The Rounds Report
October 2025: Five Breakthroughs You Need to Know
A drug we abandoned in the 1990s just outperformed modern heart failure therapy. And it's not even the most surprising finding from the past three months.
Between mid-July and mid-October, five major trials published results that directly challenge conventional wisdom across cardiology, oncology, pulmonology, and hepatology. We're talking about a cardiac glycoside making a comeback, the first new IPF drug in a decade, intravesical immunotherapy achieving unprecedented cancer responses, and vaccines targeting mutations we thought were "undruggable."
Here's what caught my attention during this quarter's analysis: these aren't incremental improvements. These are studies that resurrect abandoned therapies with modern dosing, introduce entirely new drug classes, and validate mechanisms that oncology has pursued for 40 years.
Five studies. Five paradigm shifts. Let me walk you through what matters most.
The Big Five Game-Changers
1. Digitoxin's Comeback: The Old Drug That Outperforms Modern Heart Failure Therapy
Remember when we stopped using cardiac glycosides because digoxin kept poisoning patients? The DIGIT-HF trial just proved we abandoned the right drug but for fixable reasons.
1,240 patients with advanced heart failure (LVEF ≤40%) received low-dose digitoxin on top of maximal guideline-directed therapy—96% were on beta-blockers, 95% on ACE inhibitors or ARNIs. The key difference? They used 0.07 mg daily titrated to serum levels of 8-18 ng/mL, far below digoxin's toxic threshold.
Results over 36 months: death or heart failure hospitalization dropped from 44.1% to 39.5% (HR 0.82, p=0.03). That's a number needed to treat of 22—clinically meaningful for patients who've exhausted standard options. Both mortality and hospitalization contributed to the benefit.
Clinical reality check: This works best in patients with atrial fibrillation, higher heart rates, low blood pressure, or impaired kidney function—exactly the populations where we're running out of options. The safety profile proved acceptable with only 3.4% experiencing serious cardiac events versus 2.8% on placebo.
Bottom line: Digitoxin deserves reconsideration as add-on therapy for advanced HFrEF patients despite maximal contemporary treatment. The drug itself wasn't the problem—dosing was.
2. FDA Approves First New IPF Drug in Over a Decade
Idiopathic pulmonary fibrosis patients finally have a new option after 10 years of therapeutic stagnation. The FDA approved nerandomilast (Jascayd) on October 7, 2025, offering both antifibrotic and immunomodulatory effects through phosphodiesterase 4B inhibition—a mechanism completely different from pirfenidone and nintedanib.
The FIBRONEER-IPF trial randomized 1,177 patients with biopsy-confirmed IPF. At 52 weeks, the 18 mg twice-daily dose reduced FVC decline to -114.7 mL versus -183.5 mL with placebo (difference +68.8 mL, p<0.001). The 9 mg dose also worked with -138.6 mL decline (difference +44.9 mL, p=0.02).
Here's what makes this exciting: nerandomilast delivered a nominally significant 43% reduction in mortality risk (HR 0.57) and demonstrated superior tolerability compared to existing drugs. Unlike nintedanib, it caused no liver function abnormalities. Only 15% discontinued the 18 mg dose due to adverse events versus 11% with placebo.
Practice implication: Nerandomilast can be used alone or with background antifibrotic therapy, giving flexibility for the 200,000 Americans living with this progressive, fatal lung disease. The recommended dose is 18 mg oral twice daily, reducible to 9 mg for tolerability.
3. Intravesical Immunotherapy Achieves Unprecedented Bladder Cancer Responses
Half of muscle-invasive bladder cancer patients can't receive or decline cisplatin-based chemotherapy. The SunRISe-4 trial just gave them a legitimate pre-surgical option that actually works.
TAR-200—a first-in-class intravesical device delivering sustained gemcitabine release over 3 weeks—combined with the PD-1 inhibitor cetrelimab achieved 42% pathological complete response rates (95% CI 28-56%) at cystectomy among 120 cisplatin-ineligible patients. The pathologic overall response rate hit 60%.
