Nublar Consulting

Viking Therapeutics, Inc. is ripping this morning off VK2735 oral Phase I data showing absence of GI side effects, a major differentiator vs. OZEMPIC, MOUNJARO and other branded versions of the sub-Q GLP-1/(GIP) drugs from Eli Lilly and Company and Novo Nordisk. The oral formulation of the GLP-1/GIP agonist showed mean 3.3% placebo-adjusted weight reduction over 4 weeks at the highest dose ? the company will move it into Phase II this year. Phase II topline data for the sub-Q formulation at Feb end showed 13.1% p.a. weight reduction over 13 weeks, which took the stock from the 30s to the 80-100 range. It’s since cooled a bit in anticipation of the potential for initial sub-Q followed by oral maintenance, aided by this morning’s PR. BioAge Labs and Lilly are combining azelaprag (apelin APJ pathway agonist) and tirzepatide to offset the latter’s muscle loss effects. This is where Longevity Biotech meets high-value Pharma. On the neuro-muscular topic, we await FDA’s June decision on full approval for Sarepta Therapeutics’ Elevidys to treat DMD. Other AAV players: REGENXBIO Inc. expects RGX-202 Phase I/II data by midyear to inform pivotal trial start by EOY. Solid Biosciences SGT-003 FPD delayed to Q2. Pfizer’s pivotal fordadistrogene movaparvovec data is forthcoming, but a Phase Ib study suggests efficacy mainly seen in 6-7 year olds. Current DMD gene therapy through its specific objective to replace dystrophin, addresses the root cause but may not leverage the broader pathology. Dystrophin serves to “shock absorb” the contraction-mediated stresses occurring at the sarcolemma and the ECM. Without sufficient dystrophin, progressive muscle protein and fiber degradation occurs and fails to regenerate, impairing muscle function. Key to this are vascular and metabolic dynamics associated with neuronal nitric oxide synthase (nNOS), a signaling molecule whose reduction hyperactivates HDAC activity, driving downstream disease processes including regenerative failure and ischemia. The HDAC inhibitor givinostat (DUVYZAT, developed by Italfarmaco) was approved last Thursday for patients ≥6 years old. The current SOC for DMD is steroids; DUVYZAT is the first departure from this broadly acting class and was approved based on meeting the primary endpoint in the Phase III EPIDYS trial, i.e., change in baseline for the 4-stair climb test at 18 months vs. placebo (p=0.037). This was accompanied by 40% less decline on the NSAA vs. placebo. Mutation agnostic drugs like givinostat could be used in combination with micro-dystrophin gene therapies, exon-skipping drugs, and other approaches on the horizon. Edgewise Therapeutics’ EDG-5506 is an oral allosteric inhibitor of myosin preventing muscle injury due to mechanical contraction stress. Edgewise will release 24-mo Becker Muscular Dystrophy (BMD) data in Q2 along with 3-mo 4-9 year old DMD data, pivotal BMD trial to start in 2H. ? Next: myostatin as a renewed hot target. #obesity #GLP-1 #DMD

This morning, CytomX Therapeutics announced INDs for Phase I studies for their Probody ADC, CX-2051 and their Probody cytokine, CX-801. The Probody platform at the heart of the company’s value exploits TME biology: ? concentration of proteases. By engineering antibody-target binding regions cloaked by ‘masks’ attached by a protease cleavable linker, target engagement and payload delivery is designed to occur selectively in the TME. CX-2051 is an ADC targeting EpCAM, a transmembrane glycoprotein implicated in breakdown of cell adhesion contacts leading to “activating invasion and metastasis” – one of the 8 Hallmarks of Cancer (Hanahan 2022 model). EpCAM inhibits cadherin and catenin regulation of tissue morphogenesis and homeostasis, promoting tumor invasion and #cancer progression, and is highly expressed (98% in CRC). ‘2051 has a Topo-I linker-payload and DAR(8) ? Probody could deliver the balance of stability, efficacy, and on-target safety/tolerability valued in today’s #adc market. CX-801 leverages IFNα-2b’s innate response kickstarted by ISGs (see Mon post). The conditionally active design coupled with pro-inflammatory cytokine activation (IL-12, IL-15, IL-2) confers direct cytotoxicity and indirect tumor killing through NK activation and MHC I signal induction. Mono and combo (anti-PD-L1) arms could demonstrate additive efficacy and/or signal in tumors insensitive to anti-PD-(L)1. Past hiccups have cast doubt on the Probody approach. In mid-2022, their