A Review of the Unique Drug Development Strategy of Indacaterol Acetate/Glycopyrronium Bromide/Mometasone Furoate: A First-in-Class, Once-Daily, Single-Inhaler, Fixed-Dose Combination Treatment for Asthma.

A novel, once-daily (o.d.), fixed-dose combination (FDC) of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF), delivered by the inhaler Breezhaler® device, is the first long-acting beta2-adrenergic agonist/long-acting muscarinic antagonist/inhaled corticosteroid (LABA/LAMA/ICS) therapy to be approved for maintenance treatment of asthma in adults inadequately controlled on LABA/ICS. The approval of IND/GLY/MF in the European Union (EU) also included an optional electronic sensor and smartphone (or other suitable device) application, making it the first "digital companion" that can be prescribed with an asthma medication. As a result, the European Medicines Agency included this approval as one of the "outstanding contributions to public health" (for Pneumology/Allergology) in their 2020 highlights report. Alongside IND/GLY/MF, an o.d. LABA/ICS FDC, IND/MF, was also developed and approved. This review outlines the unique strategy used in the accelerated development of IND/GLY/MF that combined various approaches: (1) selecting individual components with established efficacy/safety, (2) bridging doses to optimize efficacy/safety of IND/GLY/MF and IND/MF delivered via the Breezhaler® device, (3) developing IND/GLY/MF and IND/MF in parallel, and (4) submission for regulatory approval before formal completion of the pivotal phase III studies. IND/GLY/MF and IND/MF were combined in a single-development plan (PLATINUM program), which comprised four phase III studies: QUARTZ and PALLADIUM evaluated IND/MF while IRIDIUM and ARGON evaluated IND/GLY/MF. A unique feature was the inclusion of two LABA/ICS comparators in the pivotal IRIDIUM study-IND/MF as an internal comparator, and high-dose salmeterol xinafoate/fluticasone propionate (SAL/FLU) as a marketed comparator. In the ARGON study, IND/GLY/MF was compared against o.d. tiotropium (via Respimat®) plus twice-daily (b.i.d.) high-dose SAL/FLU (via Diskus®). As a result of this development strategy, the development and approval of IND/GLY/MF was accelerated by ca. 4 years as against what would be expected from a traditional approach, novel data were generated, and a unique optional digital companion was approved in the EU. A Video Abstract by Dr Dominic Brittain, Global Drug Development, Novartis. (MP4 228293 kb).

Water-Soluble Iridic-Porphyrin Complex for Non-invasive Sonodynamic and Sono-oxidation Therapy of Deep Tumors.

Due to conventional photodynamic therapy encountering serious problems of phototoxicity and low tissue-penetrating depth of light, other dynamic therapy-based therapeutic methods such as sonodynamic therapy (SDT) are expected to be developed. To improve the therapeutic response to SDT, more effective sonosensitizers are imperative. In this study, a novel water-soluble iridium(III)-porphyrin sonosensitizer (IrTMPPS) was synthesized and used for SDT. IrTMPPS generated ample singlet oxygen (1O2) under US irradiation and especially showed distinguished US-activatable abilities at more than 10 cm deep-tissue depths. Interestingly, under US irradiation, IrTMPPS sonocatalytically oxidized intracellular NADH, which would enhance SDT efficiency by breaking the redox balance in the tumor. Moreover, IrTMPPS displayed great sonocytotoxicity toward various cancer cells, and in vivo experiments demonstrated efficient tumor inhibition and anti-metastasis to the lungs in the presence of IrTMPPS and US irradiation. This report gives a novel idea of metal-based sonosensitizers for sonotherapy by fully taking advantage of non-invasiveness, water solubility, and deep tumor therapy.

Mitochondria-targeted Ir@AuNRs as bifunctional therapeutic agents for hypoxia imaging and photothermal therapy.

Ir(iii) complex modified gold nanorods, Ir@AuNRs, were developed as mitochondria-targeted theranostic nanoagents. Their hypoxia imaging and photothermal therapeutic properties were demonstrated in vitro and in vivo.

Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma.

