In this interview, Caitlin Dolegowski speaks with Cuong Do, Founder and Chairman of M6P Therapeutics, about the company’s groundbreaking lysosomal targeting platform, its applications in rare disease and oncology, and the experience of pitching at RESI Boston.
Caitlin Dolegowski (CD): M6P Therapeutics has achieved what was long thought impossible, delivering proteins to lysosomes. Can you explain the significance of this breakthrough?
Cuong Do (DO): An enzyme called GlcNac-1-phosphotransferase (PTase) is responsible for adding mannose 6-phosphate to the surface of lysosomal enzymes. People have tried and failed for decades to increase the expression of M6P, and everybody gave up. Our co-founder Stuart Kornfeld never gave up. He and his post-doc were able to engineer a variant of PTase that turned out to be 20X more effective than PTase itself in adding M6P to lysosomal enzymes. We built upon this breakthrough to create a platform that is able to create enzyme replacement therapies that have very high M6P content. Furthermore, our gene therapies are the only ones that result in M6P-containing enzymes being produced by the transduced cells.
We expanded upon the innovation and created chimeric antibodies that contain M6P as well. This allows these antibodies (after they bind to the targeted antigens) to be brought to lysosomes in virtually all cells in our bodies for degradation. This is a significant advantage over traditional antibodies relying on Fc clearance by only select immune cells.
CD: You have multiple rare pediatric drug designations and two programs nearing the clinic. What are the most exciting upcoming milestones for your pipeline?
DO: We are preparing to start an Investigator Initiated Trial in Australia for our M021 ERT for Pompe Disease in hopes of obtaining early human data demonstrating M021’s superiority over the standard of care.
CD: How does your lysosomal targeting platform extend beyond rare diseases, particularly in oncology with your chimeric PD-L1 and PD-1 antibodies?
DO: We figured out a way to add M6P to any protein, including antibodies. Our chimeric antibodies can be cleared by virtually all cells in the body since virtually all cells have receptors for M6P. This is especially effective for clearing surface antigens from cell surfaces. Our chimeric PD-L1 antibody is able to clear virtually all PD-L1 from the surface of tumor cells and thus activate T-cells and drive T-cell mediated tumor killing. Our chimeric version of Keytruda is able to remove PD-1 from the surface of T-cells and has shown to be more effective in inhibiting tumor growth in vivo than Keytruda itself.
CD: Can you walk us through your IP position and how it supports your growth strategy?
DO: We have invested heavily in IP that has created a portfolio of 9 patent families, 9 issued patents, and ~20 still in prosecution.
CD: Where are you in your fundraising journey, and what types of investors or partners are you looking to engage with?
DO: We have raised ~$40 million in our Seed and A rounds, which we invested to get our programs to where they are today. We are trying to raise a $5 million bridge now in anticipation of a $50+ million Series B next year. In addition to investors, we want to engage with potential partners who might be interested in our molecules.
CD: How did participating in the Innovator’s Pitch Challenge at RESI Boston help advance your business development or investor connections?
DO: We met a few companies who might be interested in partnering on some of our molecules. We’re continuing the conversations.
IPC Applications are now open for the next Innovator’s Pitch Challenge at RESI London 2025 and RESI JPM 2026, with spots filled on a rolling basis.
In healthy epithelial lung cells (top), the CFTR chloride channel translocates from the endoplasmic reticulum to the cell surface, where it participates in the production of mucus to help protect against pathogens. In cells carrying mutant ΔF508 CFTR (bottom), misfolded CFTR cannot reach the membrane and is degraded, resulting in abnormal mucus, microbial infection and lung inflammation. Trikafta restores CFTR function through a dual mechanism: the small molecules elexacaftor and tezacaftor help CFTR fold correctly, whereas ivacaftor improves its gating properties. Source: Lasker Foundation, Michael Welsh
But what about the other 10% of patients who don’t respond to Trikafta, many of whom carry so-called Class I alleles that cannot be rescued by this drug combination? Although a lot of progress has been made, several obstacles lie in the path of effective medicines for people who produce no, or negligible amounts of, CFTR protein.
Class I CFTR alleles. The first three account for ~70% of all patients who don’t respond to Trikafta. Ultra-rare alleles include Y122X, Q1412X, Q493X, and many others.
It should come as no surprise that the main therapeutic strategies for Class I alleles aim to put missing CFTR back into lung cells. Among these strategies, mRNA delivery is the most advanced. VX-522, an RNA therapeutic program from Vertex and Moderna currently in Phase 2, is an inhaled drug that aims to deliver full-length CFTR mRNA to the lung using lipid nanoparticles (LNPs). Two related, competing mRNA delivery programs are at a similar stage of clinical development: ARCT-032 by Arcturus Therapeutics using their LUNAR LNPs; and RCT-2100 by ReCode Therapeutics, which uses a lung-targeted SORT (selective organ-targeting) LNP.
