Cystinosis is a rare autosomal recessive lysosomal storage disease, associated with high morbidity and mortality. Mutations in the CTNS gene disable a membrane protein responsible for the transport of cystine out of the lysosome. Loss of transporter function leads to intralysosomal cystine accumulation and long-term damage to various tissues and organs, including the kidneys, eyes, liver, muscles, pancreas, and brain. The only cystine-depletion therapy for treatment of cystinosis is cysteamine which requires frequent administration of high doses and often causes gastrointestinal pain as well as pungent sulfurous odor in patients. The current in vitro study evaluated antioxidants, N-acetylcysteine amide (NACA; NPI-001) and (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) (diNACA; NPI-002), as potential treatments for cystinosis.

Methods:

Cytotoxicity of cysteamine, NACA and diNACA was evaluated in cultured human cystinotic fibroblasts (HCFs). HCFs were cultured in 96 well plates incubated for 0–72 h in the presence of 25, 50 or 75 μM each of either cysteamine, NACA or diNACA along with an untreated control. Media was removed and cell viability assessed. Next, cystine-depleting activities of cysteamine, NACA and diNACA were screened in HCFs cell culture utilizing an inexpensive, proven colorimetric assay. HCFs were seeded and allowed to reach approximately 80% confluence before the addition of the test articles: 50 μM of either cysteamine, NACA or diNACA in media along with an untreated control. HCFs were incubated, harvested, and cystine was reduced to cysteine, the concentration of which was then determined per quantity of protein compared to a cysteine standard. Statistically significant cystine depletion was determined by paired t-test versus untreated control (p < 0.05).

Results:

Neither cysteamine, NACA nor diNACA at 25, 50 or 75 μM caused cytotoxicity in HCFs. Treatment with all tested concentrations (25, 50 or 75 µM) of either NACA or diNACA at 48 or 72 h resulted in statistically significant increases in cell viability, relative to untreated control, whereas the higher concentrations (50 or 75 µM) of cysteamine achieved statistical significance at both timepoints but not the lowest concentration (25 µM). All test articles depleted cystine from HCFs compared to control. NACA depletion of cystine was statistically superior to cysteamine at 6, 24 and 48 h and numerically greater at 72 h. DiNACA depletion of cystine was statistically superior to cysteamine at 6 and 48 h, slightly numerically greater at 24 h and slightly less at 72 h.

Conclusions:

NACA and diNACA were non cytotoxic to HCFs and significantly increased cell viability. Cystine reduction was determined as percent of control after incubation with 50 µM of NACA, diNACA or cysteamine in HCFs cell culture for 6, 24, 48 and 72 h. Of the three test articles, NACA exhibited most rapid and greatest potency in cystine reduction. Rank order potency for cystine reduction over time was observed, NACA > diNACA ≥ cysteamine. Therefore, further study of NACA and diNACA as potential treatments for cystinosis is warranted.

01 Feb 1998·Biochemical pharmacologyQ2 · MEDICINE

Inhibition of human class 3 aldehyde dehydrogenase, and sensitization of tumor cells that express significant amounts of this enzyme to oxazaphosphorines, by chlorpropamide analogues

Q2 · MEDICINE

Article

Author: Varadahalli R. Devaraj ; Herbert T. Nagasawa ; Lakshmaiah Sreerama ; Melinda J.C. Lee ; Ganaganur K. Rekha ; Norman E. Sladek

