Delving into the Latest Updates on ASM-8 with Synapse

Overview

Basic Info

Drug Type

ASO

Synonyms

+ [1]

Target

CCR3 x IL-3R x IL-3Rβ

Mechanism

CCR3 modulators(C-C chemokine receptor type 3 modulators), IL-3R agonists(Interleukin 3 receptor agonists), IL-3Rβ modulators(colony stimulating factor 2 receptor subunit beta modulators)

Therapeutic Areas

Immune System DiseasesRespiratory Diseases

Active Indication-

Inactive Indication

Allergic asthmaAsthma

Originator Organization

Syntara Ltd.

Active Organization-

Inactive Organization

Syntara Ltd.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

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Aeroallergens are the most common triggers for the development of asthma. Recent birth cohort studies have identified viral infections occurring against a background of aeroallergen sensitization as a potent risk factor for initiation of asthma. Viral infection enhances immunopathogenic potential of pre-existing inhalant allergy via modulating airway mucosal dendritic cells. By using an allergen inhalation challenge clinical model, studies have shown that the late asthma response (LAR) is associated with more pronounced allergen-induced airway inflammation and airway hyperresponsiveness. The degree of airway eosinophilia, regulated by bone marrow progenitor cells and interleukin-5 level, correlates with the magnitude of the LAR and the increase in hyperresponsiveness. Both myeloid and plasmacytoid dendritic cell subsets have been involved in the pathogenesis of allergen-induced LAR. Myeloid dendritic cells are responsible for the allergen presentation and induction of inflammation and plasmacytoid dendritic cells play a role in the resolution of allergen-induced inflammation. A variety of potential new classes of asthma medication has also been evaluated with the allergen inhalation challenge in mild asthmatic subjects. Examples are TPI ASM8, an inhaled anti-sense oligonucleotide drug product, which attenuated both early and LARs via inhibition of the target gene mRNA of chemokine receptor 3, and the common β chain of interleukin-3, interleukin-5 and granulocyte-macrophage colony-stimulating factor receptor. Anti-human antibody interleukin-13 (IM-638) significantly attenuated both early and late allergen-induced asthma response. Pitrakinra, which targets both interleukin-4 and interleukin-13, substantially diminishes allergen-induced airway responses. Allergen-induced airway responses are a valuable way to evaluate the activity of possible new therapies in asthmatic airways.

01 Dec 2011·Clinical & Experimental AllergyQ2 · MEDICINE

TPI ASM8 reduces eosinophil progenitors in sputum after allergen challenge

Q2 · MEDICINE

Article

Author: R. M. Watson ; H. Imaoka ; G. M. Gauvreau ; H. Campbell ; R. Sehmi ; M. Mistry ; I. Babirad

SummaryBackground TPI ASM8 contains two modified phosphorothioate antisense oligonucleotides (AON), one targeting the common beta chain (βc) of the IL‐3/IL‐5/GM‐CSF receptors and the other targeting the chemokine receptor CCR3. Inhalation of TPI ASM8 significantly improves lung function and sputum eosinophilia after allergen inhalation challenge in asthmatics.Objective This study assessed whether TPI ASM8 reduces airway levels of haemopoietic progenitor cells.Methods This open‐label study was conducted in 14 stable, allergic mild asthmatic subjects with early‐ and late‐phase allergen‐induced bronchoconstriction. Subjects underwent allergen challenges after 4‐day treatment with placebo, 4 mg b.i.d. and 8 mg o.d. of TPI ASM8. Sputum was induced before, 7 and 24 h after allergen challenges for progenitor measurements. Treatments were separated by 2–3 weeks.Results TPI ASM8 reduced allergen‐induced sputum eosinophils, and the early and late asthmatic responses (P<0.05). TPI ASM8 also reduced the number of CD34+CCR3+ cells (P=0.004) and CD34+IL‐5Rα+ cells (P=0.016), and the proportion of CD34+ cells expressing IL‐5Rα (P=0.036).Conclusions and Clinical Relevance TPI ASM8 was safe and well tolerated. The results of this study demonstrate blocking of CCR3 and βc expression by TPI ASM8 significantly inhibits the accumulation of eosinophils and eosinophil progenitors in the airways after allergen challenge. Inhibition of airway progenitor cell accumulation presents a novel therapeutic target.Cite this as: H. Imaoka, H. Campbell, I. Babirad, R. M. Watson, M. Mistry, R. Sehmi and G. M. Gauvreau, Clinical & Experimental Allergy, 2011 (41) 1740–1746.

01 Sep 2011·AllergyQ1 · MEDICINE

Dose response of TPI ASM8 in allergic asthmatics

Q1 · MEDICINE

Article

Author: R. Watson ; R. Séguin ; P. M. Renzi ; G. M. Gauvreau ; H. Campbell ; J. Gauthier ; K. Killian ; R. Pageau ; M. Mistry ; D. Carballo ; M. Parry-Billings ; H. D’Anjou

BACKGROUNDTPI ASM8 contains two modified antisense oligonucleotides (AON) targeting the beta subunit (β(c) ) of the IL-3, IL-5, GM-CSF receptors and the chemokine receptor CCR3. A previous study suggested that TPI ASM8 had broader effects than just inhibition of eosinophils in asthmatics.OBJECTIVEWe assessed whether TPI ASM8 caused a dose-dependent attenuation in the inflammatory and physiological changes after inhaled allergen challenge (AIC).METHODSThis single-center, open-label, stepwise-ascending dose study was conducted in fourteen stable, mild allergic asthmatics. Following placebo AIC, subjects underwent AIC after 4 days treatment with 1, 2, and 4 mg BID and finally 8 mg once daily (OD) of TPI ASM8, inhaled via the I-Neb™ nebuliser. Treatments were separated by 2-3-week washout periods.RESULTSTPI ASM8 was safe and well tolerated at all doses. TPI ASM8 8 mg OD reduced eosinophils in sputum after AIC (by 60.9% at 7 h and 68.4% at 24 h post-AIC, P=0.016 and P=0.007, respectively). Additionally, TPI ASM8 8 mg OD significantly attenuated the early and late airway responses as shown by the reduction in the area under the curve by 45% (P=0.016) and 59%, (P=0.0015), respectively, the increase in eosinophil cationic protein (ECP) by up to 57% (P=0.021), and airway responsiveness to methacholine by more than 1 doubling dose (P=0.012). A dose-response relationship was noted, and efficacy was maintained with once per day administration.CONCLUSIONSTPI ASM8 attenuated a broad range of inflammatory and physiological changes after AIC, suggesting that CCR3, IL-3, and GM-CSF also are important targets for the management of asthma.

100 Deals associated with ASM-8

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 2	-	Syntara Ltd.	01 Nov 2011
Allergic asthma	Phase 2	GB	Syntara Ltd.	01 Jan 2008

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


AAAAI2007	Not Applicable	Mild asthma CCR3 \| β	-	ASM8	tjlzsifgil(sgfxqvdecz) = tdvjtkojel mzpxamtihg (zixjfjhtkm, 5.1)	-	01 Jan 2007
				Placebo	tjlzsifgil(sgfxqvdecz) = azyuoitesd mzpxamtihg (zixjfjhtkm, 4.0)