Clinical Trial Fundamentals

In the latest edition of CMO Confidential I discuss the notable regulatory milestones in oncology and rare disease treatments from October. The FDA's approval of Zolbetuximab (Vyloy) for gastric and gastroesophageal junction adenocarcinoma marked a step forward in targeted therapies, particularly for patients with CLDN18.2 expression. This approval offers a new therapeutic option for patients with advanced gastric or GEJ cancer, highlighting the importance of biomarker-driven treatments in oncology. In hematology, Asciminib (Scemblix) received accelerated approval for newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia, backed by compelling trial data showing substantial improvements in major molecular response rates compared to the investigator-selected tyrosine kinase inhibitors (IS-TKIs). The FDA also released an update on the Rare Disease Innovation Hub aimed at streamlining the development of treatments for rare diseases. By centralizing resources and accelerating the review process this initiative is a promising move to bring more therapies to patients with significant unmet need. The momentum we’re seeing in biomarker-driven treatments and rare disease innovation reflect the transformative changes the industry is making in how we treat complex conditions. As we look to the future, I’m optimistic that these trends of regulatory and patient centered innovation will continue to drive progress and improve outcomes for patients globally.

2025 saw 55 therapeutic interventions approved by the FDA. Those approvals came from 46 unique companies. Five companies accounted for more than one approval: - Merck: 3 - GSK: 3 - Novartis: 3 - Bayer: 2 - Boehringer Ingelheim: 2 The remaining 37 companies (80%) each delivered one approval each. Most drugs were developed by a single company: - 50 of 55 approvals (91%) had one primary developer. - 5 approvals (9%) involved a partnership. 23 of 55 approvals (42%) were from companies receiving their first explicit drug approval. Company size was split: - Global biopharma accounted for 28 approvals (51%) - Small and emerging biopharma accounted for 23 approvals (42%) - Mid-size companies accounted for 4 approvals (7%) On modality, approvals were concentrated: - Small molecules: 31 approvals (56%) - Antibodies: 11 approvals (20%) - Standard monoclonal antibodies: 8 - Antibody–drug conjugates (ADCs): 2 - Bispecific antibodies: 1 - All other modalities combined: 13 approvals (24%) Small molecules and antibodies together accounted for 42 of 55 approvals (76%). On indication, oncology was the largest single category, but not the majority. - Oncology: 15 approvals (27%) - Infectious Disease: 8 approvals (15%) - Immunology & Inflammation: 8 approvals (15%) - All other indications combined accounted for 40 approvals (73%). Among first-time company approvals, most occurred outside oncology. There were 23 first-time company approvals in 2025. ~7 were in oncology ~16 were in non-oncology That means ~70% of first-time approvals happened 𝗼𝘂𝘁𝘀𝗶𝗱𝗲 oncology. Among first-time company approvals (n = 23): - Immunology & Inflammation: 5 (21.7%) - Oncology: 4 (17.4%) - Infectious Disease: 2 (8.7%) - Rare / Genetic disease: 2 (8.7%) - Ophthalmology: 2 (8.7%) - Neurology: 1 (4.3%) First-time approvals were also concentrated in established modalities, not novel ones: - Small molecules: 13 (57%) - Antibodies: 4 (17%) - Gene therapy: 3 (13%) - Vaccines: 1 (4%) - siRNA: 1 (4%) - Peptide: 1 (4%) Put differently: - 74% (17 of 23) of first-time approvals were small molecules or antibodies - 26% (6 of 23) came from all other modalities Here's a copy of the Dataset for those that want to look deeper: https://lnkd.in/gPTinVPE

