Metagenomi, Inc. MGX  $15.00-$17.00 6.25 million shares Underwriters:  J.P. Morgan, Jefferies, TD Cowen, Wells Fargo Co-Managers: Chardan  Proposed trade date of 2/9They are  a precision genetic medicines company committed to developing curative therapeutics for patients using their proprietary, comprehensive metagenomics-derived genome editing toolbox.

Abbreviated version due to the sector this company operates in

Metagenomi, Inc   MGX 

• 6,250,000 shares to be offered between $15.00 and $17.00 per share
• Underwriters:  J.P. Morgan, Jefferies, TD Cowen, Wells Fargo Co-Managers: Chardan
• Proposed trade date of 2/9
• Rating = 3

Click here to view the prospectus.

https://www.sec.gov/Archives/edgar/data/1785279/000119312524023377/d425213ds1a.htm

They are a precision genetic medicines company committed to developing curative therapeutics for patients using their proprietary, comprehensive metagenomics-derived genome editing toolbox. Genetic diseases are caused by a diverse set of mutations that have been largely inaccessible by genome engineering approaches to date. Genetic mutations are seen in a variety of forms, including deletions, insertions, single-base-pair changes and sequence repeats, and are found throughout the genome and across a variety of different cell types, tissues, and organ systems. Additionally, many diseases lack a genetic origin but have the potential to be effectively and permanently addressed through genome editing. They are harnessing the power of metagenomics, the study of genetic material recovered from the natural environment, to unlock four billion years of microbial evolution to discover and develop a suite of novel editing tools capable of correcting any type of genetic mutation found anywhere in the genome. Their comprehensive genome editing toolbox includes programmable nucleases, base editors, and RNA and DNA-mediated integration systems (including prime editing systems and clustered regularly interspaced short palindromic repeat (“CRISPR”)-associated transposases (“CASTs”)). They believe their diverse and modular toolbox positions them to access the entire genome and select the optimal tool to unlock the full potential of genome editing for patients

They have developed an expansive and modular toolbox of next-generation genome editing systems that will allow them to interact with the human genome in a site-specific manner, where each tool can be matched to specific disease targets. Their programmable nucleases are the backbone of their broad set of genome editing tools. These novel nucleases including type II and type V Cas nucleases, of which some are ultra-small systems that they call SMall Arginine-Rich sysTems (“SMART”) nucleases, have unique targeting abilities and can be programmed by guide RNAs (“gRNA”) to target and cut at specific locations in any genome sequence. Targeted genomic breaks trigger DNA repair pathways that can be used for genome editing, for example, to integrate a gene at a target site (knock-in) or for gene inactivation (knockdown). Their toolbox contains thousands of CRISPR nucleases with diverse abilities to target different parts of the genome, allowing them to select the ideal nuclease for targeting any given gene in a site-specific manner and potentially overcome a major limitation of first-generation CRISPR/Cas9 systems.

They also modify their nucleases to either nick the genome (i.e., a nickase that cuts one strand of the DNA) or to simply bind to target sites (i.e., a nuclease dead variant). These capabilities (e.g., searching, cutting, nicking, and binding) can be leveraged as a chassis by adding on additional effector enzymes to create base editors for single nucleotide changes and RNA-mediated integration systems (“RIGS”) for both small and large genomic integrations using “Little RIGS” for prime editing and “Big RIGS” for large integrations. Using modular engineering, they match nickases with deaminases and RTs for base editing and RIGS, respectively. Furthermore, nucleases can be engineered by swapping the search modules of the enzyme to expand the targetability of the chassis, which is critical for site-specific genomic modifications. Given the measured targeting density of their toolbox, they believe that essentially any codon in the human genome could be addressed with their gene editing systems.