A key feature of RNA-based therapies is that any therapeutic benefit would likely be transient, requiring periodic administration of the medicine to achieve sustained effects. Gene therapy and gene editing have the potential to be a curative, “one and done” procedure. Thus far, however, only gene therapy programs have advanced far enough to be in human testing.
Of these, 4D Molecular Therapeutics’ 4D-710 and Spirovants’ SP-101 use different AAV subtypes designed to optimize delivery to airway basal epithelial cells of a CFTR minigene that lacks the regulatory domain. Both projects are in Phase 1/2 of clinical development.
As the large size (6.2 kb) of the CFTR transgene exceeds the packaging capacity of AAV vectors, Krystal Biotech and Boehringer Ingelheim have launched Phase 1/2 clinical programs using viral vectors with a greater payload capacity: KB407 is a re-dosable herpes simplex virus (HSV)-1 vector with a cargo capacity >30 kb that delivers two copies of the CFTR gene to lung epithelial cells using a nebulizer. BI 3720931 is Boehringer’s inhaled lentiviral vector pseudotyped with Sendai virus F and HN envelope proteins (rSIV.F/HN) engineered to deliver a single copy of the CFTR gene. Further behind in the pipeline, Carbon Biosciences’ CGT-001 is a nebulized non-AAV parvovirus-based vector capable of delivering full-length CFTR gene. Thus far, it has been tested in nonhuman primates and in human bronchial cells in culture.
Companies are also pursuing oligonucleotide therapies to modify disease-causing mutations at the RNA level. SPL84 is an inhaled antisense oligonucleotide (ASO) addressing a splicing defect (cryptic exon; class V mutation) in the ~1,600 CF patients who carry the 3849+10kb C→T mutation. SpliSense has advanced the ASO into phase 2 testing, but it also has in preclinical development an exon-skipping ASO against the class I mutant W1282X. By masking the mutant premature termination codon in exon 23, SP23 induces the splicing machinery to skip exon 23 and stitch together exon 22 and exon 24, forming a partially functional CFTRΔex23 protein.
Gene editing is also beginning to appear on the therapeutic horizon. In July, Prime Medicine announced it had received $25 million in funding to advance prime editors, with a lead program focusing on G542X. Last year, Intellia Therapeutics and ReCode Therapeutics also announced a strategic collaboration to combine the CRISPR pioneer’s Cas9 DNA ‘writing’/insertion technology with Recode’s SORT LNPs. Academic groups have now shown that G542X correction is possible using inhaled LNP- or virus–like particle-delivered adenine base editors. And for RNA editing, at this year’s American Society of Gene & Cell Therapy Wave Life Sciences reported their oligo-based ADAR editors could achieve 21% correction (EC50 = 376nM) of CFTR W1282X nonsense mutations. This is likely a sliver of all the therapeutic activity underway; other programs are targeting mucus itself, which is much thicker than in healthy individuals. If we missed any drug-discovery projects in this space, please let us know!
Despite the plethora of programs, developing genetic therapies against cystic fibrosis patients with class I CFTR mutations faces some stiff translational challenges. For starters, targeted delivery of drugs to lung tissue remains a work in progress. The optimal cell type to be targeted by gene therapy/editing remains an open question, especially as the community continues to identify new cell types in the lung; is it enough to target the more prevalent epithelial cells (alveolar type 2 cells), or will it be necessary to target rarer stem cells (alveolar type 1 cells) to see a long-lasting therapeutic effect? What about the contribution of genetic modifiers and other ion channels known to affect airway dysfunction in CF airway epithelial cells? Also, how to figure out the pharmacokinetics and pharmacodynamics of these disease-modifying therapies in lungs and measure delivery in patients? Specifically, establishing protein expression levels after inhaling a DNA- or RNA-based product would likely require a bronchial biopsy, which is impractical particularly in this fragile patient population.
Last, not unlike most pathologies, new animal and in vitro models with predictive value need to be developed. The use of human bronchial epithelium culture is not as predictive of the efficacy of genetic therapies as it has been for small molecules. At present, the ferret is the gold standard disease model. But it is a time-consuming, challenging animal model, which is only supported by a few groups. All of which slows the path to clinical translation.
Six years after the approval of Trikafta, patient foundations like the CF Foundation, Emily’s Entourage, and the Cystic Fibrosis Trust are devoting increasing resources to translational research to push forward treatments for patients with CFTR Class I mutations who do not respond to potentiators and correctors. The Lasker recognition of the science that led to Trikafta will surely inspire researchers working on those projects to overcome the remaining hurdles.