In some cases, acquired as well as constitutive tumor cell resistance to a group of otherwise clinically useful antineoplastic agents collectively referred to as oxazaphosphorines, e.g. cyclophosphamide and mafosfamide, can be accounted for by relatively elevated cellular levels of an enzyme, viz. cytosolic class 3 aldehyde dehydrogenase (ALDH-3), that catalyzes their detoxification. Ergo, inhibitors of ALDH-3 could be of clinical value since their inclusion in the therapeutic protocol would be expected to sensitize such cells to these agents. Identified in the present investigation were two chlorpropamide analogues showing promise in that regard, viz. (acetyloxy)[(4-chlorophenyl)sulfonyl]carbamic acid 1,1-dimethylethyl ester (NPI-2) and 4-chloro-N-methoxy-N-[(propylamino)carbonyl]benzenesulfonamide (API-2). Each inhibited NAD-linked benzaldehyde oxidation catalyzed by ALDH-3s purified from human breast adenocarcinoma MCF-7/0/CAT cells (IC50 values were 16 and 0.75 microM, respectively) and human normal stomach mucosa (IC50 values were 202 and 5 microM, respectively). The differential sensitivities of stomach mucosa ALDH-3 and breast tumor ALDH-3 to each of the two inhibitors can be viewed as further evidence that the latter is a subtle variant of the former. Human class 1 (ALDH-1) and class 2 (ALDH-2) aldehyde dehydrogenases were much less sensitive to NPI-2; IC50 values were >300 microM in each case. API-2, however, did not exhibit a similar degree of specificity; IC50 values for ALDH-1 and ALDH-2 were 7.5 and 0.08 microM, respectively. Each sensitized MCF-7/0/CAT cells to mafosfamide; the LC90 value decreased from >2 mM to 175 and 200 microM, respectively. Thus, the therapeutic potential of combining NPI-2 or API-2 with oxazaphosphorines is established.

Alzheimer's research & therapyQ2 · MEDICINE

Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled, confirmatory phase III trial

Q2 · MEDICINE

ArticleOA

Author: Matsuo, Kazutaka ; Nakagawa, Masaki ; Kosaka, Kenji ; Mori, Etsuro ; Ikeda, Manabu

Abstract:

Introduction:

The efficacy of a cholinesterase inhibitor, donepezil, in patients with dementia with Lewy bodies (DLB) was investigated to confirm the superiority over placebo in the 12-week, double-blind phase of this phase III study.

Methods:

Patients with probable DLB (n = 142) were randomly assigned to placebo or to 5 mg or 10 mg of donepezil administered once daily for 12 weeks. The co–primary endpoints were changes in cognitive function assessed using the Mini-Mental State Examination (MMSE) and behavioral and neuropsychiatric symptoms using the Neuropsychiatric Inventory (NPI-2: hallucinations and fluctuations). The superiority of each active group over placebo was determined with simultaneous statistical significance in both endpoints. Safety evaluations included adverse events (AEs) and the unified Parkinson's disease rating scale (UPDRS) part III.

Results:

The predefined superiority of donepezil to the placebo was not confirmed in either active group in the primary analysis. MMSE score significantly improved compared to placebo in the 10 mg group (10 mg: 2.2 ± 0.4, placebo: 0.6 ± 0.5 (mean ± standard error); P = 0.016). The change in MMSE score in the 5 mg group was not significant (1.4 ± 0.5 (mean ± standard error); P = 0.232). Although NPI-2 improved compared to baseline in the active groups, the differences from placebo were not significant. Most AEs were mild or moderate. Although the incidence of parkinsonism was slightly higher in the 10 mg group, the change in the UPDRS score was minimal and without a significant difference from the placebo group.

Conclusions:

The co–primary endpoints were not achieved in this trial. However, significant improvement in MMSE score was demonstrated with 10 mg, but not 5 mg, of donepezil. The evaluation of psychiatric symptoms might be affected by advanced education and instructions given to caregivers. Overall, donepezil was well tolerated in patients with DLB. With careful attention on gastrointestinal or parkinsonian symptoms, patients with DLB can safely benefit from treatment with donepezil.

