in 2023. Volunteers received one of six ascending doses of ALXN222 or placebo every 4 weeks for 4 months. Per the abstract,
The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro–B-type natriuretic peptide and troponin T levels [markers of cardiac damage] also seemed to be reduced .. .No apparent dose-limiting toxic effects or drug-related serious adverse reactions were observed.
An open-label extension (OLE) of the Phase Ib trial has now been reported. Enrollment and compliance were very high. “No severe or serious adverse events were considered related to ALXN2220 or resulted in the discontinuation during OLE, and no events of cytokine release syndrome or thrombocytopenia were observed. None of the participants had anti-drug antibodies throughout the trial. Cardiac biomarkers (NT-proBNP, troponin) and cardiac imaging indicated continued treatment effects beyond 12 months and supported the up-titration of participants who previously received lower doses of ALXN2220.” It is unclear to this author whether “continued treatment effects” means further reductions in cardiac amyloid or maintaining the initial reductions, though the former seems more likely.
In April 2024, Neurimmune announced that Alexion had launched DepleTTR-CM, a Phase III clinical trial to assess the safety and efficacyof ALXN2220 for TTR-driven cardiomyopathy.
NI203
NI203 is an antibody targeted against aggregated Islet Amyloid Polypeptide (IAPP), a protein produced by insulin-producing beta-cells in the pancreas. IAPP aggregates in people with Type II diabetes and other aging people and impairs the beta-cells’ ability to produce the hormone insulin (which is needed to control blood sugar) and ultimately leading to beta-cell death. After being released into the circulation, IAPP also accumulates on cells of the heart, and may contribute to declining heart function in diabetes and with age. Neurimmune claims that NI203 targets IAPP aggregates and neutralizes their toxicity, and restores insulin secretion and ameliorates symptoms in animal models of Type II diabetes.
Aducanumab (Aduhelm; formerly BIIB037)
Aducanumab is a fully human monoclonal antibody based on antibodies found in otherwise-healthy older people and AD patients with slowly progressing dementia. It targets aggregated but not monomeric forms of beta-amyloid, the key extracellular aggregate that drives Alzheimer’s disease, and preferentially binds parenchymal over vascular amyloid. Biogen and Esai picked up aducanumab for clinical testing, ending with confusion in two Phase III trials.
In March 2019, Biogen and Eisai announced that an interim analysis had predicted that EMERGE and ENGAGE would not meet their primary endpoints, and that they would terminate all aducanumab trials. Then in October 22, 2019, Biogen announced that a subsequent analysis of a larger patient dataset had found EMERGE had in fact met its primary endpoint, and that while ENGAGE had not, an exploratory analysis suggested a reduced rate of decline in subjects who had received at least ten doses of 10 mg/kg — a rate similar to comparable EMERGE subjects.
On the basis of these analyses, Biogen applied for regulatory approval for aducanumab under FDA’s accelerated approval pathway, which “allow[s] for earlier approval of drugs that treat serious conditions, and fill an unmet medical need based on a surrogate endpoint. A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit” —in this case, the clearance of beta-amyloid. FDA controversially granted approval in June.
However, full approval was conditional on a Phase IV confirmatory trial. Dubbed ENVISION, the trial launched in 2022, but Biogen announced that it would terminate the ENVISION and stop marketing aducanumab in early 2024. It bears noting that at this point, Biogen’s other beta-amyloid clearing therapy, lecanemab, had been uncontroversially shown to be effective and was approved, on the market, and enjoying much better uptake than aducanumab. The rights to aducanumab reverted to Neurimmune.
NI008
According to Neurimmune, “NI008 is a human antibody specifically targeting pathological protein produced by a mutant C9orf72 gene.” Expansion mutations in C9orf72 is the main genetic cause of amyotrophic lateral sclerosis (ALS/Lou Gehrig’s disease) and frontotemporal dementia (FTD, which is the most or second-most common cause of dementia in persons under the age of 65). Again according to Neurimmune, “The antibody showed in preclinical models to lower neuroinflammation, slow neurodegeneration and lengthen survival in” an animal model of this condition. It bears noting that most evidence points to C9orf72 gene expansions exerting harms onto neurons through processes in their interaction with ribosomes, not via the aggregation of the protein.
NI101B3
According to Neurimmune, “NI101B3 is a next generation amyloid beta targeting antibody with improved penetration of the blood brain barrier.” The current therapeutic antibodies that clear beta-amyloid have limited penetrance, which makes them more expensive and cumbersome to administer and may contribute to their side-effect profile, so an antibody that required lower doses to get therapeutic levels of antibody into the brain might be advantageous. Listed as in the discovery phase.
NI603
Neurimmune lists NI603 as a monoclonal antibody targeting an unspecified Protein Aggregation Disease and is within the cardiometabolic disease space.
NI504
NI504 is an otherwise-uncharacterized monoclonal antibody said to be in the discovery phase for “neurodegeneration.”