The FDA just approved doravirine/islatravir (DOR/ISL), a once-daily, two-drug oral pill for HIV-1 (Merck). A landmark moment for patients and for the industry. This is the first approved HIV regimen without an integrase inhibitor to demonstrate non-inferior efficacy to the current three-drug standard. Imagine two drugs instead of three, same viral suppression, simpler for patients managing HIV alongside other comorbidities. For the 1.2 million Americans living with HIV, treatment adherence is everything. Simplifying the regimen is not a minor convenience, it's a clinical and quality-of-life breakthrough. Congratulations to the Merck team on 40 years of HIV research culminating in a genuinely differentiated therapy. The FDA has approved 11 novel drugs through April 6, pacing ahead of recent years and signaling a pipeline flush with metabolic, genetic, and oncology breakthroughs. The marquee approval belongs to Eli Lilly and Company, whose oral GLP-1 receptor agonist Foundayo, the first weight-loss pill without food or water restrictions, cleared regulators April 1, launching a direct commercial assault on Novo Nordisk's oral Wegovy. The two-drug race now defines what analysts estimate as a $16 billion oral obesity market by 2030. Days earlier, Novo Nordisk struck back in a different lane: Awiqli, approved March 26, became the first once-weekly basal insulin for Type 2 diabetes, potentially upending a daily-dosing franchise long anchored by Sanofi's Lantus. Rare disease dominated the quarter's volume. Four approvals, including Rocket Pharmaceuticals' gene therapy Kresladi for a lethal pediatric immune disorder and Denali Therapeutics's enzyme replacement Avlayah for Hunter syndrome, reflect the FDA's accelerated-approval pathway operating at full stride. The pipeline ahead is equally consequential. A May 24 decision looms for LEQEMBI® (lecanemab-irmb) HCP's weekly subcutaneous starting dose, a potential home-administration breakthrough for Alzheimer's patients currently tethered to IV infusion centers. Also expected by June: baxdrostat (AstraZeneca), the first CYP11B2 inhibitor for treatment-resistant hypertension, and cytisinicline (Achieve Life Sciences), which would become the first new smoking-cessation pharmacotherapy in nearly two decades.  Novo Nordisk's CagriSema, a dual GLP-1/amylin combination showing 23% weight loss in trials , awaits a PDUFA date after its December NDA submission, with approval possible by late 2026. #FDA, #DrugApproval, #Biopharma, #PharmaceuticalIndustry #LifeSciences #ClinicalTrials #HIV #Merck #FDAApproval #Biopharma #CommercialExcellence #RealWorldEvidence #rwe #Foundayo

🦠 Major FDA Update: Two New Oral Therapies Approved for Gonorrhea 💊 December 12, 2025 U.S. Food and Drug Administration announced approval of two novel oral antibiotics for the treatment of uncomplicated urogenital gonorrhea a significant advance in sexually transmitted infection management, especially in the era of rising antimicrobial resistance. 📌 New Approvals: • Nuzolvence (zoliflodacin) – dissolvable granules (approved for adults & children ≥12 yrs, ≥77 lbs) • Blujepa (gepotidacin) – oral tablets (approved for adults & children ≥12 yrs, ≥99 lbs) These approvals mark an important milestone, expanding beyond traditional therapy (single-dose intramuscular ceftriaxone) and addressing a critical need given the global rise in drug-resistant Neisseria gonorrhoeae. 📊 Clinical Evidence: • Nuzolvence: ~91% cure rate vs ~96% with standard ceftriaxone + azithromycin in ~930 patients. • Blujepa: ~93% cure vs ~91% with standard therapy in ~628 patients. Both met non-inferiority benchmarks for bacterial clearance at 4–10 days post-treatment. ⚠️ Safety Considerations: 🔹 Nuzolvence: neutropenia, GI symptoms, dizziness; teratogenicity and fertility considerations seen in animal studies (labeling precautions). 🔹 Blujepa: GI upset, dizziness, headache, QTc prolongation, neurochemical effects — includes specific warnings. Both agents received Fast Track, Qualified Infectious Disease Product (QIDP), and Priority Review designations. 💡 Why This Matters: ✔ Adds oral treatment options for gonorrhea ✔ Critical for patients with limited access to injectable therapy ✔ Especially important as resistance to standard regimens rises globally These approvals represent progress in antimicrobial development where options have been limited for decades and reinforce the ongoing need for stewardship, surveillance, and tailored patient care. https://lnkd.in/eKS8ZDMs #InfectiousDiseases #AntimicrobialStewardship #Gonorrhea #FDA #AntibioticResistance #SexualHealth #PublicHealth #IDPharmacy #EmergingTherapies #AMR

Breakthroughs in Pediatric Neuro-Oncology: A New Era of Hope 🧠 I really enjoyed listening to a recent episode of the Cleveland Clinic Cancer Advances podcast, Dr. Amy Smith, the Director of Pediatric Neuro-Oncologist at Cleveland Clinic Children’s, discussed the rapidly evolving landscape of pediatric brain tumor treatment. For years, many pediatric brain tumors were treated similarly to adult cases, but we now know their biology is fundamentally different. These insights are leading to targeted therapies that are changing the "uniformly fatal" narrative of the past. strongly recommend you listen to the Podcast; Key Highlights from the Discussion: 1- Targeted Therapy for Low-Grade Gliomas: Low-grade doesn't always mean "benign." These slow-growing tumors can significantly impact a child's development. Dr. Smith highlights the 2024 FDA approval of tovorafenib, which targets the MAP kinase pathway. 2- A Milestone for Diffuse Midline Gliomas (DMG): In August 2025, the FDA granted accelerated approval to dordaviprone (Modeyso). This is the first systemic therapy approved for H3 K27M-mutant DMG, a disease that was previously considered untreatable. Beyond the "Home Run": While these drugs provide critical disease control, the real "win" lies in the future of combination therapies, using targeted agents alongside immunotherapy to improve long-term outcomes and quality of life. The Shift in Clinical Trials: The path to approval is getting faster. Dordaviprone went from first-in-human trials to FDA approval in just 10 years by utilizing pooled data from non-randomized trials; a potential blueprint for treating other rare pediatric tumors. #PediatricOncology #NeuroOncology #CancerResearch #ClevelandClinic #MedicalInnovation #BrainTumorAwareness

