Phase 1b, Open Label Study to Evaluate the Safety, Tolerability, and Efficacy of a 1% Topical Formulation of KM-001 for the Treatment of Type I Punctate Palmoplantar Keratoderma or Pachyonychia Congenita

This Phase 1b, open-label, single-center, prospective trial will be assessing the safety, tolerability, and efficacy of topical KM-001 1% in patients with PPPK1 or PC diseases. In this study 2 cohorts will be recruited:
1. Cohort 1: up to 11 eligible patients, will be enrolled to be treated twice daily, for 12 weeks, with 1% topical KM-001, on the plantar surfaces (2 feet).
2. Cohort 2: up to 8 eligible patients, will be enrolled to be treated twice daily, for 16 weeks, with 1% topical KM-001, on the plantar surfaces (2 feet).
Safety (AEs, blood work [at specific visits], vital signs), tolerability, and efficacy parameters (overall lesion improvement) will be assessed during in-clinic visits (Cohort 1: during Screening, Enrolment, and on Days 7, 28, 42, 63, 84 [end of treatment, EoT], 112 [End of Study, EoS] post first investigational medicinal product (IMP) administration; Cohort 2: during Screening, Enrolment, and on Days 7, 28, 42, 63, 84, 112 [EoT], 140 [EoS] post first investigational medicinal product (IMP) administration).
PK samples will be collected to assess plasma levels of KM-001 on
* Screening (Day -14 to -0): any time during the visit. (or on Day 1 up to 30 minutes pre-dose if missed during Screening)
* Day 7 and at EoT (Cohort 1: Day 84; Cohort 2: Day 112) up to 30 minutes pre-dose, and at 1 h, 2 h, 3 h, 6 h (+15 min) post-dose
* Days 28, 42 for both Cohorts, and Day 84 for Cohort 2: 1 sample after the first dose, before the second dose, as late as possible in the visit.
* End of Study (EoS, Day 112 (Cohort 1) or Day 140 (cohort 2)), or at Early Termination (ET): at any time during the visit.
The patient will complete a patient-reported diary, consisting of treatment compliance and self-assessments for efficacy.
Follow up- 2 weeks after EoT by phone call, and 4 weeks after EoT in clinic visit.

Start Date06 Mar 2023

Sponsor / Collaborator

Kamari Pharma Ltd.

NCT05435638

/ CompletedPhase 1

Phase I, Open Label Study Designed to Evaluate the Safety and Efficacy of a 1% Topical Formulation of KM-001 in the Treatment of Type I Punctate Palmoplantar Keratoderma or Pachyonychia Congenital Diseases

In this phase 1 open label study for patients with type I punctate palmoplantar keratoderma or pachyonychia congenital, 2 arms will be recruited to be treated twice daily, with 1% topical KM-001.
Arm 1: up to 10 eligible patients will be treated for 12 weeks. Arm 2: up to 8 eligible patients will be treated for 16 weeks.
Treatment safety and efficacy will be assessed in the clinic visits (for arm 1 up to day 91, for arm 2 up to day 126). In between safety will also be assessed by phone visits.
At the in-clinic visits, treatment efficacy (lesion clearance - IGA, CGI-S, PGI-C, PGI-S and VAS pain) will also be assessed.
PK blood samples will be collected for arm 1: on Days 0, 7, 84 (EoT visit). One week after the end of treatment (EoT) visit, patients will return to the clinic for final safety, efficacy and PK evaluations. For arm 2, PK blood samples will be collected on days 0, 7, 84, 112 (EoT visit). Two weeks after the end of treatment (EoT) visit, patients will return to the clinic for final safety, efficacy and PK evaluations.

Start Date17 Jul 2022

Sponsor / Collaborator

Kamari Pharma Ltd.