Orthotopic liver transplantation (OLT) alone for unresectable cholangiocarcinoma is often associated with early disease relapse and limited survival. Because of these discouraging results, most programs have abandoned OLT for cholangiocarcinoma. However, a small percentage of patients have achieved prolonged survival after OLT, suggesting that adjuvant approaches could perhaps improve the survival outcome. Based on these concepts, a protocol was developed at the Mayo Clinic using preoperative irradiation and chemotherapy for patients with cholangiocarcinoma. We report our initial results with this pilot experience. Patients with unresectable cholangiocarcinoma above the cystic duct without intrahepatic or extrahepatic metastases were eligible. Patients initially received external-beam irradiation plus bolus fluorouracil (5-FU), followed by brachytherapy with iridium and concomitant protracted venous infusion of 5-FU. 5-FU was then administered continuously through an ambulatory infusion pump until OLT. After irradiation, patients underwent an exploratory laparotomy to exclude metastatic disease. To date, 19 patients have been enrolled onto the study and have been treated with irradiation. Eight patients did not go on to OLT because of the presence of metastasis at the time of exploratory laparotomy (n = 6), subsequent development of malignant ascites (n = 1), or death from intrahepatic biliary sepsis (n = 1). Eleven patients completed the protocol with successful OLT. Except for 1 patient, all had early-stage disease (stages I and II) in the explanted liver. All patients who underwent OLT are alive, 3 patients are at risk at 12 months or less, and the remaining 8 patients have a median follow-up of 44 months (range, 17 to 83 months; 7 of 9 patients > 36 months). Only 1 patient developed tumor relapse. OLT in combination with preoperative irradiation and chemotherapy is associated with prolonged disease-free and overall survival in highly selected patients with early-stage cholangiocarcinoma.

Pharmacomodulations on new organometallic complexes of Ir, Pt, Rh, Pd, Os: in vitro and in vivo trypanocidal study against Trypanosoma brucei brucei.

New organometallic complexes have been synthesized by association of an active organic molecule with a metallic element such as Pt, Rh, Ir, Pd, Os. Their trypanocidal activity was studied in vitro and in vivo against T. b. brucei. The more active compounds were pentamidine derivatives. The Ir- COD-pentamidine complex, and Iridium (I) cationic and organometallic complex showed and in vitro activity at 60 micrograms/l. Moreover, all infected mice were cured by this compound subcutaneously administered in a single dose at 0.5 mg/kg (0.317 mumol/kg). In the same conditions, pentamidine cured all the mice at 5 mumol/kg. Ir-COD-pentamidine (or P1995) was 16 fold more efficient than pentamidine. Since the chemotherapeutic index of this molecule was 7.5 fold higher than those of pentamidine, P1995 can be considered as a potential trypanocidal drug of the future.

Interstitial thermoradiotherapy for recurrent or persistent tumours.

Between 1984 and 1986, 31 sites in 27 patients with biopsy proven tumours were treated with a combination of interstitial microwave hyperthermia (HT) and iridium 192 implants (RT). The 31 sites treated included fifteen (48 per cent) head and neck, six (20 per cent) breast, four (13 per cent) vagina and cervix, and six (20 per cent) others. All patients had prior surgery, RT, or chemotherapy. Of the 31 sites treated, 19 (61 per cent) had complete response (CR) with no recurrence in the volume treated. Additionally, eight patients remained free of tumour from 3 to 24 months. Partial response (PR) was seen in 11 (36 per cent) sites while one (3 per cent) had lesser degree tumour regression. Tumour control rate correlated well with the dose of radiation, p = 0.02, and tumour volume, p = 0.02, but not with thermal dose. Treatment complications of significance occurred in one (3 per cent) site, which developed soft tissue necrosis. This study again has demonstrated the effectiveness of RT-HT combination in treatment of recurrent tumours.

[Initial experiences with interstitial brachycurietherapy (low dose rate I-125 seeds in carrier/vicryl and high dose rate Ir-192 afterloading system) in the palliative treatment of head and neck tumors]. / Erste Erfahrungen mit interstitieller Brachycurietherapie (low-dose-rate J-125-seeds in carrier/Vicryl bzw. high-dose-rate Ir-192-afterloading system) in der Palliativbehandlung von Kopf-Hals-Tumoren.

The local control rates for previously irradiated recurrent tumours of the head and neck is dose dependent. High dose percutaneous irradiation alone is associated with a high complication rate. On the other hand it is possible to apply high local doses by interstitial irradiation, whilst sparing the surrounding tissue. In the last 2 years we have used Iodine 125-seeds in carrier (Vicryl) and a high dose rate Iridium 192-source for the afterloading technique. Our first experiences with 12 patients show reasonable palliation, but not effect on survival.

Interstitial hyperthermia and iridium brachytherapy in treatment of malignant glioma. A phase I clinical trial.

