Pipeline

Disease and Medical Need
GBM is a highly aggressive brain cancer with one of the highest unmet medical needs in oncology. Most patients die from progressive disease with a median survival of 14.6 months.¹

Rationale
Tinostamustine combines the dual activities of a bifunctional alkylating agent and a HDACi that crosses the blood brain barrier. Histone deacetylase inhibitors are recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well recognized mechanisms of HDACi lethality include, in addition to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, and promotion of apoptosis. Multiple lines of recent data suggest that biologically important synergy exists between alkylating agents and HDACi. For example, in one study the combination of bendamustine, an alkylating agent, and entinostat, a HDACi, synergistically inhibits proliferation of multiple myeloma (MM) cells via induction of apoptosis and DNA damage response.²

Clinical Findings
Tinostamustine has demonstrated both preclinical and early phase clinical evidence supporting promising activity for both MGMT promoter gene methylated and unmethylated glioblastoma phenotypes when administered following surgical resection and chemoradiation with temozolomide.^3,4,5

The above information discusses clinical research results involving an investigational new drug under development and is not intended to convey conclusions about efficacy or safety. Additional studies are needed to understand the safety and efficacy of this investigational medicine. There is no guarantee that such investigational drug will successfully complete clinical development or receive regulatory approval.

Disease and Medical Need
Insomnia is a common sleep disorder affecting up to 20% of individuals worldwide, with substantial impact on productivity, health, and overall wellbeing.¹ Despite widespread use of hypnotic therapies, many patients experience limited improvement in quality of life, highlighting a significant unmet need for novel treatment approaches.²

Rationale
Sunobinop is a first‑in‑class, investigational oral nociceptin (NOP) receptor agonist that potently and selectively activates NOP receptors following oral administration.³ Activation of nociceptin, an inhibitory neurotransmitter in the CNS, has been shown to have a dose dependent effect on increasing NREM sleep.^3,4 This novel mechanism, in addition to short half-life, non-hepatic metabolism, absence of effects on respiration, or negative impacts on sleep architecture, differentiate sunobinop from traditional hypnotics and support its potential to improve sleep.

Clinical Findings
In Phase 1 studies in patients with DSM‑V insomnia disorder, sunobinop was well tolerated, with somnolence reported as the most frequent treatment‑emergent adverse event.⁵ Across doses ranging from 0.5 – 10 mg, sunobinop demonstrated dose‑dependent, statistically significant, and clinically meaningful improvements in sleep efficiency, as well as improvements in sleep onset and maintenance, compared with placebo.^3,5 Studies in healthy subjects showed no pharmacokinetic interaction with alcohol and at therapeutic doses, limited pharmacodynamic interactions with alcohol, as well as limited next-day residual effects and abuse potential.^6,7

In a Phase 2 study in patients with insomnia symptoms recovering from Alcohol Use Disorder (AUD), sunobinop once nightly at bedtime was well tolerated and showed objective improvement in sleep maintenance and reduced nighttime awakenings.⁸ Somnolence was the most frequently reported adverse event. (NCT04035200)

The above information discusses clinical research results involving an investigational new drug under development and is not intended to convey conclusions about efficacy or safety. Additional studies are needed to understand the safety and efficacy of this investigational medicine. There is no guarantee that such investigational drug will successfully complete clinical development or receive regulatory approval.

Disease and Medical Need
Alcohol use disorder (AUD) is a common medical condition characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences. AUD is a chronic, relapsing disorder that can increase the risk of certain cancers, lead to liver diseases and can damage the brain and other organs.  Alcohol also increases the chances of developing sleep disturbances, depression, and other mental health problems including substance use disorders, where over 50% of OUD patients have AUD at some point during their lifetime.”¹

Rationale
Preclinical studies have shown that activation of NOP receptors in AUD animal models reduces the reinforcing and motivating effects of both ethanol and opioids (alcohol).^2,3,4,5 In humans, lower NOP activity in the brain (measured by PET imaging) has been associated with an increased risk of relapse in 22 recently abstinent patients with severe AUD who were followed for 12 weeks.⁶

Clinical Findings
Sunobinop studies have suggested improvements in various sleep measurements.⁷ including in abstinent patients with AUD (NCT04035200) building on these data, Knoa Pharma is conducting a two-part, randomized, double-blind, placebo-controlled, parallel-group Phase 2 study to evaluate the impact of sunobinop given at bedtime on alcohol consumption (NCT06545916), as well as alcohol craving. (NCT06545929)

The above information discusses clinical research results involving an investigational new drug under development and is not intended to convey conclusions about efficacy or safety. Additional studies are needed to understand the safety and efficacy of this investigational medicine. There is no guarantee that such investigational drug will successfully complete clinical development or receive regulatory approval.

Disease and Medical Need
Interstitial cystitis also referred to as Bladder Pain Syndrome or IC/BPS is a chronic condition that causes bladder pain, discomfort and pressure along with the frequent and urgent need to urinate during the day and night.¹ IC/BPS is not well understood and there are limited treatment options.

Rationale
Preclinical and clinical studies have shown that activating NOP in the bladder increases micturition threshold and bladder capacity. ^2,3,4 Furthermore, clinical data shows activation of NOP receptors can reduce pain in IC/BPS patients.⁵

Clinical Findings
As Sunobinop’s primary route of elimination is renal, high concentrations are achieved in the bladder.⁶ Sunobinop inhibits pain in the cyclophosphamide animal model of acute cystitis.⁷ Knoa Pharma has recently completed a multicenter, randomized, double-blind, placebo-controlled single sequence Phase 1b crossover study in IC/BPS patients (NCT06285214) and is currently planning additional clinical studies for this indication.

The above information discusses clinical research results involving an investigational new drug under development and is not intended to convey conclusions about efficacy or safety. Additional studies are needed to understand the safety and efficacy of this investigational medicine. There is no guarantee that such investigational drug will successfully complete clinical development or receive regulatory approval.

Disease and Medical Need
Overactive bladder syndrome (OAB) is a condition that causes sudden urges to urinate that may be hard to control. There is often a need to pass urine many times during the day and night and there can be a loss of urine that isn’t intended, called urge incontinence.

Rationale
Preclinical and clinical studies have shown that activating NOP in the bladder increases micturition threshold and bladder capacity.^1,2 Furthermore, clinical data shows activation of NOP receptors can reduce incontinence in OAB patients.³

Clinical Findings
As Sunobinop’s primary route of elimination is renal, high concentrations are achieved in the bladder.⁴ Existing treatments are directed to the neuromuscular junction. Sunobinop targets the sensory neurons. Sunobinop inhibits the micturition reflex in an isovolumetric cystometry animal model⁵ and a Phase 1b clinical study with sunobinop in OAB patients has suggested an improvement in multiple OAB symptoms. (NCT06024642).

Studies are ongoing.

The above information discusses clinical research results involving an investigational new drug under development and is not intended to convey conclusions about efficacy or safety. Additional studies are needed to understand the safety and efficacy of this investigational medicine. There is no guarantee that such investigational drug will successfully complete clinical development or receive regulatory approval.