NCT05454462

/ CompletedPhase 1

Double-blind, Vehicle-controlled, Phase I Study to Evaluate Safety and Efficacy of a 0.3% and 1% Topical Formulation of KM-001 for Management of Moderate to Severe Pruritus in Adult Patients With Lichen Simplex Chronicus (LSC)

This is a phase 1, multi-center, randomized, vehicle-controlled, double-blinded, parallel-group study.
Approximately 6 sites will conduct the study at Germany. Approximately 61 patients (male and female) planned to be screened. 51 patient planned to be randomized.
Patients will be randomized to 1 of 3 treatment arms (KM-001 0.3%, KM-001 1%, or vehicle cream) iina a ration of 1:1:1
Patient's duration of participation will be up to 7 weeks,
a screening period with 1 visit (Visit 1) within up to 14 days (Days -14 to -1),
a 4-week treatment period with 3 visits (Visit 2 on Day 0, Visit 3 on Day 7, Visit 4 at Day 28 and 2 phone calls on Days 14 and 21, and
a 1-week follow-up period with 1 visit (Visit 5 on Day 35), as well as unscheduled visits as needed
Since KM-001 is tested in humans for the first time, the safety of KM-001 will be evaluated in a subgroup of 6 patients (sentinel group) at selected sites prior to screening of the remaining sites.
Efficacy assessments will include subjective assessments of itch and investigator assessment of the treatment effect on LSC target lesion using scoring systems.
Safety parameter (including physical examination, vital signs, ECG, standard laboratory test, and PK analysis) will be monitored from the signing of the informed consent form (ICF) until the last follow-up visit. Recording of AEs and serious AEs (SAEs) will be done throughout the study with special attention to local AEs in the treatment area (LSC target lesion, dermal safety).

Start Date24 May 2022

Sponsor / Collaborator

Kamari Pharma Ltd.

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100 Clinical Results associated with KM-001(Kamari-Pharma)

100 Translational Medicine associated with KM-001(Kamari-Pharma)

100 Patents (Medical) associated with KM-001(Kamari-Pharma)

Literatures (Medical) associated with KM-001(Kamari-Pharma)

01 Jul 2022·Neurobiology of Disease

Neutral sphingomyelinase 2 inhibition attenuates extracellular vesicle release and improves neurobehavioral deficits in murine HIV

Article

Author: Zhu, Xiaolei ; Borjabad, Alejandra ; Witwer, Kenneth W ; Hollinger, Kristen R ; Lovell, Lyndah ; Slusher, Barbara S ; Haughey, Norman J ; Arab, Tanina ; Moniruzzaman, Mohammed ; Kim, Boe-Hyun ; Turchinovich, Andrey ; Thomas, Ajit G ; Volsky, David J ; Huang, Yiyao

People living with HIV (PLH) have significantly higher rates of cognitive impairment (CI) and major depressive disorder (MDD) versus the general population. The enzyme neutral sphingomyelinase 2 (nSMase2) is involved in the biogenesis of ceramide and extracellular vesicles (EVs), both of which are dysregulated in PLH, CI, and MDD. Here we evaluated EcoHIV-infected mice for behavioral abnormalities relevant to depression and cognition deficits, and assessed the behavioral and biochemical effects of nSMase2 inhibition. Mice were infected with EcoHIV and daily treatment with either vehicle or the nSMase2 inhibitor (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-carbamate (PDDC) began 3 weeks post-infection. After 2 weeks of treatment, mice were subjected to behavior tests. EcoHIV-infected mice exhibited behavioral abnormalities relevant to MDD and CI that were reversed by PDDC treatment. EcoHIV infection significantly increased cortical brain nSMase2 activity, resulting in trend changes in sphingomyelin and ceramide levels that were normalized by PDDC treatment. EcoHIV-infected mice also exhibited increased levels of brain-derived EVs and altered microRNA cargo, including miR-183-5p, miR-200c-3p, miR-200b-3p, and miR-429-3p, known to be associated with MDD and CI; all were normalized by PDDC. In conclusion, inhibition of nSMase2 represents a possible new therapeutic strategy for the treatment of HIV-associated CI and MDD.