This substantially exceeds historical outcomes for this population, who typically face radical cystectomy with dismal prognoses. The combination addresses both local tumor burden through sustained chemotherapy and micrometastatic disease through systemic immunotherapy.
What this means: For the roughly 50% of MIBC patients who can't get standard neoadjuvant chemotherapy, this provides a viable bridge to surgery that may actually improve outcomes rather than just delaying inevitable progression. The safety profile proved manageable with no prohibitive toxicities.
4. Cancer Vaccine Successfully Targets "Undruggable" KRAS Mutations
For 40 years, KRAS mutations have been oncology's white whale—present in 93% of pancreatic cancers and 50% of colorectal cancers but considered impossible to drug. The AMPLIFY-201 trial just proved we've been hunting with the wrong weapon.
This phase 1 study tested ELI-002 2P, an off-the-shelf vaccine targeting KRAS G12D and G12R mutations, in 25 patients with pancreatic or colorectal cancer who'd completed standard treatment but showed minimal residual disease.
The vaccine induced mKRAS-specific T cell responses in 84% of patients, with 100% response rates at the highest dose levels. Even better: 67% demonstrated antigen spreading—T cells started attacking non-vaccine tumor targets, suggesting broad anti-tumor immunity.
Survival signals look remarkable: high T cell responders achieved median overall survival not reached versus 15.98 months for low responders (HR 0.23, p=0.0099). Among pancreatic cancer patients—who historically face median OS of 17 months—this trial showed 28.94 months.
Bottom line: KRAS-targeting vaccines work. Phase 2 trials are underway testing expanded formulations in adjuvant pancreatic cancer.
5. First DGAT2 Inhibitor Reverses MASH Without Weight Loss or Metabolic Side Effects
The ION224-CS2 trial validated a completely novel mechanism for treating metabolic dysfunction-associated steatohepatitis—suppressing de novo lipogenesis at its source through DGAT2 inhibition.
160 patients with biopsy-confirmed MASH and fibrosis stages F1-F3 received the antisense oligonucleotide ION224 for 51 weeks. The highest dose (120 mg) achieved the primary endpoint—at least 2-point NAS reduction with improvement in ballooning or inflammation without worsening fibrosis—in 59% of patients versus 19% with placebo (risk difference 40.1%, p=0.0002).
Here's what makes this breakthrough: ION224 succeeded without requiring weight loss (unlike GLP-1 agonists) and without causing hypertriglyceridemia that plagued other lipogenesis inhibitors. The liver-directed antisense approach achieved high hepatic concentrations with minimal systemic exposure. Safety proved exceptional with no deaths, no treatment-related serious adverse events, and no liver function abnormalities.
Clinical reality check: With semaglutide receiving accelerated FDA approval for MASH in August 2025, ION224 represents a mechanistically distinct approach that may benefit patients unable to use GLP-1 agonists or those requiring combination therapy.