Given the ‘pipeline in a product’ potential of drugs targeting this pathway, big pharma has shown considerable interest, with Genentech/Roche snapping up Jecure Therapeutics for an undisclosed amount, and both Novartis and Roche splashing out hundreds of millions of dollars for pioneer companies IFM Tre and Inflazome, respectively. In 2022, Novo Nordisk licensed Ventus Therapeutics’ peripherally restricted NLRP3 inhibitor in a deal worth up to $703 million, lending weight to pharmacological inhibition of NLRP3 as a complement to glucagon-like peptide-1 agonists (GLP-1s) in cardiometabolic disease. And with several programs now entering the clinic, investment activity in the area has continued, with Enveda’s announcement last week of a $150 million series D round to fund a phase 1 trial for ENV-6946, an orally delivered gut-restricted small molecule targeting the NLRP3/tumor necrosis factor-like cytokine 1A (TL1A) pathway in inflammatory bowel disease.
While drugmakers have traditionally targeted downstream extracellular mediators of the inflammasome pathway (canakinumab or rilonacept against IL-1β or anakinra to block IL-1 receptor), NLRP3 represents a key upstream intracellular signaling hub, activated by innate immune pattern-recognition receptor (Toll like receptors 2/4) signaling via MyD88 and NFkappaB. Once activated, NLRP3 monomers unfold and associate into a massive 1.2 MDa oligomeric supracomplex with three other proteins: ASC, NEK7 and caspase 1. The mature complex then cleaves and activates proinflammatory cytokines interleukin (IL)-1β and IL-18 and primes gasdermin D to instigate cell pore formation and cell death via pyroptosis.
Mechanisms of NLRP3 inflammasome activation and inhibition. In priming, lipopolysaccharide (LPS) or IL-1β activates NF-κB, and induces the expression of proinflammatory cytokines and NLRP3. Activation mediated by ATP, nigericin, and particulate matter causes ion fluxes, mitochondrial dysfunction, reactive oxygen species (ROS) generation, and DNA damage. NLRP3 binds to oxidized mitochondrial DNA (ox-mtDNA) released through the mitochondrial permeability transition pore (mPTP), leading to inflammasome assembly. Inhibition mechanisms are shown for drugs that prevent NLRP3 activation or inflammasome formation (red boxes). CARD, caspase activation and recruitment domain; LRR, leucine-rich repeat domain; MCU, mitochondrial calcium uniporter; MSU, monosodium urate; NACHT, nucleotide-binding and oligomerization domain. Source: TIPS.
But it has been less than straightforward to identify compounds with sufficient potency to target this pivotal innate immune signaling pathway without debilitating off-target effects. Indeed, several of the first wave of compounds entering the clinic have been dogged by serious toxicities, including liver problems (MCC950 and GDC-2394) and hypoglycemia (glyburide). Now, a team led by Rebecca Coll (Queen’s University Belfast) and Kevin Wilhelmsen (of BioAge Labs) reports in TheJournal of Experimental Medicine the discovery and characterization of BAL-0028, a novel and selective small-molecule inhibitor of the human NLRP3 inflammasome.
Unlike previously studied inhibitors, BAL-0028 acts through a unique mechanism of action; it binds NLRP3’s NACHT domain at a site distinct from other inhibitors that act by directly interfering with ATPase activity. BAL-0028 has nanomolar potency against human and primate NLRP3 but, remarkably, has weak activity against the mouse target, highlighting species-specific differences.
As BAL-0028 showed very high plasma protein binding in mice, limiting its use in vivo, the team developed a derivative, BAL-0598, with improved pharmacokinetic properties. In a humanized NLRP3 mouse peritonitis model, BAL-0598 effectively reduced IL-1β and IL-6 production, confirming its anti-inflammatory activity in vivo. Importantly, both BAL-0028 and BAL-0598 inhibited hyperactive NLRP3 mutants associated with autoinflammatory diseases, in some cases more effectively than Vertex’s VX-765, a caspase 1 inhibitor, and compounds like MCC950, one of the best characterized NLRP3 inhibitors available.
The novel mechanism of action of BAL-0028 and BAL-0598 would suggest their off-target effects may be different from those associated with other NLRP3 inhibitors blocking ATP hydrolysis. The concern that such compounds might also bind other members of the NOD/NLR family (e.g., NLRP1, NLRP4 or AIM2 inflammasomes) is mitigated by most published studies indicating that NLRP3’s unique fold around the ATP binding site makes small-molecule binders selective for this family member alone. The most likely explanation from trials published to date is that the observed toxicities are associated with small molecule chemotype rather than any NLRP3 class-specific problem. In any case, the findings from this study support further investigation of these compounds as candidates for treating inflammatory and age-related diseases where NLRP3 plays a role. The race to develop a safe and effective NLRP3 inhibitor is on, with big pharma billion-dollar bets and startups jostling to create best-in-class assets across cancer, cardiovascular, neurodegenerative and metabolic disease.
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A venture capital firm founded in 2005 has multiple offices throughout Asia, New York, and San Diego. The firm has closed its fifth fund in 2017 and is currently raising a sixth fund, which the firm is targeting to be the largest fund to date. The firm continues to actively seek investment opportunities across a […]
Cuong Do
Caitlin Dolegowski
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