Trial registration:

ClinicalTrials.gov Identifier: NCT01278407 (trial registration date: 14 January 2011)

News (Medical) associated with NPI-002

30 Apr 2024

·www.globenewswire.com

Nacuity Pharmaceuticals Announces First Patients Implanted in Final Cohort of Phase 1/2 Clinical Trial Evaluating NPI-002 Intravitreal Implant for the Delay of Cataract Progression

Two patients have been implanted in the final cohort of the trial Final cohort is actively enrolling adult patients undergoing vitrectomy FORT WORTH, Texas, April 30, 2024 (GLOBE NEWSWIRE) -- Nacuity Pharmaceuticals, Inc., a clinical stage biopharmaceutical company developing treatments for retinitis pigmentosa, cataracts and other ocular diseases caused by oxidative stress, today announced that the first patients have been implanted in the final cohort of the Phase 1/2 clinical trial evaluating NPI-002 for delayed cataract progression in patients undergoing vitrectomy. An independent Data Safety Monitoring Board (DSMB) recommended proceeding with the final cohort after a positive safety review, which was subsequently approved by the overseeing Human Research Ethics Committee. NPI-002 is a proprietary antioxidant molecule delivered via a sustained release intravitreal implant. The Phase 1/2 NP-2 trial is a randomized, controlled, masked clinical trial assessing the safety and efficacy of NPI-002 in delaying cataract progression in adult patients undergoing vitrectomy. “Patients typically need cataract surgery within a year of their vitrectomy,” said Robert Casson, MBBS (Hons), DPhil, principal investigator of the trial and Professor, Royal Adelaide Hospital. “Delaying a subsequent cataract surgery after vitrectomy can alleviate the stress of having two ocular surgeries in a short period of time and improve surgical outcomes for patients.” The final cohort of the trial is actively enrolling patients for clinical sites at The Royal Adelaide Hospital (RAH) in Adelaide, South Australia, and personalEYES in Parramatta, New South Wales, Australia. “We’re encouraged by the positive safety signals seen to date and we’re grateful for the trial’s progression thanks to the diligent work of the trial investigators and the participation of patients,” said Halden Conner, Chairman, CEO, and Co-Founder of Nacuity Pharmaceuticals. “We look forward to continuing our evaluation of our NPI-002 antioxidant to slow cataract progression and preserve the sight of these patients.” For more information about the Phase 1/2 clinical trial of NPI-002, please visit clinicaltrials.gov (Identifier: NCT05026632). About NPI-002NPI-002 is a novel, differentiated, slow-release, small molecule being developed to slow cataract progression. For the treatment of cataract, a sterile intravitreal implant containing NPI-002 has been developed, along with a precision delivery system. In vitro and in vivo studies showed vitreal elution over time and revealed no cytotoxicity with NPI-002. In ex-vivo rat and porcine lenses, NPI-002 inhibited oxidative-induced cataracts. NPI-002 is currently being evaluated in a Phase 1/2 proof-of-concept clinical trial in Australia (NCT05026632). About Nacuity PharmaceuticalsNacuity Pharmaceuticals is a clinical-stage leader in innovative treatments for oxidative stress. The company’s powerful, targeted therapies aim to attenuate oxidative tissue damage, a driver of blinding eye diseases and a broad spectrum of serious chronic conditions. Nacuity has three highly differentiated clinical programs ongoing in retinitis pigmentosa, cataract and inherited cystinosis. Nacuity has operations in Fort Worth, TX, USA, and Australia, and extensive managerial and scientific domain expertise as well as backing from Foundation Fighting Blindness (https://www.fightingblindness.org/) and its venture arm RD Fund (https://www.retinaldegenerationfund.org). For more information, please visit www.nacuity.com. Media ContactJulia Clements267.626.1085jclements@6degreespr.com

