Summary Basis of Decision for Cresemba

Clinical Pharmacology

The medicinal ingredient of Cresemba is isavuconazole, as isavuconazonium sulfate. Isavuconazonium sulfate is the prodrug of isavuconazole, an azole antifungal.

Isavuconazole demonstrated a fungicidal effect by blocking the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P450 (CYP) dependent enzyme lanosterol 14-alpha-demethylase, responsible for the conversion of lanosterol to ergosterol. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane, thus weakening the structure and function of the fungal cell membrane.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic (PK) studies. The clinical pharmacological data support the use of Cresemba for the specified indication.

Isavuconazole is an inhibitor of CYP enzymes CYP3A4 and CYP3A5, and P-glycoprotein. Isavuconazole also acts as a CYP2B6 inducer and therefore has the potential for interactions with other medicinal products. Drug-interaction studies with specific drugs were performed, and the results and recommendations based on these studies as well as theoretical drug interactions are presented in the Cresemba Product Monograph.

The PK studies in hepatically-impaired subjects indicated that hepatic impairment due to cirrhosis caused a significant effect on total and unbound systemic exposures of isavuconazole. Additionally, the concentration of isavuconazonium sulfate in hepatically-impaired subjects was greater compared to healthy subjects in both routes of administration suggesting that exposures of isavuconazonium sulfate was changed by the hepatic condition.

The PK studies demonstrated an increase in total isavuconazole exposure of approximately 30% to 48% when isavuconazole was administered intravenously to subjects with mild liver impairment, and an increase of approximately 69% to 106% when administered intravenously to subjects with moderate liver impairment. When orally administered to subjects with mild liver impairment, there was an increase of approximately 27% to 41%. An increase in exposure of approximately 30% to 85% was reported when isavuconazole was administered orally to subjects with moderate liver impairment. Isavuconazole has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), and therefore use in these patients is not recommended unless the potential benefit is considered to outweigh the risks. These patients should be carefully monitored for potential drug related liver toxicity.

For further details, please refer to the Cresemba Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Cresemba (isavuconazole as isavuconazonium sulfate) for the treatment of invasive fungal disease caused by Aspergillus and Mucorales species was supported by two pivotal Phase III studies (Study 9766-CL-0104 and Study 9766-CL-0103), respectively. In both studies, the majority of patients infected with invasive fungal disease caused by Aspergillus or Mucorales species were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, graft-versus-host disease, and hematopoietic stem cell transplant. The majority of patients with invasive mucormycosis had pulmonary disease involvement and half of them had other organ involvement. The median treatment duration was generally longer in the treatment of invasive mucormycosis than in the treatment of invasive aspergillosis. Several mucormycosis patients received treatment for more than 6 months.

Invasive Aspergillosis (Study 9766-CL-0104)

Study 9766-CL-0104 was a Phase III randomized, multicentre, double-blind, non-inferiority, comparative, active-controlled study to evaluate non-inferiority of Cresemba vs. voriconazole (VRC) for primary treatment of invasive fungal disease caused by Aspergillus species or other filamentous fungi.

The intent-to-treat (ITT) population contained a group of 258 patients who received Cresemba and a matching control group of 258 patients who received VRC. The modified ITT (mITT) population were patients who had proven or probable invasive fungal disease as determined by a Data Review Committee. Of the number of patients in the mITT population, 143 were in the Cresemba treatment arm and 129 in the VRC treatment arm (in patient numbers approximately 50% of the ITT population). Another population, the mycological Intent-to-Treat (myITT) population, was a group of mITT patients with proven or probable invasive aspergillosis based on cytology, histology, culture or Galactomannan criteria (number of patients [n] = 123 for Cresemba and n = 108 for VRC). The species of Aspergillus involved were mostly Aspergillus fumigatus, Aspergillus flavus, and Aspergillus terreus. The majority of ITT patients in both groups had baseline hematologic malignancy and neutropenic. Twenty-percent of them were prior allogeneic bone marrow transplant recipients. The majority of the ITT patients were male and white. Most were non-Hispanic or Latino. Nearly half of the ITT patients were from Western Europe, Australia, and New Zealand and 11 percent of the patients were from North America. Demographic features of the mITT patients (including myITT) were similar to the ITT patient cohort. Over 90% of the mITT patients had lower respiratory tract disease (LRTD) at baseline and only 8% of the patients had non-LRTD invasive fungal disease when treatment started.