CD166-targeting Probody ADC, praluzatamab ravtansine did not perform up to expectations in a Phase II HR+/HER- breast cancer trial. AbbVie was partnered on an anti-CD71 ADC, which CytomX (re)acquired fully last year but discontinued in November. Bristol Myers Squibb is a notable partner via the Probody afucosylated version of YERVOY (BMS-986288). Moderna and CytomX entered a co-dev pact ~12 months ago to leverage mRNA and conditional activation, and other partnerships persist with Amgen, Astellas Pharma (TCE bispecific), and Regeneron (‘Veloci-Bi’ + Probody bispecific). ??LEAD ASSETS CX-904 (EGFR x CD3 T cell engager; w Amgen): data from Phase Ia dose escalation trial delayed from 1H to 2H 2024. '288 Phase II data expected this year in NSCLC and MSS CRC, latter which has high unmet need (recent CheckMate-8HW Phase III update was excellent in 1L mCRC, but for MSI-H). Multiple EGFR bi- and tri-specific Abs and ADCs are in development, including from Janssen Inc. and AstraZeneca, but Takeda’s 2021 acquisition of Maverick Therapeutics gave them TAK-186, another conditionally active EGFR x CD3 bispecific developed from the COBRA platform (TAK-280 is a B7-H3 COBRA bispec). Takeda’s modakafusp alfa is a compelling asset based on clever engineering of IFNα-2b to target CD38+ cells in r/r multiple myeloma and behind strong data in Phase I/II (ORR: 42%; mPFS: 5.7 mo), moda has plans with pembro in metastatic solid tumors such as melanoma. Showdowns between CytomX and Takeda in play. ??

Last week, ProQR Therapeutics provided updates on their Axiomer RNA editing platform. The company showed specific and efficient in vivo editing of RNA transcripts of the ANGPTL3 gene, a hot target in #cardiovascular genetic med, as it regulates lipoprotein. KO or KD of the gene/transcript reduces triglycerides and LDL, which contribute to ASCVD. PCSK9 has been a focus target to date; see Novartis’ siRNA LEQVIO (inclisiran; from Alnylam Pharmaceuticals). The Axiomer tech produced the K63E variant in WT mice and primary human hepatocyte-derived spheroids (60% RNA editing) disrupting ANGPTL3 function resulting in desired biomarker changes (?LDL-C and ApoB). ADAR (adenosine deaminase acting on #rna) is a vital enzyme; in humans, immune factors bind to viral dsRNA, targeting it for destruction. ADAR protects self RNA by swapping out adenosine for inosine, which reads as guanosine during mRNA processing and translation. A-to-I dsRNA editing corrects G-to-A point mutations and premature stop codons, and regulates cell and organ development by changing the RNA code at appropriate times. Because dsRNA is required for this editing, ProQR developed editing oligonucleotides (EONs), which bind to the complementary target ssRNA sequence to enable ADAR and restore/modulate protein function. The company’s psEON system is specific to premature termination codons (PTCs), also the target of Alltrna’s tRNA tech. ?Other ANGPTL3 programs include: CRISPR Therapeutics: in vivo CRISPR/Cas9 editing ? Verve Therapeutics: in vivo base editing Arrowhead Pharmaceuticals: siRNA Wave Life Sciences is developing A-to-I oligos called AIMers that direct endogenous ADAR with high potency, efficiency, and specificity as shown in NHP hepatocytes. Korro Bio, Inc.’s OPERA platform provides transient, precision, and redosable/titratable RNA editing. Both have lead programs in AATD up against other editing/RNA approaches. The McGovern Institute for Brain Research and the Broad Institute of MIT and Harvard are developing reprogrammable ADAR sensors (RADARS) that detect endogenous mRNA transcripts with incredibly high sensitivity. Insertion of a stop codon in the guide RNA sequence upstream of a payload (e.g., luciferase) requires binding of the target RNA to the reprogrammed sensor in order to allow payload translation ? the sensor is engineered to recruit ADAR only upon binding of the endogenous sequence to form the dsRNA structure needed to induce A-to-I editing in the stop codon, abolishing it and driving payload production. ADAR is exploited by tumors to evade immune response, i.e., IFN signaling driven by innate sensors in response to dsRNA, characteristic of invading pathogens or transcriptionally dysregulated cancer cells. This is in parallel with NLRP3 inflammasome and cGAS/STING activation, which further feeds IFN anti-invader or anti-tumor effect. Cancers use ADAR to modify the dsRNA and destabilize mRNA produced by interferon-stimulated genes (ISGs): #oncology ???

