Zacks Small Cap Analysis – AZTR: Netherton Syndrome Evaluation and ATR-12 Scientific Trial – Nexus Vista

By John Vandermosten, CFA

NYSE:AZTR

Azitra, Inc. (NYSE:AZTR) is a medical stage precision dermatology firm growing candidates for quite a lot of uncommon and severe pores and skin illnesses. It’s growing genetically engineered micro organism for therapeutic use in dermatology leveraging a microbial library of 1,500 distinctive bacterial strains which might be candidates for quite a lot of indications.

Azitra’s lead candidate is ATR-12 for Netherton Syndrome (NS), a uncommon illness. A second candidate is ATR-04 focusing on epidermal development issue receptor inhibitor (EGFRi)-associated rash and a 3rd, ATR-01, ichthyosis vulgaris. All are topically formulated. Preclinical work has proven efficient and protected use of ATR-12 as a probably illness modifying remedy in a position to colonize the pores and skin and exchange a lacking protein. An IND has been cleared for ATR-12 and a Part I examine has began. An IND is predicted for ATR-04 by 12 months finish 2024. Exterior of its pipeline, the corporate has signed a Joint Growth Settlement with Bayer Shopper Care AG for shopper well being candidates.

We now have developed this notice to supply background on Azitra’s main indication in NS which is a uncommon illness with an incidence of 1 in 100,000 to 200,000 births with its options tied to an autosomal recessive gene. The gene implicated within the illness is the serine protease inhibitor Kazal Kind 5 (SPINK5) which produces a protein referred to as lympho-epithelial Kazal-type-related inhibitor (LEKTI). The protein inhibits kallikrein associated proteinase 5 (KLK5), 7 (KLK7) and 14 (KLK14) in addition to elastase 2. When these enzymes persist in excessive sufficient concentrations, they break down proteins necessary for sustaining the pores and skin barrier, cell adhesion within the dermis and the structural integrity of the pores and skin.

Major Indication

Netherton Syndrome

Traits of NS embody scaly pink pores and skin (ichthyosiform erythroderma), bamboo hair (trichorrhexis invaginate) and atopic dermatitis-like options similar to eczema, bronchial asthma, and itch. At beginning, the syndrome can current life-threatening issues on account of extreme dehydration, infections and failure to thrive. The illness is brought on by a profound pores and skin barrier defect on account of uncontrolled proteolytic exercise. The epidermal proteases break down the pores and skin which ends up in decomposition of the highest layer of pores and skin referred to as the stratum corneum. The disrupted pores and skin barrier permits micro organism and allergens to penetrate the dermis probably inflicting infections, systemic unfold and immune response.

NS was first described by M. Comel in 1949 in Dermatologica and later by Earl Netherton, for whom the illness was named. Netherton reported it in 1958 within the Archives of Dermatology as a congenital pores and skin illness characterised by “bamboo hairs.” Within the Nineteen Eighties, analysis discovered that the syndrome resulted from impaired perform of the serine protease inhibitor concerned in pores and skin desquamation and hair formation. Within the Nineties, the genetic foundation of the illness was traced to mutations within the SPINK5 gene, which encodes the LEKTI protease inhibitor protein.

There is no such thing as a remedy or efficient remedy for NS. Nonetheless, topical corticosteroids, topical calcineurin inhibitors, topical retinoids, narrowband ultraviolet B phototherapy, psoralen and ultraviolet irradiation and oral acitretin are remedy choices getting used. Intravenous immunoglobulin and anti-TNF-α are therapeutic choices for extreme sickness. Merchandise in growth embody Sixera’s KLK inhibitor, Quoin’s broad spectrum serine protease inhibitor, Krystal’s gene remedy and Boehringer’s anti-IL-36 inhibitor amongst others.1

Prevalence

Some sources estimate Netherton syndrome to happen in one among each 100,000 or 200,0002 births, suggesting 20 to 40 new instances per 12 months in america. Nonetheless, the frequency of NS could also be underestimated on account of early mortality and misdiagnosis. Prevalence all through the inhabitants is estimated to be between one and 9 people per a million, which equates to 333 to three,000 individuals within the U.S.3 The First Pores and skin Basis, which is an academic help group for uncommon pores and skin situations estimates that there are about 150 reported instances yearly and fewer than 5,000 folks residing with NS in america.

