AZD4785 / Ionis, AstraZeneca - LARVOL DELTA

AstraZeneca pays $24M to join race for next big KRAS opportunity, bagging Chinese rival to Mirati asset (FierceBiotech) - "The deal furthers AstraZeneca’s long-standing interest in KRAS. In 2012, the drug developer licensed an anti-KRAS antisense oligonucleotide, AZD4785, from Ionis. That candidate never progressed past phase 1, with AstraZeneca pulling the plug after wrapping up a trial in 2019, but the company’s research teams continued to work on the target...After discovering the KRAS G12C inhibitor AZD4625, AstraZeneca tweaked the molecule to generate the clinical candidate AZD4747...the potential for its molecule to penetrate the central nervous system could offer a point of differentiation."

Pipeline update • Solid Tumor

Antisense oligonucleotide activity in tumour cells is influenced by intracellular LBPA distribution and extracellular vesicle recycling. (PubMed, Commun Biol) - "Moreover, both cell lines recycle AZD4785 in extracellular vesicles (EVs); however, AZD4785 quantification by advanced mass spectrometry and proteomic analysis reveals that LK2 recycles more AZD4785 and RNA-binding proteins. Finally, stimulating LBPA intracellular production or blocking EV recycling enhances AZD4785 activity in LK2 but not in PC9 cells thus offering a possible strategy to enhance ASO potency in tumour cells with poor productive uptake of ASOs."

Journal • Oncology • CD63 • KRAS

Specific targeting of the KRAS mutational landscape in myeloma as a tool to unveil the elicited anti-tumor activity. (PubMed, Blood) - "Therefore, there is still a need to develop novel therapeutic approaches to target the KRAS mutational events found in other tumor types, including MM. We have used AZD4785, a potent and selective antisense oligonucleotide (ASO) which selectively targets and down-regulates all KRAS isoforms, as a tool to dissect the functional sequelae secondary to KRAS silencing in MM within the context of the bone marrow niche; and demonstrated its ability to significantly silence KRAS, leading to inhibition of MM tumor growth, both in vitro and in vivo, confirming KRAS as a driver and a therapeutic target in MM."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • KRAS

Newly added product (clinicaltrials.gov) - P1,NSCLC, Solid Tumor

Pipeline update • Non Small Cell Lung Cancer • Solid Tumor

Specific Targeting of KRAS Using a Novel High-Affinity KRAS Antisense Oligonucleotide in Multiple Myeloma (ASH 2019) - "Synergism between AZD4785 and bortezomib, in modulating MM growth was tested. CONCLUSION. Taken together, these data suggest that AZD4785 may represent a novel therapeutic approach for targeting mutant KRAS in MM, either alone or in combination with proteasome inhibitors; and warrant further development."

CASP3 • HRAS • KRAS • NRAS • PARP • PXN • TP53

Differential uptake, kinetics and mechanisms of intracellular trafficking of next-generation antisense oligonucleotides across human cancer cell lines. (PubMed, Nucleic Acids Res) - "AZD4785 is a potent and selective therapeutic KRAS cEt-ASO currently under clinical development for the treatment of cancer...An siRNA screen identified several factors mechanistically involved in productive ASO uptake, including the endosomal GTPase Rab5C. This work provides novel insights into the trafficking of cEt-ASOs and mechanisms that may determine their cellular fate."

Journal • Preclinical

"It seems that $AZN discontinued KRAS asset AZD4758 is IONIS-KRAS-2.5Rx $IONS https://t.co/FPaBnuXoBl" (@JacobPlieth)

"...also, there might be a typo in the $AZN slide deck. Should AZD4758 say AZD4785?" (@JacobPlieth)

Phase I Dose-Escalation Study of AZD4785 in Patients With Advanced Solid Tumours (clinicaltrials.gov) - P1; N=28; Completed; Sponsor: AstraZeneca; Active, not recruiting ➔ Completed; N=50 ➔ 28

Clinical • Enrollment change • Trial completion