Clinical Study

15 Jun 2022

·www.biospace.com

Money on the Move: Industry Invests in AI, Precision Medicine, Ocular Diseases

Summer is heating up, and so is venture capital funding. This week’s money on the move focuses on some hot financing for precision medicine with AI-enabled pathology, drug formulation, delivery innovations and ocular diseases. Elektrofi Boston-based biotech Elektrofi closed a Series B round of financing worth $40 million. The funding was led by Marshall Wace and BVF Partners with support from Janus Henderson and Logos Capital. Elektrofi, which focuses on drug formulation and delivery innovations, has big plans for the money. The company is looking to double its headcount in the next 12-18 months and establish a centralized GMP manufacturing line to help its upcoming clinical trials. The company will also accelerate the growth of its licensed programs with leading pharma and biotech as well as hone its platform that develops small-volume injections for monoclonal antibodies, therapeutic proteins, and other large molecule drugs. “This financing sets the stage for advancement of multiple lead programs to human trials, clinical validation of Elektrofi’s high concentration technology, and pipeline expansion in response to significant inbound platform interest,” said Chase Coffman, CEO and co-founder, of Elektrofi. ImCheck Therapeutics In the last outstanding tranche of Series B converted into Series C shares, France-based ImCheck Therapeutics gathered a total of €96 million (USD 103 million). The round of financing included support from existing investors the Growth Opportunity Fund of founding investor Kurma Partners, Eurazeo, Gimv, EQT Life Sciences (previously LSP), Boehringer Ingelheim Venture Fund, Pfizer Ventures, Bpifrance, Wellington Partners, Agent Capital, Pureos Bioventures and Alexandria Venture Investments. New investors Invus and The Leukemia & Lymphoma Society Therapy Acceleration Program also supported the financing. The funding will accelerate the further advance ImCheck’s goals in developing additional antibody candidates in immuno-oncology, auto-immune and infectious diseases, starting with ICT01. ICT01 is ImCheck’s lead candidate, and the cash will support Phase IIa clinical trial expansions of the drug in solid tumors and hematologic cancers. Gimv European investment company Gimv created its fifth investment platform, which will have a focus on venture capital investments in innovative life sciences companies. Previously, Gimv had launched a healthcare investment platform, but it had grown so quickly and had so much success—especially with companies like Ablynx, where Gimv was a founding investor and Covagen, which was acquired by Johnson & Johnson—that Gimv decided to create a separate life sciences platform. Gimv hopes to double its portfolio to 20 companies and have the cash to invest €10-15 million per company. Focuses on the investment platform include drug development, medical technology, digital health, life science tools and agro-biotechnology. Proscia Digital and computational pathology solutions company Proscia raised $37 million in a Series C round of financing, bringing the company’s total funding to $72 million. The round’s existing investors Scale Venture Partners, Hitachi Ventures, ROBO Global, Emerald Development Managers and Razor's Edge Ventures were joined by Highline Capital Management, Triangle Peak Partners, and Alpha Intelligence Capital. With the funding, Proscia will focus on precision medicine with AI-enabled pathology. The company also hopes the money will help to expand its sales, marketing and support teams, as well as grow more distribution partnerships following its recent OEM agreement with Siemens Healthineers. "Digital pathology is a critical catalyst in the acceleration of precision medicine, creating a wealth of new data that is driving novel therapies and optimizing diagnosis so that each patient receives the most individualized treatment. We are excited to be a part of Proscia's journey as it expands its leadership position with its AI-enabled platform," Jacob Doft, CEO of Highline Capital Management, said. Nacuity Pharmaceuticals Texas-based Nacuity Pharmaceuticals scooped up $16.5 million in a Series B financing. The financing was led by Foundation Fighting Blindness and its venture arm RD Fund, along with some existing investors. Nacuity is a clinical-stage biopharma company developing treatments for ocular diseases caused by oxidative stress, such as cataracts and retinitis pigmentosa. The funding will help the company advance clinical trials for NPI-001, a treatment for retinitis pigmentosa associated with Usher syndrome, and NPI-002, an antioxidant molecule designed to slow cataract progression that is delivered via an intravitreal implant.