Current momentum in #oncology is lead by #adc deals, but anticipated readouts in other classes could see Pharma and VC inflows for other IO tech spaces that have been teasing for the past 2-4 years (depending on when you started to believe). Almost 70 ADCs entered the clinic in 2023, 28 of which are under evaluation in one or more Phase III trials. The flurry of deal activity into EOY/1 wk 2024 resulted in ~$119 B in dealmaking, not including undisclosed value collaborations, and marked most recently by Janssen Inc. – Ambryx ($2 B) and Roche – Medilink (>$1 B potential). AbbVie’s purchase of ImmunoGen, Inc. ($10 B) gives them ready FCF from Elahere and a strong pipeline lead by pivek, mirv expansion across PROC LoT and PSOC, a next-gen FRα targeting biparatropic version (think Carvykti’s advantage with BCMA), and a compelling pan-solid target in ADAM9. Despite internal program growth in other TAs (neuro, I&I), they’re relying on deals like this for the cancer portfolio such as a 5-asset pact including a licensing option with Umoja Biopharma, an in vivo CAR-T leader. Other players going in situ include Mustang Bio (collaboration with Mayo Clinic); Sanofi’s 2021 acquisition of Tidal Therapeutics provides capabilities to deliver mRNA encoding CARs to T cells in vivo, and although quiet, similar immune cell reprogramming programs have emerged such as Generation Bio + Moderna and a Phase I asset (MT-302) from Myeloid Therapeutics that generates TROP-2?targeting CARs on myeloid cells (no, this is not ADC). Even after announcing a revival to the allo ex vivo CAR-T program in heme and solid, CRISPR Therapeutics has planned dose escalation for in vivo candidates this year. As we await Q3 approval of Adaptimmune’s afami-cel – the first TCR-T, and importantly a solid tumor cell therapy (MAGE-A4 targeting) – their other advanced asset, lete-cel (NY-ESO targeting) is in a pivotal trial, with combined potential for $400 M in PYS. Following that, a next-gen SPEAR-T cell that boosts cytotoxicity via a CD8α co-receptor has already delivered 40% ORR in a Phase I heavily pretreated PROC trial. AbbVie has company, and not just from R-DXd. ?? Other TCR Cos to watch: Immunocore: ImmTAX platform | high affinity TCR bispecifics | IMC-F106C (PRAME) ? 1L HLA-A2+ cutaneous melanoma (TAM: 10K pts/yr) | Phase I data in Q2 | Phase III trial start in Q1 Immatics: ACTengine platform | T cell engaging receptors (TCER) | IMA203/CD8 (PRAME) ? PD-1 refractory met melanoma, HLA-A2+ | Phase II registrational study expected in 2024 (TBC) Rising Tide ?? A week ago, Merck struck a deal to acquire Harpoon Therapeutics for $680 M, arming themselves with the TriTAC tri-specific T cell engager platform, and Phase I assets HPN328 (DLL3; solid) and HPN217 (BCMA, heme). The former has generated promising early responses in SCLC and various NETs (cORR = 35%, N=31), and looks to compete with Amgen’s tarlatamab BiTE, which could gain approval this year under priority review.

Glykos Finland and Orion Corporation entered into an R&D collaboration / licensing agreement to initiate a next-gen ADC program with option for two additional assets based on Glykos’ hydrophilic linker platform that boasts superior PK and therapeutic window. Importantly, tolerability and efficacy – so far a difficult balancing act for ADCs – are selling points to Orion, a Finnish Pharma focused in oncology with a strong prostate pipeline led by Bayer-partnered darolutamide, and in pain; Orion’s Phase I NaV 1.8 channel blocker trails Vertex Pharmaceuticals’ VX-548, which has now moved to Phase III following the strong Dec readout in DPN. A popular microtubule inhibitor payload class (disrupts mitosis) is represented by two synthetic aurisatin derivatives. MMAE is the payload used in well-known marketed ADCs such as Adcetris, Tivdak, Padcev, and Polivy, all based on Seagen’s vedotin payload-linker tech. The Pfizer-acquired ADC pioneer is expanding this repertoire with ladiratuzumab vedotin (α-LIV-1) and disitamab vedotin (α-HER2). The closely related MMAF is used in GSK’s Blenrep and a host of pipeline ADCs, and while less membrane permeable, is more hydrophilic, a key ADC linker-payload property that reduces aggregation and clearance. Glykos is introducing a novel auristatin, MMAU, which is MMAE modified to confer the aforementioned biochemical advantages. Glykos has additional payloads: Exetecan, as in Enhertu’s deruxtecan (‘DXd’) – a topoisomerase I-inhibiting