A loading dose of Cresemba (200 mg three times daily [TID] on Days 1 and 2) or VRC (6 mg/kg every 12 hours [q12h] on Day 1) was administered via the intravenous (IV) route, and then followed by maintenance doses of Cresemba (200 mg once daily IV or oral from Day 3 to end of treatment) or VRC (4 mg/kg q12h IV or 200 mg q12h orally from Day 2 to end of treatment). The median dosing duration of Cresemba in the ITT population was 45 days. The median IV dosing only duration of Cresemba in the ITT population was 5 days. The maximum dosing duration of this study was 84 days for the ITT population.

The all-cause mortality at Day 42 in the ITT population (primary efficacy endpoint) was 18.6% in the Cresemba arm and 20.2% in VRC arm. The study met the primary objective of demonstrating non-inferiority of Cresemba relative to VRC. The upper bound of the 95% confidence interval (CI) of 5.9 around the adjusted treatment difference (Cresemba minus VRC: -1.0%) was lower than the pre-specified non-inferiority margin of 10%. The all-cause mortality through Day 42 in the Aspergillus-infected population (myITT) also met the non-inferiority criteria for Cresemba-treated patients (18.7%) vs. 22.2% in VRC-treated patients (Cresemba minus VRC: -2.7%, upper bound of 95% CI: 7.54). Similar results were reported in all-cause mortality rates at Day 84. Most of the patient deaths at Day 42 and Day 84 were attributed to the consequences of the invasive fungal disease progression. The treatment failure rates (including stable and progression) for the myITT population at end of treatment in the Cresemba and VRC arms were similar (65.0% and 61.1%, respectively).

The overall success rates (including complete and partial response) in the myITT population at the end of treatment showed non-inferiority for the Cresemba-treated patients as compared to VRC-treated patients (VRC minus Cresemba: 4.0%; 95% CI: -7.97, 15.88) (>-10%). It is noted and acceptable that the overall response rates presented in Table 12 of the Cresemba Product Monograph is Cresemba minus VRC in which case the difference between the treatment groups is -4% and the upper bound of the 95% CI: 8.4 which is lower than +10% for a favourable non-inferiority judgement.

Invasive Mucormycosis (Study 9766-CL-0103)

Study 9766-CL-0103 was an open-label, single-arm study of Cresemba in the treatment of patients with aspergillosis and renal impairment, or of patients with invasive fungal disease caused by rare moulds, yeasts or dimorphic fungi (ITT, n = 146). The primary efficacy endpoint was the efficacy of Cresemba in the invasive aspergillosis with renal impairment or in patients with invasive fungal diseases caused by rare moulds including Mucorales, yeasts or dimorphic fungi. Descriptions of Cresemba treatment were focused on two distinct patient groups among the ITT population: patients infected with invasive mucormycosis caused by Mucorales species (mIT-Mucorales) (n = 37) and patients infected with aspergillosis and with renal impairment (mITT-Aspergillus) (n = 57). In the ITT cohort, 47% of patients had underlying malignancy at baseline. In the mITT-Mucorales cohort, 60% of patients had hematologic malignancy at baseline and half of the patients were immunocompromised. Fifty-nine percent (59%) of these patients had pulmonary disease involvement, half of whom also had other organ involvement. The most common non-pulmonary disease locations were sinus (43%), eye (19%), central nervous system (16%) and bone (14%).

