The Science Behind Kurve’s Breakthrough Technology

Kurve addresses two principal challenges to the advancement of CNS disease treatment:

  1. Difficulty in getting drugs past the blood-brain barrier (BBB) and into the CNS.
  2. Need for new science and new mechanisms of action to address the complex biology of challenging diseases such as Alzheimer’s disease and autism.

Kurve Therapeutics (“Kurve”) is addressing both of these challenges with innovative science.

Challenge #1:
The blood-brain barrier (BBB)

The BBB is a specialized layer of cells that protects the brain — and also makes it difficult for many drugs to enter the brain. According to some researchers, poor penetration of the BBB is the greatest cause for failure of CNS (central nervous system) drugs in clinical trials.1 This challenge for CNS drugs only increases for larger molecules, such as the peptides, therapeutic proteins, and antibodies that show some of the greatest problems in treating Alzheimer’s, Parkinson’s, and other debilitating CNS disorders.2

The Need: A safe, clinically proven, cost-effective technology to quickly deliver drugs through the BBB.

There are a number of sophisticated, promising approaches on the horizon to getting drugs through the BBB, such as “Trojan horse” molecules (peptides or antibodies) and nanoparticles. Almost all of them, however, are at an early stage (discovery or preclinical in vitro / animal work) and require significant time and money for each molecule developed. Costs tend to include ambitious medicinal chemistry efforts and in many cases new, extensive toxicology programs. Additionally, a number of promising treatments for CNS disorders have safety issues with systemic exposure (outside the brain).

The Answer:
Kurve’s Controlled Particle Dispersion® platform

Kurve’s ViaNase™ device has a patent-protected technology — Controlled Particle Dispersion® — that provides focused drug delivery to the olfactory mucosa at the top of the nasal cavity, where the BBB is thinner and multiple drugs have penetrated successfully. Current intranasal technologies tend to be restricted to the lower regions of the nasal cavity and involve appreciable loss to the GI tract (Figure 1a). Kurve’s technology provides precisely-controlled (1) particle size and (2) turbulent flow dynamics that navigate past the curved and sharply angled surfaces of the nasal cavity and reach the olfactory mucosa (Figure 1b).

Example:

Administration of intranasal insulin Kurve’s ViaNase™ device has been used in at least 10 placebo-controlled trials with Intrulin™ (Kurve intranasal insulin), including five in Alzheimer’s disease where the primary endpoint metrics were met. The delivery is challenging and important: Insulin is a complex molecule that does not cross the blood-brain barrier (BBB) well. This means that administering insulin the usual way (injection) results in systemic exposure with a risk of hypoglycemia without getting a useful dose to the brain. Kurve’s device shifts the landscape heavily in favor of the patient, delivering focused, effective doses to the brain without yet a single incident of clinically-significant hypoglycemia.

Five of the published Intrulin™ trials have been in Alzheimer’s disease. All have delivered statistically significant results vs. placebo. The most recent study showed continuing improvements vs. the placebo group in cognition and quality of life 18 months out (Figure 2)3, supported also by brain imaging data4 and favorable changes in cerebrospinal fluid (CSF) biomarkers of inflammation.5 Insulin from a different device in the same trial failed vs. placebo (Figure 2), supporting Kurve’s distinctive capability to penetrate the BBB and deliver drugs to the brain. Intrulin™ also has several encouraging, compassionate use cases in Alzheimer’s and Parkinson’s diseases.

Underscoring the targeted efficacy and enhanced safety of Kurve Intrulin™ is a 2017 research publication (healthy subjects):

“The major new finding of our study is [favorable change in brain activity, shown on functional MRI] after intranasal application of insulin. Furthermore, we found that circulating glucose and insulin levels did not change after intranasal application of insulin compared to placebo, indicating that there was no spillover to the systemic circulation and we were able to target the CNS specifically.”6

Further, extensive experience:

Ranging from small molecules through peptides to monoclonal antibodies (and beyond), Kurve has delivered a broad variety of drugs for partner organizations, including Stem Cells, Emulsions, Nanoparticles, Proteins, Peptides, Monoclonal Antibodies, Polyclonal Antibodies, Live Vaccines, Inert Vaccines, Solutions, Suspensions and Combination Products (as many as four in series and in parallel).

Rapid, versatile, cost-effective development for new treatments:

Kurve’s ViaNase™ platform can be adapted and calibrated quickly (usually within 6 weeks) to deliver precisely-sized droplets of almost any liquid formulation. The company has successful experience delivering viscosities ranging from 1 to 5000 centipoise. Development can be highly cost-effective, avoiding the cost (and much of the uncertainty) of medicinal chemistry and animal toxicology involved with carrier (e.g., “Trojan horse”) molecules and most other strategies to penetrate the BBB.

Figure 2. 18 month, placebo-controlled Alzheimer’s trial using Kurve Intrulin™ and a competing intranasal-insulin product (“Other”) also intended to penetrate the BBB. Intrulin’s continuing improvement vs. placebo 18 months out on the primary endpoint metric suggests durable, disease-modifying activity not possible with other technologies. NS = Not significant.

Challenge #2:
The Need for New Science and New Mechanisms of Action

Efforts to treat challenging CNS disorders — Alzheimer’s disease in particular — have been thwarted by the need for new science (such as biochemical models of disease) and new mechanisms of action to address that science.

Taking Alzheimer’s disease (AD) as an example: Currently approved AD treatments only address symptoms and do not modify the course of the disease, yet global revenues for AD drugs were $6.5 billion in 2021,7 suggesting significant opportunity. Meanwhile, industry focus has been on drugs targeting the beta-amyloid pathway, yielding a long, significant series of failed trials and (finally) one approval. That approval (Biogen’s Aduhelm) was based on equivocal efficacy results and challenging safety data (brain swelling [35% of patients] and brain bleeding [>15%]),8 yielding unenthusiastic uptake and what one analyst termed “potentially the worst drug launch of all time.”9 A different approach with new science is urgently needed.

The Answer: Intrulin™, new technology delivering a new mechanism of action of Alzheimer’s therapy

As discussed above, Kurve’s Intrulin™ product uses the company’s patented ViaNase™ device to deliver intranasal insulin to the brain via Controlled Particle Dispersion®. Intrulin™ has been used with encouraging results in 10 placebo-controlled trials, including five in Alzheimer’s disease (mentioned above) where the primary endpoint metrics were met. Other published, placebo-controlled clinical results include favorable effects upon Parkinson’s disease symptoms10 and cognitive aging. The effects upon cognitive/ brain aging were seen both in reported both in diabetes patients (≥50 years) and in age-matched controls.11,12

New Mechanism: EF2K/GSK3 inhibitor (EGI)

While insulin’s metabolic role has been well known for decades, its brain activity is distinct and only recently understood. Intranasal insulin upregulates several important substances such as synapsin and BDNF (brain-derived neurotrophic factor) that are diminished in Alzheimer’s disease. It does this via inhibiting two key enzymes: EF2K (elongation factor 2 kinase)13 and GSK-3 (glycogen synthase kinase-3).14 Both of these enzymes are involved in the longevity of brain cells and are of significant interest. In particular, GSK-3 has >13,000 PubMed papers and has been targeted since its discovery in 1980.15 EF2K inhibition is a more recent but highly promising CNS target. Its promise in Alzheimer’s disease was featured on the cover16 (and in the contents17) of the March 2022 issue of the Journal of Neurochemistry. This new, combined mechanism of action is termed EF2K/GSK3 inhibitor, or EGI (pronounced “edgy”).

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