Interim CDER head Høeg is out days after Makary: report

FDA's Interim CDER Director Høeg Departs Amid Controversy

Tracy Beth Høeg, the interim director of the FDA's Center for Drug Evaluation and Research (CDER), is reportedly exiting the agency, just days after FDA Commissioner Marty Makary resigned. Høeg served for approximately five months, making her the fifth person to hold the CDER post in the past 16 months, reflecting significant leadership instability. Her departure follows reports of internal tension, including an alleged disagreement with staff over expanding the label for Sanofi's diabetes drug, teplizumab (Tzield). Sanofi reportedly requested the drug's removal from the Commissioner’s National Priority Review program amidst this dispute. This turnover is part of broader workforce reductions and resignations at the FDA and HHS.

• Tracy Beth Høeg's reported exit as interim CDER Director signifies continued leadership instability at the FDA, occurring shortly after Commissioner Marty Makary's resignation. Høeg was the fifth individual to lead CDER in just 16 months, underscoring a period of high turnover and challenges in maintaining consistent leadership within the agency, particularly since the start of President Trump's second term.
• A key controversy preceding Høeg's departure involved Sanofi's diabetes drug, teplizumab (Tzield). Høeg allegedly disagreed with staff recommendations to expand the drug's label, leading Sanofi to reportedly request its removal from the Commissioner’s National Priority Review program. This incident highlights internal conflicts over regulatory decisions and potential impacts on drug development timelines.
• The press release points to a wider pattern of deep workforce reductions and widespread resignations across the FDA and its parent agency, HHS. Beyond Makary and Høeg, Vinay Prasad, who headed the Center for Biologics Evaluation and Research (CBER), also recently departed, with Katherine Szarama stepping in as acting director. This indicates systemic challenges in leadership and operational stability within the regulatory bodies.

Teplizumab's Safety and Tolerability Profile Across Indications

A comprehensive meta-analysis of 8 randomized controlled trials involving 1,052 patients (754 receiving teplizumab) demonstrates that while teplizumab does not significantly increase overall adverse event rates compared to placebo (OR = 2.25, 95%CI: 0.80-6.29, P = 0.12), it does present specific safety considerations across organ systems. The analysis revealed statistically significant increases in dermatological adverse effects (OR = 6.33, 95%CI: 4.05-9.88, P < 0.00001), hematological adverse effects (OR = 19.03, 95%CI: 11.09-32.66, P < 0.00001), and gastrointestinal adverse effects (OR = 1.60, 95%CI: 1.01-2.52, P = 0.04). Additionally, patients receiving teplizumab demonstrated significantly higher likelihood of active Epstein-Barr virus infection (OR = 3.16, 95%CI: 1.51-6.64, P < 0.002), highlighting the immunosuppressive effects of the therapy.

Phase 3 trial data from 516 patients aged 8-35 years with new-onset type 1 diabetes revealed similar overall adverse event rates between teplizumab and placebo groups (99% in both cohorts), with serious adverse events occurring in 10% of teplizumab recipients versus 9% of placebo recipients. However, rash emerged as the most distinctive clinical manifestation, affecting 53% of teplizumab-treated patients compared to 20% of placebo recipients. The prevention trials in 76 high-risk relatives demonstrated expected adverse events of rash and transient lymphopenia, with extended follow-up confirming the safety profile in individuals without established diabetes.

Real-world experience from Italian compassionate use programs in three adult patients with Stage 2 type 1 diabetes provides additional safety insights, showing generally well-tolerated treatment with manageable complications. One patient experienced mild transient transaminase elevation and lymphopenia that resolved spontaneously, another developed a 40% lymphocyte count reduction without clinical symptoms, and a third patient experienced mild cytokine-release syndrome on day 5 that resolved with supportive care but necessitated treatment discontinuation due to patient anxiety. These findings underscore that while adverse effects are typically mild and transient, the requirement for intravenous administration and potential for generalized immunosuppression present practical challenges for routine clinical implementation.

Navigating the Evolving Diabetes Treatment Landscape

The diabetes treatment landscape has undergone substantial transformation over the past five years, characterized by a pronounced shift toward novel therapeutic classes with demonstrated cardiovascular and renal benefits. The most notable change has been the rapid adoption of GLP-1 receptor agonists and SGLT2 inhibitors as preferred therapeutic options. From 2019 to 2023, first-line use of GLP-1RAs increased dramatically from 6% to 18%, while SGLT2 inhibitor use grew from 4% to 7%. This expansion occurred alongside a corresponding decline in traditional metformin monotherapy from 76% to 64%, reflecting evolving clinical practice patterns that prioritize agents with proven cardiovascular protective effects. Danish registry data corroborates this trend, showing a 6-fold increase in GLP-1RA initiators and 3-fold increase in SGLT2 inhibitor initiators between 2016 and 2023, with treatment initiation occurring at progressively lower HbA1c levels.