Causes

NS arises from lack of perform mutations from the serine protease inhibitor Kazal-type 5 (SPINK5) gene. This gene seems on chromosome 5 at location 5q32 and encodes the lymphoepithelial Kazal- type-related protease inhibitor (LEKTI) protein. LEKTI is a direct inhibitor of kallikrein-related peptidases (KLKs). This contains KLK5, KLK6, KLK7, KLK13 and KLK14. It is usually a direct inhibitor of cathepsin G and an oblique inhibitor of elastase 2. With out LEKTI, the KLK and different enzymes improve in focus and break down pores and skin buildings and result in irritation. This results in the pores and skin desquamation course of, untimely stratum corneum detachment and pores and skin barrier defect.

Signs

Typical signs of NS embody pink, scaly pores and skin that’s obvious at beginning. Outbreaks of pink, round scaly rashes come up periodically. NS affected person hair is skinny, patchy and the shaft of the hair strand is fragile. Beneath shut examination, the hair strand is additional characterised by the distal portion of the shaft invaginated into the proximal portion in a characteristic termed trichorrhexis invaginata (bamboo hair). Sufferers are prone to immune reactions similar to hay fever, bronchial asthma, itchy pores and skin and eczema. As a result of impaired pores and skin barrier, dehydration and an infection are frequent and could be severe. Infants often develop slowly and don’t acquire weight simply.

Prognosis

NS is recognized in early infancy first indicated by the presence of erythroderma and failure to thrive. Different indicators embody hair abnormalities similar to patchy growth and bamboo hair. The prognosis is confirmed by biopsy, histology, molecular analyses and genetic sequencing that reveals a germline mutation within the SPINK5 gene. Immuno-stained tissue samples will present low ranges of LEKTI expression within the dermis. Different histology will present hyperkeratosis (pores and skin thickening), nucleated keratinocytes and thickened stratum spinosum. NS can also be related to excessive ranges of immunoglobulin E (IgE) which is elevated on account of irritation and the penetration of allergens by way of a sufferers’ porous pores and skin barrier.

Remedy

There aren’t any illness modifying therapies authorized for NS and remedy is oriented in direction of addressing the signs of dry, itchy and scaly pores and skin. Anti-infective measures are additionally taken as a result of threat from injury to the pores and skin barrier. There are all kinds of ameliorative approaches which embody retinoids, prednisolone, cyclosporine, immunoglobulins and biologicals. Emollients and topical therapies are used to deal with the pores and skin situation and antibacterial soaps and ointments are additionally used.

Intravenous immunoglobulin (IVIG) remedy is used for NS sufferers to assist handle recurrent infections and immune dysregulation. IVIG gives a broad spectrum of antibodies that may enhance the immune system and assist battle infections, notably in youthful sufferers.

Dry and broken pores and skin is handled with petroleum-based and ceramide-containing lotions requiring frequent software relying upon severity which might help enhance the integrity of the pores and skin barrier. Non-detergent liquids with a modestly acidic pH to counteract the proteases is really helpful for each day washing. Topical corticosteroids and calcineurin inhibitors might help scale back irritation and pruritus, however should be used sparingly on account of threat of extreme unintended effects. NS sufferers additionally present greater susceptibility to allergens which requires allergen-specific immunotherapy to handle these situations. Additional vulnerabilities for these sufferers embody poor absorption of vitamins which can require a particular food regimen applicable to the situation. Lastly, the extremely seen pores and skin and hair situation many instances leaves sufferers with psychosocial challenges and psychological help could also be mandatory. Different therapies embody:

➢ Calcipotriol (artificial analog of vitamin D3)

➢ Calcineurin inhibitors (tacrolimus and pimecrolimus)

➢ Phototherapy

Experimental Therapies

Gene remedy to right the SPINK5 gene or introduce the useful LEKTI protein.

➢ Inhibition of KLKs

SPINK5 gene substitute

There are case stories that consider biotherapies focusing on a broad vary of interleukin (IL) targets for NS. Beneath we spotlight a number of of those approaches:4

➢ Secukinumab focusing on IL-17A

➢ Spesolimab focusing on IL-36

➢ Ustekinumab focusing on IL-12 & IL-23

➢ Dupilumab focusing on IL-4

➢ Infliximab focusing on TNF-α

Prognosis

Newborns with extreme signs have a poor prognosis as they’re liable to an infection and failure to thrive. The mortality price is estimated to be from 10%5 to twenty%6 for newborns. After the primary 12 months, signs and well being often enhance; nonetheless, youngsters stay underweight and exhibit under common peak.