linker-payload that prevents relaxation of supercoiled DNA during replication, and thus DNA damage. PNU-EDA, a topo II inhibitor derived from daunorubicin and more cytotoxic than common anthracycline anti-cancer agents such as doxorubicin. Despite hydrophobic linker-payloads providing a greater bystander effect (enhanced by poor linker cleavability), payload aggregation, systemic clearance, and toxicity (on- and off-target) are increased. Thus, an increase in pipeline hydrophilic systems is notable. Mablink Bio’s (now Lilly) PSARLink platform adds a polysarcosine chain to the linker to mask the hydrophobic component, delivering the best of both worlds ? a highly cytotoxic payload with extended half-life, stability, drug exposure, bystander effect, and high DAR without added toxicity. Other novel antibody-linker-payload concepts: ?? Alternatives to ‘val-cit’ linkers: alanine (val-ala) and glycine (EDA-Gly5) enable hydrophilic de-aggregation, prevent payload dissociation, and improve intratumoral tumor biodistribution ??Homogenous (site-specific) bioconjugation: consistent and stable DAR providing improved therapeutic window ??PEG phosphonamidates conjugation: high DAR (8) while remaining stable, increasing efficacy and limiting off-target effects ??Bivalent / biparatropic ADCs (ImmunoGen, Inc.’s next-gen to Elahere): greater target engagement, clustering, and internalization ??Other private innovations circulating VC desks Fodder for #jpm2024 chats. #ADC #Oncology #Biotech

Is Biopharma back? Neuroscience is hot; ADC deals are flourishing with a boost from China-based developers (Zai Lab , Hansoh Bio, MediLink Therapeutics, SystImmune); and obesity bolt-ons are opening new doors to multi-indication benefits in cardio and neuropsych (Inversago Pharma, Versanis Bio, Embark Laboratories, Carmot Therapeutics, Inc.). 2023 returned inflammation to the spotlight across therapeutic areas with Ventus Therapeutics showcasing NLRP3 and cGAS-STING. Refocus on autoimmune leverages new conceptions of pathophysiology, and new-er targets in B cell depletion (TACI, APRIL, BLyS) and complement (MASP-2) to join C5, C3, and Factor B inhibitors. Nanobody and trispecifics hold promise of taming complex immune constellations. Anti-FcRn (argenx, Immunovant) vs. IgG cleavage (Hansa Biopharma; Biohaven) are also relevant to gene therapy to combat AAV immunogenicity (imlifidase + Elevidys). The tail end of the year saw acquisitions in RLTs (POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company, RayzeBio), Neuropsych (Karuna Therapeutics, Cerevel Therapeutics, Caraway Therapeutics, Inc.), and immune modulation (Icosavax, Inc., T3 Pharmaceuticals AG). Strategic plays were in vogue with LOE looming for big players prompting refill of the coffers, but also venturing into the emerging indication/technology space. Platform company purchases from the Covid boom were blamed for the 2022/2023 $XBI hangover. Although asset-based deals or those based on platforms with late-stage/approved proof-of-concept (ImmunoGen, Inc., Seagen) are likely to see more traction, gen med is proving that a new class of platform Biotechs could create R&D focused pipelines that aren’t reliant on Pharma. Regeneron and Alnylam Pharmaceuticals are good models from the pre-pandemic era; we’ll be keeping an eye on itepkimab for COPD (IL-33 is compelling), NTLA-2001 and Amvuttra in ATTR, as well as ALN-APP: partnered siRNA for Alzheimer’s. Novartis meanwhile is picking up gene delivery systems (Voyager Therapeutics, Inc., DTx Pharma, A Novartis Company). CRISPR Therapeutics' partnerships and IP position have enabled the diversification, including the first approval of a product based on their eponymous technology in exa-cel, with allo T1D and CAR-T on the horizon. Caribou Biosciences and Intellia Therapeutics, Inc. are developing next-gen versions to improve specificity (chRDNA) or are indexing on in vivo LNP delivery. Tome Biosciences is looking to edit large chunks of DNA, and is making acquisitions of their own (Replace Therapeutics). RNA editing is on the doorstep with Korro Bio, Inc. Bio and ProQR Therapeutics. David Liu’s hand in Beam Therapeutics, Prime Medicine, Inc., and Verve Therapeutics has been important for faith in Biotech’s potential to unlock in vivo editing (VERVE-101), editing for prevalent diseases (cardio-metabolic), and editing to support regimens (Beam’s ESCAPE program in SCD conditioning). Cell therapy also ready ?? Happy 2024!