01 Jan 2021·Environment International

Effects of a human-based mixture of persistent organic pollutants on the in vivo exposed cerebellum and cerebellar neuronal cultures exposed in vitro

Article

Author: Duale, Nur ; Paulsen, Ragnhild Elisabeth ; Myhre, Oddvar ; Ropstad, Erik ; Hofer, Tim ; Halsne, Ruth ; Rakkestad, Kirsten Eline ; Rangel-Huerta, Oscar Daniel ; Boge, Gudrun ; Bjørklund, Cesilie Granum ; Berntsen, Hanne Friis ; Østby, Gunn ; Dyrberg, Kine

Exposure to persistent organic pollutants (POPs), encompassing chlorinated (Cl), brominated (Br) and perfluoroalkyl acid (PFAA) compounds is associated with adverse neurobehaviour in humans and animals, and is observed to cause adverse effects in nerve cell cultures. Most studies focus on single POPs, whereas studies on effects of complex mixtures are limited. We examined the effects of a mixture of 29 persistent compounds (Cl + Br + PFAA, named Total mixture), as well as 6 sub-mixtures on in vitro exposed rat cerebellar granule neurons (CGNs). Protein expression studies of cerebella from in vivo exposed mice offspring were also conducted. The selection of chemicals for the POP mixture was based on compounds being prominent in food, breast milk or blood from the Scandinavian human population. The Total mixture and sub-mixtures containing PFAAs caused greater toxicity in rat CGNs than the single or combined Cl/Br sub-mixtures, with significant impact on viability from 500x human blood levels. The potencies for these mixtures based on LC₅₀ values were Br + PFAA mixture > Total mixture > Cl + PFAA mixture > PFAA mixture. These mixtures also accelerated induced lipid peroxidation. Protection by the competitive N-methyl-D-aspartate (NMDA) receptor antagonist 3-((R)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) indicated involvement of the NMDA receptor in PFAA and Total mixture-, but not Cl mixture-induced toxicity. Gene-expression studies in rat CGNs using a sub-toxic and marginally toxic concentration ((0.4 nM-5.5 µM) 333x and (1 nM-8.2 µM) 500x human blood levels) of the mixtures, revealed differential expression of genes involved in apoptosis, oxidative stress, neurotransmission and cerebellar development, with more genes affected at the marginally toxic concentration. The two important neurodevelopmental markers Pax6 and Grin2b were downregulated at 500x human blood levels, accompanied by decreases in PAX6 and GluN2B protein levels, in cerebellum of offspring mice from mothers exposed to the Total mixture throughout pregnancy and lactation. In rat CGNs, the glutathione peroxidase gene Prdx6 and the regulatory transmembrane glycoprotein gene Sirpa were highly upregulated at both concentrations. In conclusion, our results support that early-life exposure to mixtures of POPs can cause adverse neurodevelopmental effects.

01 Aug 2003·European Journal of PharmacologyQ3 · MEDICINE

Antitussive effect of WIN 55212-2, a cannabinoid receptor agonist

Q3 · MEDICINE

Article

Author: Kayo Morita ; Junzo Kamei

Several lines of evidence indicate that the opioid and cannabinoid systems produce synergistic interactions. The present study examined the opioid receptors involved in the antitussive effect of WIN 55212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-[4-morpholinylmethyl]-pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl) methanone mesylate), a high-affinity cannabinoid receptor agonist, in mice. WIN 55212-2, at doses of 0.3-3 mg/kg ip, produced a dose-dependent antitussive effect. This antitussive effect of WIN 55212-2 was antagonized by pretreatment with either methysergide (3 mg/kg ip), a 5-HT receptor antagonist, or naloxone (1 mg/kg ip), an opioid receptor antagonist. Furthermore, pretreatment with N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A, 3 mg/kg ip), a cannabinoid CB(1) receptor antagonist, also significantly reduced the antitussive effect of WIN 55212-2. Blockade of mu-opioid receptors by pretreatment with beta-funaltrexamine (40 mg/kg sc) significantly reduced the antitussive effect of WIN 55212-2. However, pretreatment with nor-binaltorphimine (20 mg/kg sc), a kappa-opioid receptor antagonist, did not affect the antitussive effect of WIN 55212-2. Pretreatment with naloxonazine (35 mg/kg sc), a mu(1)-opioid receptor antagonist, also did not affect the antitussive effect of WIN 55212-2. These results indicate that the antitussive effect of WIN 55212-2 is mediated by the activation of cannabinoid CB(1) receptors and mu(2) (naloxonazine-insensitive)-opioid receptors, but not mu(1) (naloxonazine-sensitive)- or kappa-opioid receptors.

