TRDA - Entrada Therapeutics: Early Stage But Interesting

2023-08-03 18:39:00 ET

Summary

• Entrada Therapeutics is developing endosomal escape vehicles (EEV) to deliver oligonucleotides for neuromuscular diseases.
• Despite having no clinical data, the company has a market cap of nearly $600mn and received a major deal with Vertex.
• Preclinical tests have shown high intracellular uptake, efficient endosomal escape, and long duration of effect for EEV molecules.

Entrada Therapeutics ( TRDA ) is developing a new class of drugs called endosomal escape vehicles ( EEV ) targeting a few neuromuscular diseases. Despite having no clinical data, the company is valued at a respectable market cap of nearly $500mn.

Here’s the pipeline:

Endosomal escape vehicles enable delivery of oligonucleotides in neuromuscular disorders. A recent article on Cell discusses the technology. After giving some context about antisense oligonucleotides or ASOs and their potential therapeutic benefits, the article goes on to say:

There are 2 major barriers to attaining high efficacy with ASO therapeutic agents. First, the ASOs must reach and be internalized by the target cell. Second, ASOs must escape endosomal/lysosomal compartments to reach the cytosol or nucleus after cellular entry. In the case of DMD, currently approved ASO-based exon-skipping therapies have modest clinical benefits, especially in cardiac tissues, likely because of limited cellular uptake and poor biodistribution. 7 One approach to enhance intracellular delivery of oligonucleotides is use of cell-penetrating peptides (CPPs). 8 Most CPPs deliver their cargo into the cell via endocytosis and are initially localized in the endosome. The CPP-cargo conjugates must escape from endosomal compartments to reach their intracellular targets. This process, known as endosomal escape, poses a significant barrier to delivery of intracellular therapeutic agents. Canonical linear CPPs are generally limited by low efficiencies of cellular uptake and endosomal escape, minimal proteolytic stability, and toxicity. To overcome these shortcomings, we leveraged a family of proprietary cyclic CPPs that form the core of our endosomal escape vehicle ( EEV ) technology. These cyclic CPPs, first described by Qian et al., have shown improved proteolytic stability, enhanced cellular uptake, and endosomal escape when conjugated to peptides, proteins, and other large molecules.

Entrada in a presentation says that 75% of all disease-causing targets are located inside cells. However, these remain inaccessible because of, one, the difficulty of getting the therapy inside the cell, and two, the difficulty in avoiding the cell’s natural clearing system.

Now, lead candidate ENTR-601-44 is an exon 44 skipping oligonucleotide in preclinical stages targeting Duchenne Muscular Dystrophy. In December, the FDA sent a clinical hold notice to the company regarding its IND for its ENTR-601-44 therapy for the potential treatment of DM. As of the latest update, this clinical hold has still not been resolved.

In February, despite the lack of clinical data, preclinical data was robust enough for Vertex to sign a major deal with Entrada for one product candidate.

Vertex paid Entrada $224mn in upfront payment and $26mn in equity investment. The deal also entails $485mn in milestone payment. In this 4-year collaboration, Vertex is responsible for global development and commercialisation and Entrada is eligible to receive payments for ENTR-701 and DM1-related research activities.

In preclinical tests, EEV molecules have shown high intracellular uptake of up to 90%, efficient endosomal escape of up to 50%, and long duration of effect. Various unique moieties ranging from 1 kDa to 600 kDa have been tested, and all have shown these effects.

In a mice model test in DM, robust exon 23 skipping was observed after four monthly IV doses of EEV-PMO-23. Broad dystrophin expression and restoration of muscle integrity was also observed. These three are key metrics of the disease, so this preclinical data shows some proof of the EEV concept. Similar effects were also observed in non-human primates with a single IV dose of ENTR-601-44. These effects were observed in both skeletal and cardiac muscles, and historically, other molecules have not had as strong an effect in the latter. The duration of effect was at least 12 weeks.

This asset will conduct a first-in-human phase 1 trial in healthy volunteers, followed by a phase 2 safety trial with a MAD (Multiple Ascending Dose) cohort and then an efficacy trial in Exon 44 Skipping amenable Patients. In this efficacy trial, Change in dystrophin level (skeletal muscle) will be the primary outcome. A second, next generation asset called ENTR-601-45 is also in preclinical testing.

The third indication is myotonic dystrophy type 1, or DM1, where ENTR-701 is partnered with Vertex. Here, too, there is robust preclinical data in vitro and in vivo data set demonstrating:

? Highly specific reduction of pathogenic CUG-repeat containing mRNA

? Reduction of nuclear foci

? Correction of Mbnl1 and downstream aberrant splicing

? Correction of global transcriptome

• Single dose of ENTR-701 demonstrated durable splicing correction and amelioration of myotonia for at least 8 weeks post-dose in HSA-LR model [quoted from here ]

Financials

TRDA has a market cap of $494mn and a cash balance of $412mn. R&D expenses were $23.1 million for the first quarter of 2023, while G&A expenses were $7.9 million. That gives them a cash runway well into 2025.

Most of the stock is held by institutions, hedge funds and PE/VC firms, with a small 10% portion in retail hands. Key holders are MPM Bioventures, 5am Ventures, BlackRock and so on. Insiders regularly sell stock, and have no recent purchases.

Risks

TRDA has no clinical data so that is a standard risk for these small companies with early stage assets. Average trading volume seems to be inordinately low, and I am not too happy with the insider sells. The cash balance is strong, however that is perhaps the only thing going for this company, which came as a result of the Vertex deal.

Bottomline

TRDA is certainly doing novel and interesting science, and the Vertex deal is its primary value driver. Valuation is a bit high for a company with no clinical data, so I am just going to sit here and watch this name; but I am certainly interested enough to add it to a watchlist somewhere.

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