An oncolytic effect of hyperthermia in the 42 degrees to 43 degrees C range has been previously demonstrated in cell culture and animal models. To apply this modality clinically, an interstitial microwave antenna array system has been developed for the delivery of controlled hyperthermia to an intracranial tumor volume, and a Phase I clinical trial involving six patients with malignant gliomas was undertaken. The protocol to study technical feasibility and patient tolerance combined interstitial iridium-192 irradiation and interstitial hyperthermia with 60-minute hyperthermia sessions immediately before and after brachytherapy. After-loading catheters suitable for both treatment modalities were implanted using a computerized tomography-assisted technique. Thermometry data confirmed the ability of a microwave antenna system to achieve reliable temperature distributions, and reasonable patient tolerance was documented.

Interstitial radiation implantation for unresectable nonoat cell carcinoma of the lung. Techniques and preliminary results.

The majority of lung cancers are unresectable at diagnosis. The radiation tolerance of the surrounding spinal cord and heart limits the external radiation therapy dose. Interstitial radiation implantation was utilized to deliver higher radiation dose, sparing the surrounding normal tissues in patients with unresectable nonoat cell cancers of the lung less than 8 cm in diameter localized to the thorax with no associated pleural effusion. The methods of implantation included permanent interstitial iodine-125 implantation of the gross disease in the lung and/or lymph nodes delivering about 120 Gy (12,000 rads) in 1 year and removable iridium-192 interstitial implantation of residual disease in the mediastinum, chest wall, or margin or resection in the lung, delivering about 30 Gy (3000 rads) in three days. Supplementary external radiation therapy of 40 Gy (4000 rads) in 4 weeks is delivered 4-6 weeks after implantation. The interstitial implant procedure adds only about 45 minutes to 1 hour to the operating time, and converts a palliative procedure into a potentially curative treatment. This article presents our experience with 11 cases, with early short-term follow-up results, and is designed to stimulate others to evaluate a similar approach to improve local control and survival in unresectable lung cancers.

Improved response of a murine fibrosarcoma (Meth-A) to interstitial radiation when combined with hyperthermia.

Removable Iridium-192 implants provided a dose of 10 Gy/day or 41.5 cGy/hr at 0.5 cm from the center of 1.0 cm diameter tumors. The total radiation (x) alone was 20, 40 or 60 Gy, representing 2, 4, or 6 days of continuous radiation. The doses used for the combined treatments at elevated temperatures were 10, 20 or 30 Gy. The local tumor hyperthermia (LTH) treatment (43.6 for 35 min, water bath) was administered once for each 10 Gy of dose. The combined radiation + LTH was clearly superior to that achieved with radiation or LTH alone and yielded Thermal Enhancement Ratios (TER) of 3.4-3.9. Local tumor control rate was 67% and 89% for the 20 and 30 Gy x + LTH groups, respectively. A comparison of the results obtained in this study with those of earlier studies on the same tumor system indicate that the effects of Iridium-192 alone on this rapidly proliferating tumor were comparable to similar total doses of fractionated external beam radiation. Iridium + LTH produced a tumor response comparable to that achieved with external fractionated radiation + LTH. Combined treatment effect of elevated temperature appears to be less dose rate dependent in the range of 40 cGy/hr to 100 cGy/min and more dependent upon total dose accumulation.

Results of the treatment of 165 lid carcinomas by iridium wire implant.

A group of 160 adult patients with epithelial tumors of the lid and/or canthi treated by iridium 192 wire implant are presented. There were 165 epithelial tumors, most of them were basocellular type (85%). In all cases, a nonradioactive procedure was used with disposable angiocatheters before introducing active wires. Respectively, 111/114 (97.4%) of "new" lesions and 48/51 (94%) of previously treated tumors were definitively cured by iridium wire implant. Among the 6 local recurrences, 4 were salvaged by a second iridium implant, and the two others by extensive surgery. Local side effects were present in 30 patients (18%): impairment of the eyelid aperture 9, stenosis of lacrymal ducts 7, eversion of the lid 7, lack of substance 7. These postherapeutic complications were significantly more frequent in treating recurrent lesions (15/48, 31.2%) than in previously untreated tumors (15/112, 13.4%). No visual complication was observed even in the early patients of this series.

Tumoricidal effects of sodium hexachloroiridate on an ascitic tumor in mice.

Sodium hexachloroiridate injected 1 day after i.p. injection of 10(6) mouse ovarian tumor cells prevents the appearance of ascitic tumors in mice. Mice given injections of tumor cells all die at 20 to 30 days after tumor injection. Mice treated with sodium hexachloroiridate after tumor injection either have significant prolongation of life span without ascites or show no evidence of cancer even up to 7 months after tumor injection.