News (Medical) associated with KM-001(Kamari-Pharma)

17 May 2024

·www.biospace.com

Kamari Pharma Announces New Data Presented at the 81st Annual Meeting of the Society for Investigative Dermatology

Phase 1b clinical trial of KM-001 demonstrated favorable safety pro high responder rate of 87% in patients with palmoplantar keratoderma and pachyonychia congenita In vitro and in vivo data of KM-001 and KM-023 demonstrated significant improvements in skin histology and significant reductions in scratching NESS ZIONA, Israel, May 17, 2024 (GLOBE NEWSWIRE) -- Kamari Pharma, a privately-held clinical stage biotechnology company developing first and best-in-class treatments for rare and severe genetic skin diseases, today announced two presentations reporting results for its novel TRPV3 inhibitors, KM-001 (topical) and KM-023 (oral), were given at the 81st Annual Meeting of the Society for Investigative Dermatology (SID) that is taking place May 15-18, 2024 in Dallas, TX, USA. Below are summaries of the presentations: Poster #LB941: “KM-001, a novel TRPV3 inhibitor, demonstrates safety and preliminary efficacy in Phase 1b clinical study for the treatment of palmoplantar keratoderma” presented by Edel O’Toole, M.D., Ph.D. Professor of Molecular Dermatology and Centre Lead of the Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University of London and lead investigator in the study. Presented results from twelve-week, Phase 1b open-label studies (UK and Israel) assessing 4g/day of KM-001 1% cream applied to each foot twice daily for the treatment of pachyonychia congenita (PC) and punctate palmoplantar keratoderma type 1 (PPPK1). Eight patients in the UK (7 PC;1 PPPK1) and seven patients in Israel (3 PC;4 PPPK1) completed the treatment period. Safety: No drug-related severe adverse events nor systemic side effects were observed. Minimal treatment emergent adverse events occurred (n=11); all were mild and did not lead to patient discontinuation. Efficacy: Responder rate at the end of treatment was 88% (CI 52.9-97.8%) in UK (n=8) and 86% (CI 48.7-97.4%) in Israel (n=7), as defined by an improvement in at least one of six pre-defined disease parameters. Additionally, 47% of patients improved in at least two parameters with a disease severity reduction trend and pain score measured by VAS was reduced in 60% of PC patients; PPPK1 patients do not have pain as a symptom. Presentation #771: “Novel TRPV3 inhibitors developed for the treatment of palmoplantar keratodermas, demonstrate safety and efficacy in preclinical models” presented by Liora Braiman-Wiksman, Ph.D., Chief Scientific Officer at Kamari. Presented preclinical results for KM-001 and KM-023, Kamari’s specific and highly selective TRPV3 inhibitors designed to address both molecular and local damage to the skin by regulating Ca²⁺ influx into the cell. In 3D skin models of PC and PPPK1, KM-001 and KM-023 normalized proliferation and differentiation markers and enhanced epidermal barrier formation. In in vivo efficacy studies performed in DS-Nh mice, a gain-of-function TRPV3 mutation model, KM-001 showed significant improvement in skin histology vs vehicle (70% vs 30%) and exhibited significant reduction in scratching bouts (80%, p>0.04) and KM-023 showed a significant reduction in keratoderma severity score (p=0.003) and reduced scratching significantly (p<0.001) vs vehicle. Based on these results, Kamari plans to initiate Phase 2 development of KM-001 for the treatment of palmoplantar keratoderma and advance KM-023 into first-in-human studies for the oral treatment of Olmstead syndrome, severe keratoderma and Ichthyosis. The full content of these posters is available in the News page of Kamari's corporate website ( ). About Kamari Pharma Kamari Pharma is a privately-held clinical stage biotechnology company developing first and best in class treatments for rare and severe genetic skin diseases. Kamari’s lead molecules, KM-001 (topical) and KM-023 (oral) are novel, highly specific and selective TRPV3 inhibitors that are initially being developed to treat palmoplantar keratodermas, Olmstead syndrome and Ichthyosis. Kamari’s management team is comprised of industry leaders highly experienced in drug discovery, dermatological pharmaceutical development and rare disease drug development. Contact Information Investors and Media Marcy Nanus Managing Partner Trilon Advisors, LLC mnanus@trilonadvisors.com