The 37 patients with Mucorales-only infection were assessed by the Data Review Committee (DRC) as having a proven or probable Mucorales infection. The most common pathogens were Rhizopus oryzae and Mucormycetes. There were a few patients with other Mucorales including Lichtheimia corymbifera, Mucor amphibiorum, Mucor circinelloides, Rhizomucor pusillus, Rhizopus azygosporus, and Rhizopus microspores. The DRC also categorized each patient in the mITT-Mucorales cohort by therapy status; these groups were primary therapy, refractory and intolerant. There were 21 patients receiving Cresemba as primary therapy (56.8%), 11 patients refractory to prior antifungal treatment (29.7%) and 5 patients intolerant to prior antifungal treatment (13.5%). The median treatment duration was 84 days (2 to 882 days) for the overall mucormycosis patient population (102 days for patients receiving Cresemba as a primary therapy, 33 days for patients refractory to prior antifungal treatment and 85 days for patients intolerant to prior antifungal treatment). There were 7 patients in the mITT-Mucorales cohort who received treatment for longer than 6 months.

The all-cause mortality rates through Day 42 and Day 84 for the ITT population were 19% and 25%, respectively. For the mITT-Mucorales cohort, the all-cause mortality rates through Day 42 and Day 84 were 38% and 43%, respectively. There were similar rates of all-cause mortality in patients treated with Cresemba as primary therapy or in patients refractory or intolerant to prior antifungal treatment at each time point. The overall response rate at the end of treatment (i.e., success rate) was 31% in the mITT-Mucorales cohort and the rate was similar in patients with Cresemba as primary therapy or in patients refractory or intolerant to prior antifungal treatment. Although these results provide certain evidence for Cresemba as an effective treatment for mucormycosis, it has not been evaluated under vigorous, well-controlled clinical trials.

Indication

The New Drug Submission for Cresemba was filed by the sponsor with the following indication which was approved by Health Canada.

Cresemba (isavuconazole, as isavuconazonium sulfate) is an azole antifungal indicated for use in adults for the treatment of:

• Invasive aspergillosis;
• Invasive mucormycosis.

For more information, refer to the Cresemba Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The Phase III clinical studies involved 403 patients with invasive fungal infections treated with Cresemba. The most frequently reported adverse reactions among patients treated with Cresemba were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (16%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%). In both studies, serious adverse reactions occurred in 223/403 (55%) of patients, and 56/403 (14%) of patients permanently discontinued treatment with Cresemba due to an adverse reaction. The adverse reactions which most often led to permanent discontinuation of Cresemba therapy were confusional state (0.7%), acute renal failure (0.7%), increased blood bilirubin (0.5%), convulsion (0.5%), dyspnea (0.5%), epilepsy (0.5%), respiratory failure (0.5%), and vomiting (0.5%).

In the randomized, double-blind, active-controlled clinical study for treatment of invasive aspergillosis (Study 9766-CL-0104), treatment-emergent adverse reactions occurred in 247/257 (96%), and 255/259 (99%) patients in the Cresemba and VRC treatment groups, respectively. Treatment-emergent adverse reactions resulting in permanent discontinuation were reported in 37 (14%) Cresemba-treated patients and 59 (23%) in VRC-treated patients. All-cause mortality was the primary efficacy endpoint for the treatment groups of this study. The proportion of all known patient deaths (any death after first dosing) was similar between treatment groups (Cresemba: 31.5%, 81/257; VRC: 33.6%, 87/259). Deaths due to an adverse event occurred in 24.1% of patients who received Cresemba and 27.8% of patients who received VRC. The major reasons for these deaths (≥ 2% of patients) in the Cresemba or VRC groups, respectively, were septic shock (3.1% vs. 1.5%), sepsis (2.7% vs. 1.9%), respiratory failure (2.3% vs. 2.3%), acute myeloid leukemia (1.2% vs. 2.7%) and multi-organ failure (0.4% vs. 2.3%).

Serious TEAEs that occurred in ≥3% of either of the respective Cresemba or VRC groups were respiratory failure (5.4% vs. 4.6%), septic shock (5.4% vs. 3.9%), febrile neutropenia (5.4% vs. 1.9%), pyrexia (3.1% vs. 3.9%), sepsis (2.7% vs. 3.1%), acute renal failure (2.3% vs. 3.1%), pneumonia (1.9% vs. 3.9%) and acute myeloid leukemia (1.2% vs. 3.1%).

