Delpacibart zotadirsen

Plus, news about BioCryst, GSK and Roche. 🙃 Entrada’s Duchenne drug disappoints: The biotech reported initial data in six patients who received the low dose of its exon 44 skipping drug, which is Entrada’s lead asset. The data showed ENTR-601-44 led to an increase of 2.36% of normal dystrophin. Entrada plans to test higher doses, where it could see more potent efficacy. But the drug would have to make up a lot of ground in efficacy. Entrada’s key competitor Avidity Biosciences — whose program is further along — reported last year that its drug del-zota led to an increase of approximately 25% of normal dystrophin. Entrada’s shares $TRDA fell 59% when markets opened Thursday. — Lei Lei Wu 🏆 Medicare’s Wegovy deal : Starting on July 1, Medicare beneficiaries will be able to get Novo Nordisk’s obesity drug in both its shot and pill forms for a $50 monthly copay. All doses of Wegovy will be covered under the CMS-supported program, which is called the Medicare GLP-1 Bridge and is designed to test new approaches to care delivery. It will last until the end of 2027, Novo said . — Elizabeth Cairns ✂️ BioCryst cuts eye drug: The biotech is ceasing the development of avoralstat for diabetic macular edema (DME), the most common cause of vision loss in people with diabetes. BioCryst didn’t give much detail on its reasoning, but said the move will “focus the pipeline on rare diseases.” It had originally been investigating avoralstat for hereditary angioedema, but pivoted to DME in 2023. — Nicole DeFeudis 🤝 GSK partners with Halozyme: GSK has licensed Halozyme’s technology to develop subcutaneous drugs for multiple oncology targets, including antibody-drug conjugates. The deal comes as GSK beefs up its ADC pipeline, most recently with a deal for a preclinical prostate cancer candidate from Syndivia. — Nicole DeFeudis 🔬 Roche’s AI diagnostics deal: The Swiss drugmaker will pay $750 million upfront, plus as much as $300 million in milestones, for the digital pathology company PathAI. Roche has long invested in diagnostics to pair with its medicines, and said the deal will help it use AI and digital views of pathology samples to more quickly diagnose diseases. The companies have a partnership that dates back to 2021, Roche said in the announcement. — Drew Armstrong

The first cut of data for Entrada Therapeutics' experimental Duchenne muscular dystrophy (DMD) therapy ENTR-601-44 has come in well below expectations of its dystrophin-increasing capabilities, sending the company's shares down about 58% on Thursday. However, the exon 44-skipping oligonucleotide posted a clean safety profile — and early signs of functional improvement — that warrant further testing at higher doses. ENTR-601-44 is a phosphorodiamidate morpholino oligomer (PMO) conjugated to an endosomal escape vehicle (EEV) designed to have increased cellular uptake, including into quiescent satellite cells. The topline readout from the the Phase I/II ELEVATE-44-201 study comes a little more than a year after the FDA lifted a hold that had prevented the trial's launch for more than two years. The trial's Cohort 1 includes eight ambulatory patients aged four to 20 with a confirmed mutation in the DMD gene amenable to exon 44 skipping; six were randomised to receive three 6-mg/kg doses of ENTR-601-44, and two to the placebo group. Six weeks after participants received their last dose, those receiving the oligonucleotide saw a 2.36% increase in dystrophin above their 4% baseline of normal levels. Company executives had previously said they expected a double-digit dystrophin increase.The result also falls short of the bar set by Avidity's antibody-oligonucleotide conjugate delpacibart zotadirsen (del-zota), which is also targeting DMD patients amenable to exon 44 skipping. In the Phase I/II EXPLORE44 study, del-zota increased dystrophin production to approximately 25% of normal levels. Less than two months after the EXPLORE44 data were shared, Novartis moved to buy Avidity's neuromuscular pipeline for $12 billion. Solid on safetyWhile the dystrophin data didn't meet Entrada's own expectations, the company touted ENTR-601-44's favourable safety and tolerability profile. No serious adverse events (AEs) were reported, and no AEs led to study discontinuation; the most common AE was headache. In addition, biomarkers of kidney function, including eGFR, Cystatin C and magnesium, read out normally."Although dystrophin levels are disappointing, the clean safety allows for dose escalation to 12-18 mg/kg that can ultimately deliver a competitive profile based on juvenile [non-human primate] (NHP) data," Oppenheimer analysts wrote in a note. The trial is now dosing patients in Cohort 2 with three 12 mg/kg-doses of ENTR-601-44, with plans to evaluate an 18-mg/kg dose in Cohort 3. Data from the open-label portion of Cohort 1, as well as the multiple-ascending dose results from Cohort 2, are due by year-end.Functional benefit findingsEntrada also pointed to functional data that suggest while the dystrophin increase is small, patients may already be benefiting from ENTR-601-44.Per a post hoc analysis, patients who received the experimental treatment achieved a statistically significant 0.115 improvement in mean time to rise (TTR) velocity versus placebo — 3.5 times higher than the minimal clinically important difference threshold of 0.023. According to Entrada, this result suggests ENTR-601-44 "is potentially changing the trajectory of the disease," with CEO Dipal Doshi noting that TTR velocity is an approvable clinical endpoint in Phase III studies. The Oppenheimer analysts wrote that not only does ENTR-601-44's TTR velocity improvement appear to be dystrophin-correlated, it's larger than competitors, suggesting a potential clinical benefit. "We look to understand whether ENTR-601-44 could drive a functional benefit with lower dystrophin levels than competitors (due to differentiated delivery in satellite cells)," they added.Entrada's President of R&D Natarajan Sethuraman also attributed ENTR-601-44's impact on satellite cells as a potential reason for the functional benefit. "Access to satellite cells enables the repair of existing muscle fibers and importantly, the formation of new healthy fibers," he said in a company release. "These drivers are emerging as a potentially significant competitive differentiator and may explain why the dystrophin levels in Cohort 1 were sufficient to improve TTR velocity."