FDA Drug Approvals in 2025: A Year of Innovation #4 Key Trends and Conclusion The FDA has approved over 40 new drugs in 2025, reflecting significant advances across oncology, rare diseases, and immunology. We examine these approvals by therapeutic modality and indication. This is part 4: Key Trends and Conclusion 1. Precision Oncology Continues to Expand Multiple NSCLC approvals targeting specific mutations demonstrate the maturation of biomarker-driven therapy. Combination approaches like avutometinib/defactinib address historically difficult targets like KRAS. 2. RNA Therapeutics Come of Age Three siRNA/ASO approvals spanning coagulation disorders, lipid metabolism, and inflammatory disease confirm this modality's versatility beyond the liver. 3. Rare Disease Focus Nearly a quarter of approvals address orphan indications, incentivized by regulatory pathways and demonstrating that small patient populations can support drug development. 4. Antibody Innovation Beyond traditional monoclonals, bispecific antibodies (linvoseltamab) and novel targets (FcRn, Factor XII, APRIL) expand the therapeutic antibody toolkit. 5. New Mechanisms for Old Problems Non-opioid pain management (suzetrigine), new antibiotic classes for resistant infections (gepotidacin, zoliflodacin), and non-hormonal menopause treatment (elinzanetant) address significant unmet needs. 6. Nephrology Renaissance Multiple approvals for IgA nephropathy mark a transformation in treating this common cause of kidney failure. Pending Approvals Two additional drugs await FDA decisions: - Tradipitant – NK-1 receptor antagonist (indication pending) - Relacorilant – Glucocorticoid receptor modulator (indication pending) Conclusion The 2025 FDA approval class demonstrates pharmaceutical innovation across modalities and therapeutic areas. Small molecules remain the backbone of drug development, while biologics, particularly ADCs, bispecific antibodies, and RNA therapeutics, continue gaining ground. The strong representation of rare disease treatments and the emergence of new mechanisms for common conditions like pain and infection suggest a productive year for addressing both specialized and widespread medical needs. Data compiled from FDA approval announcements and public disclosures through 2025.

🌟 Big milestone in oncology: The FDA has approved dordaviprone (ONC-201) as the first systemic therapy for recurrent H3 K27M-mutant diffuse midline glioma in patients 2 years and older. This targeted oral drug 💊 brings hope for those battling this devastating brain cancer. As someone passionate about medical advancements, I'm thrilled to share what this means and the incredible journey behind it. The path to FDA approval for any new drug is long and fraught with challenges – ONC-201's story is no exception. The original chemical compound was discovered in the 1970s but it took some time for it to have oncology applications. In early 2010s through lab screening for compounds that could activate natural cancer-killing pathways, it faced early obstacles like a structural error that led to ineffective copies being tested. Overcoming this required rigorous science, from preclinical models to human trials. Founded by academics, the company Oncoceutics navigated funding hurdles, partnerships (like with MD Anderson), and an acquisition by Chimerix in 2021 to scale up. Clinical trials involved proving safety in diverse patients, gathering data on effectiveness, and meeting strict regulatory standards. It's a reminder that drug development often takes 10+ years, billions in investment, and resilience against setbacks – only a fraction of candidates succeed. This approval targets a particularly challenging disease: H3 K27M-mutant diffuse midline gliomas, including deadly forms like diffuse intrinsic pontine glioma (DIPG) in children. These tumors grow in critical brain areas, making surgery risky or impossible, and they resist traditional chemo and radiation. With a historical survival rate of just 9-11 months, families face immense emotional and logistical burdens, especially since it's rare and under-researched. Clinically, ONC-201 has shown remarkable impact. By selectively stressing cancer cells to trigger self-destruction (via pathways like TRAIL), it has extended median survival to about 21 months in studies, with some patients experiencing tumor shrinkage and improved quality of life. Data from five key trials and expanded access programs highlight durable responses, minimal side effects (like mild fatigue), and its ability to penetrate the brain – a huge win for non-invasive treatment. On the horizon, the ongoing Phase 3 ACTION study is evaluating ONC-201 for newly diagnosed patients, potentially in combination with other therapies to boost outcomes further. Research is expanding to other brain cancers and related compounds like ONC-206, paving the way for personalized medicine in neuro-oncology. Kudos to the scientists, clinicians, advocates, and brave patients who've driven this forward. What are your thoughts on accelerating drug approvals for rare cancers? Let's connect and discuss! #FDAApproval #Oncology #BrainCancer #DrugDevelopment #RareDiseases WeTrials OncoDaily Targepeutics