Clinical trial evidence has fundamentally reshaped therapeutic positioning within the diabetes treatment algorithm. SGLT2 inhibitors and GLP-1 receptor agonists have achieved prominent positions due to demonstrated reductions in major adverse cardiovascular events, with regulatory authorities now requiring cardiovascular safety evidence for new antidiabetic agent approvals. Comparative effectiveness data reveals that SGLT2 inhibitors demonstrate superior outcomes for heart failure hospitalization and renal endpoints, while GLP-1RAs show particular benefit for stroke prevention. The emergence of dual GIP/GLP-1 receptor agonists, exemplified by tirzepatide, represents a significant therapeutic advancement with cost-effectiveness ratios of $25,563 to $59,434 per quality-adjusted life year when compared to existing GLP-1RAs. Expert consensus now recommends early implementation of agents with proven cardiovascular benefits, advocating for GLP-1RA use at earlier disease stages than SGLT2 inhibitors, particularly in patients with subclinical atherosclerotic disease.

Despite therapeutic advances, significant gaps in optimal diabetes management persist globally. Only 21.2% of all people with diabetes worldwide achieved optimal glycemic concentrations on treatment in 2023, with substantial delays in treatment intensification remaining problematic. The cumulative probability of initiating basal insulin reached only 43.1% at 8-year follow-up despite clear clinical indications, highlighting persistent therapeutic inertia. Novel therapeutic approaches under investigation include triple receptor agonist retatrutide, which demonstrated HbA1c reductions up to 2.02% and weight loss up to 16.94% in phase 2 trials, and regenerative approaches using mesenchymal stem cells showing promising preliminary results. The treatment paradigm increasingly emphasizes combination therapy approaches and fixed-ratio formulations to address both glycemic control and cardiovascular risk reduction simultaneously.

Addressing Key Unmet Needs in Diabetes Treatment

Recent literature highlights several critical populations and unmet needs in diabetes care, with particular emphasis on addressing health inequities and improving access to quality care. Geographic and socioeconomic disparities remain a central concern, with patients in disadvantaged and rural areas consistently showing lower rates of optimal diabetes management. The emergence of early-onset type 2 diabetes and challenges in pediatric-to-adult care transitions represent growing areas of clinical focus.

• Geographic and socioeconomic disparities - Patients in the most deprived areas (ADI quintile 5) versus least deprived (quintile 1) show significant care gaps: 56% vs 72% obtained at least 1 A1c test and 62% vs 70% adherence to noninsulin medications, with $363.50 higher per-member-per-month costs in deprived areas

• Young adults and transition care challenges - The transition from pediatric to adult care represents a critical vulnerability period, with young adults with type 1 diabetes experiencing gaps in care engagement and suboptimal health outcomes during this transition

• Black young adults with type 1 diabetes - This population faces unique diabetes distress challenges that contribute to health disparities, with few interventions designed to center their specific experiences and needs

• Digital health access disparities - Paradoxically, patients in poorer health are less likely to use digital health solutions despite potentially benefiting most, with data security concerns reducing likelihood of adoption by up to 89%

• Early-onset type 2 diabetes - Increasing diagnosis in adolescents and young adults presents a public health challenge requiring a paradigm shift from treatment-focused to prevention-focused approaches

• Elderly and frail populations - Patients aged ≥75 years with type 2 diabetes, particularly those with severe frailty, present complex management challenges with limited evidence for advanced diabetes technology in this population

• Screening and prevention gaps - Despite widespread glucose screening recommendations, prediabetes screening and treatment remain suboptimal, with the greatest improvements seen among uninsured patients (OR=3.8) following 2015 USPSTF recommendations

• Data-scarce regions - Sub-Saharan Africa, particularly Zimbabwe, lacks comprehensive diabetes prevalence data and etiologic characterization, with classification relying primarily on clinical criteria at diagnosis

FDA Turmoil Casts Shadow on Breakthrough T1D Therapy

The recent leadership changes within the FDA's Center for Drug Evaluation and Research (CDER), particularly the swift departure of its interim director amid reports of internal tension, sends ripples across the pharmaceutical industry. This instability, reportedly linked to disagreements over expanding the label for Sanofi's teplizumab (Tzield), highlights a critical challenge in the regulatory environment for novel therapies. Teplizumab represents a significant advancement, being the first FDA-approved disease-modifying treatment to delay the onset of clinical Type 1 Diabetes (T1D). Its approval marked a paradigm shift from merely managing symptoms with insulin to actively intervening in the autoimmune process that destroys pancreatic beta cells.

Clinical literature consistently demonstrates teplizumab's ability to preserve beta-cell function, increase C-peptide levels, and reduce exogenous insulin requirements in patients, particularly when administered early in the disease course or in new-onset T1D. This evidence underpins the strategic importance of expanding its label beyond the initial indication of delaying progression from Stage 2 to Stage 3 T1D. However, the reported regulatory friction suggests that even breakthrough therapies face substantial hurdles in achieving their full clinical and market potential.

For Sanofi, this situation introduces considerable uncertainty into its commercial strategy for teplizumab. Delays or increased difficulty in securing label expansions could limit the drug's reach to a broader patient population that stands to benefit from its unique mechanism of action. More broadly, the perceived lack of regulatory predictability and internal cohesion at a key agency like the FDA could deter investment in other complex, high-risk therapeutic areas, potentially slowing the pace of innovation across the industry. Ultimately, the most significant risk lies with patients, who may experience delayed access to therapies that could profoundly improve their quality of life and long-term health outcomes by addressing the underlying autoimmune pathology of diseases like T1D. Ensuring a stable, transparent, and scientifically driven regulatory pathway is paramount for fostering continued progress in medical science.