Hemophilia A—novel, durable, knock-in approach for expression of Factor VIII Hemophilia A is the most common X-linked inherited bleeding disorder and is caused by mutations in the Factor VIII (“FVIII”) gene leading to loss of functional FVIII protein that impacts the body’s ability to form normal clots in response to injury. FVIII is normally produced in the liver within sinusoidal endothelial cells and is then secreted into the bloodstream where it acts as a cofactor for the catalytic activation of Factor X in the clotting pathway. In an ongoing NHP study they demonstrated integration of a surrogate cynomolgus-FVIII cassette (used to avoid immune response that would occur with a foreign human FVIII protein) and observed therapeutically relevant levels of the cyno-FVIII protein encoded by the integrated cassette in all 3 treated animals that has extended for 4.5 months following a single dose of the AAV-cFVIII virus followed five weeks later by a liver trophic LNP encapsulating the mRNA encoding MG29-1 and guide 2 at a dose of 1mg/kg body weight. They intend to continue measuring FVIII levels in these monkeys up to the 12 month time point to generate a robust data set on durability.

Primary Hyperoxaluria, Type 1 (“PH1”)—a durable knockdown of HAO1 for substrate reduction therapy PH1 is a rare autosomal recessive metabolic disease arising from loss of function mutations in the alanine-glyoxylate aminotransferase (“AGXT”) gene that encodes alanine glyoxylate aminotransferase. This enzyme is found in peroxisomes of the liver where it catalyzes the conversion of glyoxylate to glycine and pyruvate. Lack of functional AGXT leads to an accumulation of glyoxylate substrate, which is then converted to oxalate and excreted in the kidney. The goal of their genome editing approach is to durably knock down HAO1 resulting in stable and permanent reduction of oxalate levels to effect a lifelong benefit. They have performed nuclease and guide screening to select an optimal nuclease and gRNA combination. Along with their partner ModernaTX, Inc. (“Moderna”), they have achieved preclinical proof-of-concept in an AGXT knock-out mouse which is an accepted disease model of PH1. They are in the final stages of confirming the candidate to take into NHP studies and expect to have NHP data in 2024 to support final development candidate selection.

Transthyretin Amyloidosis—a single treatment to knockdown TTR gene expression Transthyretin amyloidosis is a disease of misfolded and aggregated transthyretin (“TTR”) protein that can deposit in tissues causing organ dysfunction, primarily in the heart and/or peripheral nerves. The TTR protein is normally produced in the liver and circulates in a homotetramer (four copies of the same TTR protein bound together) where it serves as a carrier protein for vitamin A and thyroxine. Certain mutations have been identified that can cause TTR homotetramers to fall apart, misfold, and aggregate into insoluble fibrils that deposit in cardiac tissue and peripheral nerves. However, more commonly, the normal aging process is associated with an increased propensity for TTR misfolding and aggregation in the heart without any known genetic sequence variation. These distinctions lead to TTR amyloidosis being characterized as either hereditary transthyretin amyloidosis (“ATTRv”) caused by mutations in TTR, or wild-type ATTR amyloidosis (“ATTRwt”). It is estimated that globally there are approximately 50,000 patients with ATTRv and between 300,000 and 500,000 patients with ATTRwt.

Further areas of therapeutic activity and interest Building on their experience delivering their nucleases to the liver via LNP systems, they are extending that experience delivering novel RIGS to the liver to potentially correct ATP7B mutations in Wilson’s disease and PiZ mutations in alpha-1-antitrypsin deficiency (“A1AT deficiency”). They are also exploring addressing A1AT deficiency via a base editor approach given the predominant mutation involves a single base pair. Both of these liver diseases have well-defined biology, readily available translational biomarkers for early proof-of-concept, established development pathways based on prior drug approvals, and important unmet medical needs.

Based on their current plans, they believe their existing cash and cash equivalents and available-for-sale marketable securities, together with the net proceeds from this offering, will be sufficient to fund their operations and capital expenditure requirements into 2027.

They will need substantial additional funding in addition to the net proceeds they receive from this offering. They are very early in their development efforts, and they have not yet initiated IND-enabling studies or clinical development of any product candidate. As a result, they expect it will be many years before they commercialize any product candidate, if ever. The genome editing field is relatively new and is evolving rapidly. They are focusing their research and development efforts on genome editing using programmable nucleases, base editing, and RNA and DNA-mediated integration systems (including prime editors and Cas transposases), but other genome editing technologies may be discovered that provide significant advantages over such technologies, which could materially harm their business. Positive results from early preclinical studies of any product candidates they may develop are not necessarily predictive of the results of later preclinical studies and any future clinical trials of such product candidates. Rating = 3