On topics of this review: Last week, what happened in Immune-Mediated Inflammatory Diseases (IMIDs), since February 9, 2026. 1. Regulatory Submissions & Approvals (Feb 2026) • Upadacitinib (Rinvoq) for Vitiligo: o Status: FDA and EMA applications submitted on Feb 3, 2026.[1][2][3][4] o Impact: Positioned to be the first-ever systemic (oral) therapy for non-segmental vitiligo.[2] o Clinical Data: Phase 3 Viti-Up trials showed over 75% facial re-pigmentation (F-VASI 75) in a significant portion of patients at 48 weeks.[2][3] • Brepocitinib for Dermatomyositis: o Status: New Drug Application (NDA) submitted to the FDA (Feb 8, 2026).[5] o Mechanism: Selective TYK2/JAK1 dual inhibitor.[6] o Significance: Targets a rare, debilitating inflammatory skin and muscle disease with very few approved options. • Depemokimab (Exdensur): o Status: Now entering clinics following its late December 2025 approval. o Note: It is the first biologic for severe eosinophilic asthma that requires only two doses per year (ultra-long-acting IL-5 inhibitor). 2. Clinical Pipeline & Trial Highlights • Icotrokinra (JNJ-2113) in Psoriasis: o Update: 52-week data from the ICONIC-TOTAL study presented this week shows 67% of patients achieved clear/almost clear skin.[7] o Mechanism: First-in-class oral IL-23 peptide.[8] o Competitive Edge: Efficacy now rivals leading injectable biologics, but in a once-daily pill format. • Nipocalimab (FcRn Blocker): o Update: J&J announced (Jan 6, 2026) the initiation of a Phase 3 program for Systemic Lupus Erythematosus (SLE) following positive Phase 2b JASMINE results.[9] o Expanded Reach: New data published in The Lancet also confirms its effectiveness in reducing autoantibody levels in Sjogren’s Disease. • Obefazimod in Ulcerative Colitis (UC): o Update: Phase 3 maintenance data (ABTECT program) is finalized; NDA submission to the FDA is confirmed for 2H 2026.[10] o Novelty: An oral miR-124 enhancer that represents a entirely new way to regulate immune homeostasis in the gut. 3. Scientific & Technology Breakthroughs • The Fn14 "Back-Door" Pathway in RA: o Finding: Research published last week (Jan 30, 2026) identified the Fn14 receptor as an alternate route for inflammation that bypasses traditional TNF-blockers.[11] o Clinical Potential: This explains why 40% of RA patients are non-responders to Humira/Enbrel and provides a new target for "dual-pathway" therapy. • Neuromodulation: o Status: First commercial use of the FDA-approved vagus nerve stimulator for RA has begun. o Mechanism: A leadless implant that "resets" the immune system via electrical pulses to the vagus nerve, reducing systemic cytokine production. • Rilzabrutinib Breakthrough: o Update: Sanofi's oral BTK inhibitor received FDA Breakthrough Therapy Designation today (Feb 9, 2026) for warm autoimmune hemolytic anemia (wAIHA).[12] Crossroads between autoimmunity and cancer: underlying mechanisms and clinical implications. https://lnkd.in/gwJYYVWt

In Q2 2024, the FDA approved several new drugs, as detailed in a recent analysis by Paul Verdin at Evaluate Pharma. Highlights include the first IL-15 receptor agonist, a telomerase inhibitor, and others. The following are some of the interesting ones. Anktiva (nogapendekin alfa inbakicept): Indication: BCG-unresponsive non-muscle invasive bladder cancer. Mechanism: Activates NK and CD8+ T cells, and CD4+ helper T cells. Sales Forecast: Over $1.6 billion by 2030. Approval: FDA breakthrough designation. Ohtuvayre (ensifentrine): Indication: Maintenance treatment of COPD. Mechanism: PDE3/4 inhibitor. Sales Forecast: $1.5 billion by 2030. Significance: First novel inhaled COPD therapy in over 20 years. Rytelo (imetelstat): Indication: Low- to intermediate-1 risk myelodysplastic syndromes. Mechanism: Inhibits telomerase, reducing malignant cell proliferation. Sales Forecast: $1.3 billion by 2030. Ojemda (tovorafenib): Indication: Relapsed/refractory pediatric low-grade glioma. Mechanism: Pan-RAF kinase inhibitor. Sales Forecast: Over $1 billion by 2030. Approval: Accelerated approval, requires confirmatory evidence. https://bit.ly/3S6i9Nw