NEJM This Week · In Review

The Week in the New England Journal

Issue of July 30, 2026  ·  Vol. 395, No. 5

One trial for the generalist and one outstanding review. APPLAUSE-IgAN converts iptacopan's earlier proteinuria surrogate into a real kidney-function benefit in IgA nephropathy — halved eGFR loss and ~43% fewer kidney-failure events over 2 years, at the price of tripled serious infections. The anti–platelet factor 4 review is the best available map of HIT and its heparin-independent cousins (autoimmune HIT, VITT, VITT-like MGTS) and why they need IVIG or a BTK inhibitor on top of anticoagulation. A superb mucosal leishmaniasis teaching case rounds out the ID content. Three trials are summarized for awareness: TALAPRO-3 (talazoparib in HRR-altered prostate cancer), MajesTEC-9 (teclistamab at first relapse in myeloma — note the >40% grade 3/4 infection rate), and a phase-2b NaV1.8 inhibitor for acute postoperative pain.

NephrologyAPPLAUSE-IgAN · RCTHigh yield · IM

Iptacopan in IgA Nephropathy — Final 24-Month Data

In IgA nephropathy with persistent proteinuria despite supportive care, does oral iptacopan vs placebo slow the decline in kidney function?

Population
477 adults analyzed (238 vs 239) with IgA nephropathy, eGFR ≥30 mL/min/1.73 m², and 24-h urinary protein-to-creatinine ratio ≥1 g/g despite supportive care. Phase 3, double-blind, placebo-controlled.
Intervention
Iptacopan 200 mg orally twice daily — complement factor B inhibitor (alternative pathway).
Comparison
Placebo twice daily.
Outcome
24-month annualized eGFR slope −3.10 vs −6.12 mL/min/1.73 m²/yr (difference 3.02; 95% CI 2.02–4.01; adjusted P<0.001). Composite kidney-failure endpoint 21.4% vs 33.5% (HR 0.57; 95% CI 0.40–0.81; P=0.003). Serious AEs 12.2% vs 11.7%; serious infections 6.7% vs 2.1%; no deaths.
Clinical takeaway. The 9-month interim analysis had shown only a 38.3% proteinuria reduction — a surrogate. The final analysis delivers the endpoint that matters: iptacopan roughly halved the rate of eGFR loss and cut hard kidney-failure events by ~43% over two years, in a disease where up to half of patients reach kidney failure within 10–20 years. The trade-off is a genuine infection signal (serious infections roughly tripled) — expected with alternative-pathway blockade, so vaccinate against encapsulated organisms and counsel patients. What this changes: extends complement-targeted therapy in IgAN from a proteinuria surrogate to a kidney-function benefit, in line with KDIGO's push to treat the IgAN-specific immunologic driver alongside CKD care.

Heme / OncologyTALAPRO-3 · RCTNotable · narrow onc

PARP and Androgen-Signaling Inhibition plus ADT in Metastatic Prostate Cancer

In hormone-sensitive metastatic prostate cancer with homologous recombination repair (HRR) gene alterations, does adding talazoparib to enzalutamide vs placebo plus enzalutamide improve imaging-based progression-free survival?

Population
599 men (300 vs 299) at 266 centers in 27 countries with metastatic androgen-pathway-modulation–sensitive prostate cancer and an alteration in ≥1 of 12 HRR genes (BRCA2 30%, ATM 28%, CDK12 19%, CHEK2 15%); 35% BRCA1/2-altered, 71% high-volume, 84% de novo metastatic. Phase 3, double-blind.
Intervention
Talazoparib 0.5 mg (PARP inhibitor) + enzalutamide 160 mg once daily, on ongoing ADT.
Comparison
Placebo + enzalutamide 160 mg once daily.
Outcome
3-year imaging-based PFS 77% vs 56% (HR 0.48; 95% CI 0.36–0.65; P<0.001); BRCA1/2 subgroup HR 0.37, non-BRCA HR 0.57. Interim 3-year overall survival 78% vs 72% (HR 0.77; 95% CI 0.56–1.04 — not yet significant). Serious AEs 42% vs 32%; grade ≥3 anemia in 51%; two treatment-related deaths.
Clinical takeaway. A clear PFS win moving talazoparib from castration-resistant disease (TALAPRO-2) earlier into the hormone-sensitive setting, with the largest effect in BRCA-altered patients — but overall survival is immature and hematologic toxicity is substantial. The editorial (McKay, "Precision Intensification") frames this as genomically selected intensification, not a new blanket standard. Two practical points for the internist: HRR/BRCA testing is now decision-relevant in metastatic prostate cancer, and a patient on this regimen will be anemic. What this changes: extends TALAPRO-2 into hormone-sensitive HRR-altered disease; OS unresolved.