ATR-12 Preclinical Trials

Azitra has carried out in vivo and ex vivo preclinical work to discover the potential efficacy of ATR-12 as a illness modifying remedy for Netherton syndrome. In vivo research had been carried out to measure the flexibility of ATR-12 to colonize sterile reconstructed human dermis and to check whether or not or not the auxotrophic modification would efficiently stop colonization. Outcomes confirmed that the micro organism did colonize the pores and skin as desired however wouldn’t persist with out D-alanine, confirming that the amino acid should be current for ATR-12 to persist.

In vitro research sampled tape stripped pores and skin from wholesome volunteers spiked with KLK5 to imitate Netherton syndrome. The experiment confirmed that diluted SE351 tradition supernatant dose-dependently inhibited trypsin-like (KLK5) exercise. Trypsin-like exercise within the Netherton syndrome surrogates returned to regular wholesome ranges when the SE351 tradition supernatant was added.

Ex vivo research employed a pig pores and skin mannequin to measure secretion of energetic human recombinant LEKTI (rhLEKTI-D6). A single topical dose of ATR-12 was administered at three dose ranges to supply the consequence. Ex vivo research utilizing wholesome human pores and skin demonstrated {that a} single topical dose of ATR-12 can ship enough rhLEKTI-D6 into the decrease layers of the stratum corneum to successfully inhibit KLK5 at ranges noticed in NS sufferers.

ATR-12 Scientific Trials

Azitra obtained investigational new drug (IND) clearance for its remedy of Netherton Syndrome, ATR-12 in January 2023. The corporate has launched a Part Ib medical trial underneath the identifier NCT06137157 and expects to enroll 12 sufferers with a goal of producing first knowledge to be offered in late 2024. The examine will consider the tolerability, security and pharmacokinetics of topically administered ATR-12. A medical web site at Yale College has been established and different websites are being sought.

The examine will apply ATR-12 to lesions on one facet of a topic’s physique and apply the automobile to the opposite. Software of ATR-12 and the automobile might be carried out twice each day for 2 weeks. Sufferers might be randomized to obtain ATR-12 on both the appropriate or left facet.

The first endpoint is hostile occasions at 84 days in addition to quantifying or qualifying incidence, severity, seriousness and relatedness. Secondary endpoints embody investigators’ and sufferers’ international evaluation of severity, focus of recombinant human lymphoepithelial Kazal-type associated inhibitor (rhLEKTI) within the plasma and on the pores and skin following topical software. Biomarkers might be evaluated together with KLK5, KLK7, IL-36, TARC/CCL17, trypsin-like exercise and chymotrypsin-like exercise.

The continued Part I examine for ATR-12 might evolve right into a proof-of-concept trial that might enroll as much as 20 sufferers together with these within the Part I portion. If supportive, the Part II may result in a bigger pivotal trial acceptable to the FDA for BLA submission and approval.

SUBSCRIBE TO ZACKS SMALL CAP RESEARCH to obtain our articles and stories emailed on to you every morning. Please go to our web site for added data on Zacks SCR. 

DISCLOSURE: Zacks SCR has obtained compensation from the issuer instantly, from an funding supervisor, or from an investor relations consulting agency, engaged by the issuer, for offering analysis protection for a interval of a minimum of one 12 months. Analysis articles, as seen right here, are a part of the service Zacks SCR gives and Zacks SCR receives quarterly funds totaling a most payment of as much as $40,000 yearly for these providers offered to or relating to the issuer. Full Disclaimer HERE.

________________________

1. Mut Quej, J.E., et al. Netherton Syndrome: Unraveling the Molecular Underpinnings of a Uncommon Epidermal Dysfunction. Worldwide Journal of Medical Science and Scientific Analysis Research. November 2023.

2. Mut Quej, J.E., et al. Netherton Syndrome: Unraveling the Molecular Underpinnings of a Uncommon Epidermal Dysfunction. Worldwide Journal of Medical Science and Scientific Analysis Research. November 2023.

3. Netherton syndrome. MedlinePlus. Accessed April 2024.

4. Pontone, M., et al. Organic therapies for pediatric Netherton syndrome. Frontiers in Pediatrics. December 2022.

5. Qasim, W., et al. Genetic Correction of Netherton Syndrome Keratinocyte Stem Cells. Molecular Remedy. Could 2010.

6. Renner, E.D., et al. Comel-Netherton syndrome outlined as main immunodeficiency. Journal of Allergy and Scientific Immunology, 2009.

Add a Comment

Your email address will not be published. Required fields are marked *