Clinical ResultPhase 1AACR

16 Apr 2024

·www.globenewswire.com

Kamari Pharma Announces Abstracts Accepted for Presentation at the 81st Annual Meeting of the Society for Investigative Dermatology

Late breaking poster presentation includes Phase 1b clinical trial results demonstrating the safety and preliminary efficacy of KM-001, a topical TRPV3 inhibitor, for the treatment of palmoplantar keratoderma Oral presentation highlights favorable in vitro and in vivo safety and efficacy data of novel TRPV3 inhibitors KM-001(topical) and KM-023 (oral) in preclinical 3D skin and mouse models NESS ZIONA, Israel, April 16, 2024 (GLOBE NEWSWIRE) -- Kamari Pharma, a privately-held clinical stage biotechnology company developing first and best-in-class treatments for rare and severe genetic skin diseases, today announced two abstracts reporting results for its novel TRPV3 inhibitors, KM-001(topical) and KM-023 (oral), have been selected for presentation at the 81st Annual Meeting of the Society for Investigative Dermatology (SID), being held May 15-18, 2024 in Dallas, TX, USA. TRPV3 plays a central role in skin disease as it regulates proliferation, differentiation and barrier function of human skin. KM-001 and KM-023 are specific and selective TRPV3 inhibitors that address both molecular and local damage to the skin by regulating Ca²⁺ influx into the cell, thereby reconstructing the skin barrier and reducing inflammation. Kamari is currently developing KM-001 for the treatment of palmoplantar keratoderma and KM-023 for the treatment of Olmstead syndrome, severe keratoderma and Ichthyosis. The details of the presentations are as follows: Title: KM-001, a novel TRPV3 inhibitor, demonstrates safety and preliminary efficacy in Phase 1b clinical study for the treatment of palmoplantar keratodermaFinal ID Number: LB941Session Type: Poster PresentationCategory: Clinical Research - Interventional ResearchSession Date & Time: Thursday, May 16, 2024, 4:30-6:30pm CT Title: Novel TRPV3 inhibitors developed for the treatment of palmoplantar keratodermas, demonstrate safety and efficacy in preclinical modelsFinal ID Number: 771Session Type: Oral PresentationCategory: Translational Studies and Early Preclinical to ClinicalSession Date & Time: Friday, May 17, 2024, 4:30-6:00pm CT About Kamari Pharma Kamari Pharma is a privately-held clinical stage biotechnology company developing first and best in class treatments for rare and severe genetic skin diseases. Kamari’s lead molecules, KM-001 (topical) and KM-023 (oral) are novel, highly specific and selective TRPV3 inhibitors that are initially being developed to treat palmoplantar keratodermas, Olmstead syndrome and Ichthyosis. Kamari’s management team is comprised of industry leaders highly experienced in drug discovery, dermatological pharmaceutical development and rare disease drug development. Contact Information Investors and MediaMarcy NanusManaging PartnerTrilon Advisors, LLCmnanus@trilonadvisors.com

Phase 1

100 Deals associated with KM-001(Kamari-Pharma)

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Keratosis Palmoplantaris Papulosa	Phase 1	IL	Kamari Pharma Ltd.	17 Jul 2022
Pachyonychia Congenita	Phase 1	IL	Kamari Pharma Ltd.	17 Jul 2022
Neurodermatitis	Phase 1	DE	Kamari Pharma Ltd.	24 May 2022
Pruritus	Phase 1	DE	Kamari Pharma Ltd.	24 May 2022

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05435638 (Biospace) Manual	Phase 1	Pachyonychia Congenita \| Keratosis Palmoplantaris Papulosa	15	KM-001 1% cream (UK)	(zodufbgoxk) = luinkqwidx rfisjtporv (zqjmxrwnqa, 52.9 - 97.8) View more	Positive	17 May 2024
				KM-001 1% cream (Israel)	(zodufbgoxk) = wbrngzjyre rfisjtporv (zqjmxrwnqa, 48.7 - 97.4)

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