Heme / OncologyMajesTEC-9 · RCTNotable · narrow heme-onc

Teclistamab in Multiple Myeloma with One to Three Previous Lines of Therapy

In relapsed or refractory myeloma after 1–3 prior lines, does teclistamab monotherapy vs investigator's choice of PVd or Kd improve progression-free survival?

Population
593 patients (296 vs 297) at 162 sites in 24 countries; all had received an anti-CD38 monoclonal antibody and lenalidomide; prior BCMA-directed therapy excluded. Phase 3, open-label.
Intervention
Subcutaneous teclistamab (BCMA×CD3 bispecific), step-up dosing then 3 mg/kg maintenance; glucocorticoid-sparing. Antimicrobial prophylaxis (incl. PJP, herpes zoster) and IVIG to keep IgG ≥400 mg/dL recommended.
Comparison
Investigator's choice of pomalidomide–bortezomib–dexamethasone (PVd) or carfilzomib–dexamethasone (Kd).
Outcome
18-month PFS 69.8% vs 26.9% (HR 0.29; 95% CI 0.23–0.38; P<0.001); ≥complete response 65.9% vs 16.8%; 18-month OS 79.2% vs 68.6% (HR 0.60; P=0.002). CRS 66.0% (mostly grade 1–2), ICANS 4.1%, grade 3/4 infection 41.6% vs 29.0%; grade 5 AEs 6.5% vs 3.5%.
Clinical takeaway. Large PFS and OS gains for an off-the-shelf bispecific used far earlier than its heavily-pretreated origins; the editorial (Mateos) argues the field should stop treating "early relapse" as a low-stakes setting and use the most effective agent at first relapse. The consult-relevant reality is toxicity: two thirds develop CRS and grade 3/4 infection exceeds 40% — which is exactly why PJP and herpes-zoster prophylaxis plus IgG replacement are written into the protocol. What this changes: extends BCMA bispecific therapy from late salvage to 2nd–4th line.

Pain / AnesthesiaLTG-001-010 · RCTNotable · phase 2b

Phase 2b Trial of a NaV1.8 Inhibitor for Acute Pain

In moderate-to-severe pain after abdominoplasty, does oral LTG-001 (a selective NaV1.8 inhibitor) vs placebo reduce pain over 48 hours — and spare opioids?

Population
343 patients with moderate-to-severe pain after abdominoplasty, randomized 1:1:1:1. Phase 2b, double-blind, placebo- and active-controlled.
Intervention
LTG-001 low dose (300 mg load → 150 mg q12h) or high dose (450 mg load → 300 mg q12h), orally over 48 h.
Comparison
Hydrocodone bitartrate–acetaminophen 5/325 mg q6h, or placebo q6h.
Outcome
SPID48 (higher = more relief): 185.30 high dose, 161.05 low dose, 164.08 hydrocodone–acetaminophen, 123.22 placebo. Vs placebo: high dose +62.08 (P<0.001), low dose +37.82 (P=0.003). High dose also cut opioid rescue (11.00 vs 18.35 MME, P=0.01) and raised the share needing no rescue opioid (52% vs 22%, P<0.001). Pyrexia 7% vs 2%; presyncope 6% vs 1%.
Clinical takeaway. A second NaV1.8 inhibitor clears a phase-2b analgesia signal, numerically edging hydrocodone–acetaminophen at the high dose and roughly halving opioid rescue. The class promise is analgesia without abuse liability, because NaV1.8 sits peripherally in nociceptors and dorsal-root ganglia. Worth knowing for context: suzetrigine, the first-in-class NaV1.8 inhibitor, was approved for acute moderate-to-severe pain in 2025. This is dose-finding in a single elective-surgery model, with pyrexia and presyncope to watch. What this changes: incremental — supports the class and a phase 3 program, no practice change yet.