Elevations in liver enzymes and other enzymes including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, direct bilirubin, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), blood urea nitrogen (BUN), creatinine, amylase, and urate as TEAEs were observed in patients treated with Cresemba. The number of patients who met the criteria of Hy's law (ALT or AST >3x the upper limit of normal [ULN] and ALP <2x ULN and total bilirubin >2x ULN) in the Cresemba group was lower than that in the VRC group, 1.2% vs. 2.7% respectively. These observations have been included in the Warnings and Precautions section of the Cresemba Product Monograph.

Serious hypersensitivity and severe skin reactions, such as anaphylaxis or Stevens-Johnson syndrome, have been reported during treatment with other azole antifungal agents. Overall, TEAEs in the anaphylaxis and severe cutaneous adverse reactions were reported rarely in both Cresemba-treated and VRC-treated patients (1.9%, 5 patients vs. 1.9%, 5 patients, respectively). Infusion/injection site reactions were reported in a numerically higher proportion of Cresemba-treated patients compared to VRC-treated patients (4.3%, n = 11 vs. 1.5%, n= 4, respectively).

The electrocardiogram (ECG) evaluation at the end of treatment showed fewer patients treated with Cresemba compared to VRC-treated patients had QTcF values >450 msec. Conversely, a higher number of Cresemba-treated patients had QTcF values <360 msec. than VRC-treated patients. The QTcF decreasing effect is consistent with the results of a thorough QT study of Cresemba. Appropriate text for clinical prescribers is included in the Cresemba Product Monograph.

Treatment-emergent ECG abnormalities were infrequent and comparable to that of the control group. There was a numerically lower proportion of Cresemba-treated patients (5.8%) compared to VRC-treated patients (7.3%) with TEAEs in the Torsade de Pointes standardized Medical Dictionary for Regulatory Activities (MedDRA) queries. Syncope and loss of consciousness were reported in a higher proportion of patients treated with Cresemba than VRC-treated patients, while QT prolonged and cardiac arrest were reported in a lower proportion of Cresemba-treated patients than VRC-treated patients.

In the open-label, non-comparative study of Cresemba in patients with invasive aspergillosis and renal impairment or invasive mucormycosis (Study 9766-CL-0103), treatment-emergent adverse reactions occurred in 139/146 (95%) of patients treated with Cresemba. Overall, in the ITT population, the most common treatment-emergent adverse reactions were vomiting (24.7% overall; 27.1% renal impaired [RI] patients and 23.0% for non-renal impaired patients [NRI]), nausea (23.3% overall; 32.2% RI patients and 17.2% NRI patients) and diarrhea (18.5% overall; 27.1% of RI patients and 12.6% of NRI patients). Treatment discontinuation was high among patients of this study especially in those with mucormycosis (64.9%). The three most common primary reasons for treatment discontinuation were death, adverse events (AEs)/intercurrent illness, and non-compliance. As expected in patients with impaired renal function, the percentage of patients experiencing certain AEs and serious adverse events (SAE) was numerically higher than the percentages seen in patients with normal renal function. More RI patients than NRI patients experienced a fatal AE, which was due to a larger percentage of RI patients experiencing a fatal event of infections. Nonetheless, the safety evaluation demonstrated that Cresemba was generally safe and tolerated in patients with RI, and NRI patients, as well as patients with mucormycosis. No fatal AEs were thought to be drug-related. A few patients who met the Drug-Induced Liver Injury (DILI) criteria for drug-induced hepatotoxicity were judged as having AEs unrelated to Cresemba. The medium duration of dosing for mucormycosis patients was 84 days (2 to 882 days) and 7 patients received treatment for more than 6 months. Similar to Study 9766-CL-0104, very few patients experienced events of visual impairment or hallucinations. None of the patients experienced photophobia.

For more information, refer to the Cresemba Product Monograph, approved by Health Canada and available through the Drug Product Database.