Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes.

It has been 100 years since the life-saving discovery of insulin, yet daily management of type 1 diabetes (T1D) remains challenging. Even with closed-loop systems, the prevailing need for persons with T1D to attempt to match the kinetics of insulin activity with the kinetics of carbohydrate metabolism, alongside dynamic life factors affecting insulin requirements, results in the need for frequent interventions to adjust insulin dosages or consume carbohydrates to correct mismatches. Moreover, peripheral insulin dosing leaves the liver underinsulinized and hyperglucagonemic and peripheral tissues overinsulinized relative to their normal physiologic roles in glucose homeostasis. Disease-modifying therapies (DMT) to preserve and/or restore functional ß-cell mass with controlled or corrected autoimmunity would simplify exogenous insulin need, thereby reducing disease mortality, morbidity, and management burdens. However, identifying effective DMTs for T1D has proven complex. There is some consensus that combination DMTs are needed for more meaningful clinical benefit. Other complexities are addressable with more innovative trial designs and logistics. While no DMT has yet been approved for marketing, existing regulatory guidance provides opportunities to further "de-risk" development. The T1D development ecosystem can accelerate progress by using more innovative ways for testing DMTs for T1D. This perspective outlines suggestions for accelerating evaluation of candidate T1D DMTs, including combination therapies, by use of innovative trial designs, enhanced logistical coordination of efforts, and regulatory guidance for expedited development, combination therapies, and adaptive designs.

Phase 1b study of AVB-500 in combination with paclitaxel or pegylated liposomal doxorubicin platinum-resistant recurrent ovarian cancer.

OBJECTIVE: GAS6 and AXL are expressed in high-grade serous ovarian cancer but not in normal ovarian tissue. AVB-500, a novel high affinity Fc-sAXL fusion protein, binds GAS6 preventing AXL signaling. This Phase 1b study (NCT03639246) evaluated safety, efficacy, and exploratory predictive markers of AVB-500 combined with paclitaxel (PAC) or pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer (PROC), and used a model informed drug development (MIDD) approach for identification of the recommended phase 2 dose (RP2D). METHODS: Eligible patients received AVB-500 at 10, 15, or 20 mg/kg IV q2wk combined with PAC (n = 23) or PLD (n = 30). Patients were treated until progression or unacceptable toxicity. All were followed for survival. RESULTS: No dose limiting toxicities were observed and serum GAS6 was completely suppressed across the three dose levels evaluated. AVB-500 + PAC yielded better clinical activity than AVB-500 + PLD with an ORR of 34.8% (8/23, 2 complete responses) and median DoR, PFS, and OS of 7.0, 3.1, and 10.3 months, respectively. Subgroup analyses showed AVB-500 + PAC patients who had no prior bevacizumab or whose AVB-500 trough levels were >13.8 mg/L exhibited the best clinical response. The ORR and median PFS and OS in patients with these characteristics were ≥50%, ≥7.5 months, and ≥19 months, respectively. Given AVB-500 nor the combination with chemotherapy was expected to cause DLTs, the RP2D of AVB-500 was 15 mg/kg identified using an MIDD approach. CONCLUSION: AVB-500 was well-tolerated in combination with PAC or PLD and contributed to the clinical activity of PAC in PROC patients. Subgroup analyses identified a population of PROC patients who may benefit the most from AVB-500 treatment, which will be further assessed in an ongoing Phase 3 PROC trial.

Presumed "sulfa allergy" in patients with intracranial hypertension treated with acetazolamide or furosemide: cross-reactivity, myth or reality?

PURPOSE: To determine whether acetazolamide or furosemide produce allergic cross-reactions in patients with self-reported "sulfa allergy." DESIGN: Retrospective case series. METHODS: A retrospective review included patients with intracranial hypertension and a self-reported sulfa allergy treated with either acetazolamide or furosemide seen at the University of Iowa Hospitals and Clinics from 1972 to 2003. All presumed medication-related side effects were collected, including both predictable adverse effects (for example, paresthesias, fatigue) and unpredictable adverse reactions (for example, cutaneous fixed eruptions, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, anaphylaxis). RESULTS: We reviewed 363 charts. Of these, 329 patients (91%) were excluded. Of the remaining 34 cases that did report a so-called sulfa allergy, 13 (38%) received acetazolamide alone, 7 (21%) received furosemide alone, and 14 (41%) received both acetazolamide and furosemide. Of the 27 patients who received acetazolamide, 10 (37%) had no documented allergic cross-reaction to sulfa, and 2 (7%) cases had urticaria. The remaining 15 (56%) of acetazolamide-treated patients experienced predictable adverse reactions for this drug (for example, paresthesias). No patient experienced a severe allergic cross-reaction to sulfa. Of 21 patients who received furosemide, no unpredictable adverse reactions or allergic cross-reactions to sulfa were noted. CONCLUSIONS: We find little clinical or pharmacological evidence to suggest that a self-reported sulfa allergy is likely to produce a life-threatening cross-reaction with acetazolamide or furosemide. These medications should be considered for intracranial hypertension if the risk-to-benefit ratio warrants their use.