CollaborateAntibody

15 Jun 2022

·www.globenewswire.com

Nacuity Pharmaceuticals Announces $16.5 Million Series B Financing Led by Foundation Fighting Blindness & RD Fund

Funds to support advancement of two clinical trials through proof of concept: NPI-001 for retinitis pigmentosa in Usher syndrome and NPI-002 to slow cataract progressionFORT WORTH, Texas, June 15, 2022 (GLOBE NEWSWIRE) -- Nacuity Pharmaceuticals, Inc., a clinical stage biopharmaceutical company developing treatments for retinitis pigmentosa, cataracts and other ocular diseases caused by oxidative stress, today announced the closing of a $16.5 million Series B financing led by Foundation Fighting Blindness and its venture arm RD Fund. Additional existing investors also participated in the round. Maxim Merchant Capital, a division of Maxim Group LLC, served as sole placement agent for the financing. Proceeds from the financing will be used to support the advancement of Nacuity’s clinical trials for NPI-001 and NPI-002 through proof of concept, as well as for general operations. NPI-001 tablets are currently being evaluated in a Phase 1/2 clinical trial, known as the SLO-RP Study (ClinicalTrials.gov Identifier: NCT04355689), in patients with retinitis pigmentosa associated with Usher syndrome. Nacuity expects to have interim results from this study in the second quarter of 2023. NPI-002, a proprietary sustained release antioxidant molecule designed to slow cataract progression delivered via intravitreal implant, is being evaluated in a Phase 1/2 clinical trial that is currently enrolling patients undergoing vitrectomy in Australia (ClinicalTrials.gov Identifier: NCT05026632). Nacuity expects to have results from this study in the second quarter of 2023. “We are grateful for the support of Foundation Fighting Blindness, RD Fund, Maxim Merchant Capital and our private investors as we progress our lead programs and seek to establish proof of concept,” said Halden Conner, Chairman, CEO, and Co-Founder of Nacuity Pharmaceuticals. “This funding will help further our mission to develop a breakthrough treatment for retinitis pigmentosa and other serious blinding and chronic diseases caused by oxidative stress.” Nacuity’s lead technology is based on studies from the laboratory of Dr. Peter Campochiaro at the Wilmer Eye Institute involving oxidative stress in the retina. Oxidative stress has been implicated in a variety of ocular conditions and diseases, including retinitis pigmentosa, cataract, age-related macular degeneration, diabetic retinopathy, glaucoma, presbyopia, retinal detachment, and vitreous degeneration. “We are proud to support Dr. Campochiaro’s research and Nacuity’s clinical trials as the company works diligently to develop treatments for ocular diseases,” said Benjamin R. Yerxa, Ph.D., CEO of Foundation Fighting Blindness. “Foundation Fighting Blindness is looking forward to results of the NPI-001 trial as a next step toward addressing an unmet need, as retinitis pigmentosa affects approximately 1.5 million people worldwide and the majority of patients are legally blind by age 40.” About Nacuity PharmaceuticalsNacuity Pharmaceuticals is a clinical-stage leader in innovative treatments for oxidative stress. The company’s powerful, targeted therapies aim to stop oxidative tissue damage, a driver of blinding eye diseases and a broad spectrum of serious chronic conditions. Nacuity has three highly differentiated clinical programs ongoing in retinitis pigmentosa, cataracts and cystinosis with the potential to be first-of-a-kind therapies and gateways to wider applications. Based in Fort Worth, TX, the company has extensive managerial and scientific domain expertise as well as backing from Foundation Fighting Blindness (www.foundationfightingblindness.org) and its venture arm RD Fund (https://www.retinaldegenerationfund.org). For more information, please visit www.nacuity.com. About Foundation Fighting Blindness and RD FundEstablished in 1971, the Foundation Fighting Blindness is the world’s leading private funding source for retinal degenerative disease research. The Foundation has raised more than $750 million toward its mission of preventing, treating, and curing blindness caused by the entire spectrum of retinal degenerative diseases including: retinitis pigmentosa, age-related macular degeneration, Usher syndrome, and Stargardt disease. Visit www.FightingBlindness.org for more information. Media ContactTony Plohoros908-591-2839tplohoros@6degreespr.com

Financial Statement

100 Deals associated with NPI-002

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Indication	Highest Phase	Country/Location	Organization	Date
Cataract	Phase 2	AU	Nacuity Pharmaceuticals, Inc.Startup	27 Jan 2022

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