HematologyReview · High yield · IM

Platelet-Activating Anti–Platelet Factor 4 Disorders

When do you suspect HIT, which assay actually confirms it, and which anti-PF4 disorders need more than anticoagulation?

•Suspect HIT when thrombosis, thrombocytopenia (or a falling platelet count), or both appear ≥5 days after heparin is started — and onset can occur even after heparin is stopped. Venous thrombosis complicates 40–70%; arterial events favor limb arteries ("white-clot syndrome"). LMWH carries a 50–90% lower HIT risk than unfractionated heparin. •Assay hierarchy — the "iceberg model": only a subset of immunoassay-detectable anti–PF4–polyanion antibodies can cross-link FcγRIIa and activate platelets, so platelet-activation assays are more specific than immunoassays for diagnosing HIT. •Heparin-independent variants — autoimmune HIT, spontaneous HIT, VITT, and VITT-like monoclonal gammopathy of thrombotic significance (MGTS) — activate platelets without heparin, so anticoagulation alone is insufficient: add Fc-receptor blockade with high-dose IVIG (acute) or a BTK inhibitor (ibrutinib, pirtobrutinib) for chronic disease. •Why two different assays: heparin-dependent HIT antibodies bind PF4 neoepitopes exposed when heparin binds its cationic "equator," whereas VITT antibodies bind that equatorial site directly, without heparin. In carriers of IGLV3-21*02/*03, a K31E somatic hypermutation redirects anti–adenovirus-protein-VII antibodies onto PF4 — and VITT-like illness can follow natural adenovirus infection, not just adenoviral-vector vaccines.

Teaching Case · Case Records of the MGH

Case 22-2026: A 37-Year-Old Woman with Persistent Nasal Ulceration · Infectious Disease / Otolaryngology

High yield · ID

Key learning point. Final diagnosis: mucosal leishmaniasis due to Leishmania (Viannia) braziliensis. The triad that made it — Latin American residence (Honduras), chronic unilateral nasal ulceration over 17 years, and a healed cutaneous arm scar (the antecedent primary lesion, which precedes mucosal disease by months to years) — plus a relative with the same lesion pointing at shared exposure. Confirmation was molecular: mini-exon DNA amplification on formalin-fixed tissue. Note the pitfall: Giemsa staining showed no amastigotes, which reflects low-volume disease and does not exclude the diagnosis. Management: prompt ENT evaluation to stage extent; in patients at risk for airway obstruction give glucocorticoids before antiparasitic therapy; and every mucosal case needs systemic treatment — liposomal amphotericin B, amphotericin B deoxycholate, pentavalent antimonials (US: IND protocol) ± pentoxifylline, or oral miltefosine. Expect improvement by 40–60 days, healing over 3–5 months, then follow 1–2 years for relapse.

Also in this issue. Perspectives — the paradox of medical aid in dying; medical standards by federal fiat; whether litigation can protect us from health-risk products when government fails; "Braking Bad News." Images in Clinical Medicine — Milwaukee shoulder syndrome; pulsatile liver in severe tricuspid regurgitation. Correspondence — cross-correction in hematopoietic stem-cell gene therapy for metachromatic leukodystrophy; T-cell engager–mediated HLA antibody depletion before kidney transplantation; LDL cholesterol targeting in cardiovascular disease; transdermal estradiol patches in prostate cancer; sex hormone influences on cardiovascular risk.

Summaries are original paraphrases prepared for educational use; figures are drawn from the published full text. Read the full articles at NEJM.org (subscription required). Trial registrations: APPLAUSE-IgAN (NCT04578834), TALAPRO-3 (NCT04821622), MajesTEC-9 (NCT05572515), LTG-001-010 (NCT07102459). Citations: N Engl J Med 2026; Vol. 395, No. 5. DOIs: 10.1056/NEJMoa2600743, 10.1056/NEJMoa2604126 (editorial 10.1056/NEJMe2605582), 10.1056/NEJMoa2603870 (editorial 10.1056/NEJMe2605404), 10.1056/NEJMoa2602910, 10.1056/NEJMra2502459, 10.1056/NEJMcpc2603178.