The Clinical Pearls That Matter
Extended low-dose apixaban dramatically reduces VTE recurrence in provoked thromboembolism with persistent risk factors. The HI-PRO trial showed apixaban 2.5 mg twice daily for 12 months reduced recurrent VTE by 87% (1.3% vs 10.0%, HR 0.13, p<0.001) with only one major bleeding event (0.3%) in patients whose provoking factors persisted after initial anticoagulation. HI-PRO trial
Early tirofiban after thrombolysis significantly improves stroke outcomes. The ASSET-IT trial demonstrated that adding tirofiban infusion within 60 minutes of IV thrombolysis increased excellent functional outcomes (mRS 0-1 at 90 days) from 54.9% to 65.9% (RR 1.20, p=0.001), with symptomatic ICH occurring in only 1.7% versus 0% with standard care. ASSET-IT trial
Important negative trial: spironolactone provides no cardiovascular benefit in dialysis patients. The ACHIEVE trial definitively showed no reduction in cardiovascular death or heart failure hospitalizations with spironolactone 25 mg daily in 2,538 dialysis patients (HR 0.92, 95% CI 0.78-1.09, p=0.35), ending speculation about mineralocorticoid receptor antagonist benefits in this population. ACHIEVE trial
First randomized trial of tirzepatide in type 1 diabetes shows promising results for weight management and glycemic control. The TIRTLE1 trial (n=24) demonstrated 10.3 kg weight loss versus 0.7 kg with placebo over 12 weeks in adults with type 1 diabetes and obesity. Daily insulin requirements decreased 25%, time in range improved from 65% to 74%, and HbA1c dropped from 7.3% to 6.9% without increased hypoglycemia or diabetic ketoacidosis episodes at the 5 mg twice-weekly dose. TIRTLE1 trial
Monday Morning Rounds: 5 Key Discussion Points
1. Digitoxin's evidence-based comeback - Low-dose digitoxin (0.07 mg daily, titrated to 8-18 ng/mL) reduced death or heart failure hospitalization by 18% when added to maximal guideline-directed therapy in advanced HFrEF patients.
2. IPF gets its first new drug in a decade - Nerandomilast (Jascayd) slowed FVC decline by 68.8 mL versus placebo and reduced mortality risk by 43%, offering superior tolerability compared to existing therapies without liver toxicity.
3. Intravesical immunotherapy transforms bladder cancer - TAR-200 plus cetrelimab achieved 42% pathological complete response rates in cisplatin-ineligible muscle-invasive bladder cancer patients, providing a viable pre-surgical option for half the MIBC population.
4. KRAS-targeted cancer vaccine proves viable - The AMPLIFY-201 trial induced mKRAS-specific T cell responses in 84% of pancreatic and colorectal cancer patients, with high responders achieving dramatically prolonged survival (median OS not reached vs 15.98 months).
5. First DGAT2 inhibitor reverses MASH without weight loss - ION224 antisense oligonucleotide achieved 59% MASH improvement rates through de novo lipogenesis suppression, succeeding without requiring weight loss or causing hypertriglyceridemia that plagued other approaches.
Before You Go...
This quarter delivered breakthroughs across multiple fronts—resurrecting abandoned therapies with modern dosing strategies, introducing first-in-class mechanisms for previously untreatable conditions, and validating approaches oncology has pursued for decades. From digitoxin's evidence-based comeback to KRAS-targeting vaccines, these advances demonstrate that innovation comes in many forms.
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The convergence of precision dosing, antisense technology, targeted immunotherapy, and mechanistic innovation signals internal medicine's evolution toward more effective therapeutics. The question isn't whether these breakthroughs will change your practice—it's how quickly you'll integrate them to optimize patient outcomes.
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Essential Reading for Deep Dives
Cardiology & Pulmonology Advances: • DIGIT-HF - Digitoxin in Heart Failure • FDA Approval - Nerandomilast for IPF
Oncology Breakthroughs: • SunRISe-4 - TAR-200 Plus Cetrelimab for Bladder Cancer • AMPLIFY-201 - KRAS Cancer Vaccine
Hepatology & Metabolic Disease: • ION224-CS2 - DGAT2 Inhibitor for MASH
Practice-Changing Guidance: • HI-PRO Trial - Extended Apixaban for Provoked VTE • ASSET-IT - Tirofiban After Thrombolysis for Stroke • ACHIEVE Trial - Spironolactone in Dialysis (Negative) • TIRTLE1 Trial – Tirzepatide for Type 1 DM
Disclaimer: The content provided in The Rounds Report is for educational and informational purposes only and does not constitute medical advice, diagnosis, treatment recommendations, or professional medical guidance. This newsletter presents summaries and analysis of published medical research and should not be used as a substitute for professional medical judgment, clinical decision-making, or consultation with qualified healthcare providers. Always consult with appropriate medical professionals and refer to original research sources before making any clinical decisions. The Rounds Report does not establish a doctor-patient relationship and readers should not rely on this content for patient care decisions.