Opelconazole

BACKGROUND

Opelconazole is an antifungal agent that is potent against Aspergillus.¹² It is designed to be administered via inhalation directly to the site of infection in the lungs with high lung retention and low systemic exposure. It may offer a new way of treating patients with pulmonary aspergillosis with the potential for improved patient outcomes, while minimizing the risk of antifungal-related side effects and drug-drug interactions. Pulmonary aspergillosis has a historical growth rate of 3% per year, and is expected to increase as a result of new immunosuppressive therapies and increased prevalence of pulmonary disease after COVID-19 infection.¹³

Opelconazole Features

Opelconazole is a new chemical entity designed to be delivered as an inhaled antifungal agent specifically intended for activity in the lungs, where most Aspergillus disease occurs. Opelconazole has been shown to inhibit the growth of Aspergillus fumigatus clinical isolates and other pathogenic Aspergillus species, such as Aspergillus terreus, Aspergillus flavus, and Aspergillus carbonarius in vitro.¹⁴ The anti-Aspergillus fumigatus effect has also been demonstrated in vitro and in non-clinical in vivo studies, with encouraging results having also been observed in patients participating in a limited “Specials” program (similar to a compassionate use program) ongoing in the United Kingdom.^15-18

The safety and efficacy of inhaled opelconazole is currently being investigated in clinical trials as a treatment for patients with invasive pulmonary aspergillosis who are not responding to systemic standard-of-care antifungal treatment. Opelconazole has not yet been approved by any health authority for commercial use.

Inhaled route of administration

Opelconazole has a particle size ideal for delivery via inhalation similar to the size of Aspergillus spores (2 µm to 3 µm) and is designed to target infection in the lungs.¹⁷

Low systemic exposure

Opelconazole was specifically designed to be retained in the lung to target the site of infection with limited systemic exposure. The properties of opelconazole (low solubility and slow dissolution rate) have resulted in very low systemic exposure.¹² In animal studies, the concentration of opelconazole in the lung was substantially higher, more than 2000 fold, compared to the concentration in plasma, whereas other inhaled anti-infectives may be easily systemically absorbed, signaling a less targeted delivery to the lungs.¹²^,¹⁹

The targeted delivery of opelconazole in the lungs and the resulting minimal systemic distribution may potentially:

Improve efficacy in treating the lung disease

Result in fewer systemic side effects

Reduce the risk for drug-drug interactions

Extended duration of activity at the site of infection

Opelconazole has demonstrated a long lung retention time and high local potency in animal studies.¹² The long residence time allows opelconazole to accumulate in the airway cells.¹² This local concentration may enhance the ability of host cells to clear the fungus — a potential advantage for both the treatment and prevention of pulmonary aspergillosis.

Results to Date

Robust data from in vitro, in vivo, and clinical outcomes in patients with refractory invasive pulmonary aspergillus supported studying opelconazole in a Phase 3, randomized, controlled superiority study. Opelconazole has already shown significant efficacy against Aspergillus fumigatus in an immunocompromised mouse model, exhibiting more than a 47-fold increased potency over the current first-line standard-of-care.²⁰

Multiple Phase 1 and Phase 2 clinical trials have been undertaken with opelconazole to date. Available data from clinical trials and the “Specials” program (described below) has shown no major safety or tolerability concerns after single and repeat dosing of opelconazole.

Clinical experience with opelconazole under the Specials Program (UK)

Opelconazole is being supplied within the UK for patients with serious or life-threatening pulmonary Aspergillus infections according to Medicines & Healthcare Products Regulatory Agency (MHRA) of the UK Guidance Note 14: “The supply of unlicensed medicinal products (‘specials’)”.²¹ The supply of opelconazole via this process has been limited to adults with laboratory-confirmed Aspergillus infections who are not eligible to enter any known, available clinical trials and for whom there is currently no equivalent licensed medicinal product that can meet the special needs of the patient. Patients treated with opelconazole in this program included patients with confirmed invasive pulmonary aspergillosis (fungal pneumonia), tracheobronchitis, and Aspergillus infection of the anastomosis site in lung transplant recipients. The program also included patients with severe asthma and allergic bronchopulmonary aspergillosis (ABPA) who had been chronically treated with high dose steroids. All the patients included in the program had either failed or could not tolerate multiple standard-of-care antifungal therapies before initiating treatment with opelconazole.

Although drawing definitive conclusions regarding efficacy and safety from this program is limited by the open-label, non-randomized, uncontrolled nature of the program, observations suggest that inhaled opelconazole was generally well tolerated and effective in treating these patients.¹²^,¹⁸^,²² The clinical observations in this program were exciting in that patients had failed, or were intolerant of, prior antifungal therapy. These encouraging treatment responses led to advancing the clinical development of this investigational product which is currently in a Phase 3 clinical trial. These observations do not constitute substantial evidence of efficacy or safety and opelconazole cannot be used outside of this program or the currently approved clinical trials. Opelconazole has not been approved for the treatment of Aspergillus related diseases by any regulatory agency.

Global Clinical Development Program

Based on the encouraging antifungal effects observed in vitro and in the in vivo animal studies, as well as in the clinical results observed in patients included in the “Specials” program (UK), Pulmocide has now advanced the clinical development of opelconazole into a registration program described below:

PC_ASP_007 (NCT05037851) is a Phase 2 clinical trial evaluating the safety and tolerability of opelconazole for the prevention of pulmonary aspergillosis in patients who have received a lung transplant
PC_ASP_006 (NCT05238116) is a randomized, placebo-controlled Phase 3 superiority study assessing the efficacy of opelconazole in combination with standard-of-care systemic antifungal therapy for the treatment of refractory invasive pulmonary aspergillosis vs. standard-of-care alone
- Enrolled patients must have previously failed to adequately respond to the current standard-of-care antifungal therapy

Opelconazole has received several FDA designations that may facilitate its expedited development and/or review, including orphan drug designation, Fast Track designation, and qualified infectious disease product (QIDP) designation. It has also been granted orphan drug designation in the European Union.

Access to Opelconazole

The goal of our current clinical study program for opelconazole is to enroll patients and obtain clinical data that is required by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and other regulatory authorities for review and approval of marketing applications for this investigational agent. We believe that focusing on clinical studies is the most appropriate way to achieve this goal; therefore, we do not currently offer access to opelconazole outside of clinical studies and, at this time have no Expanded Access program outside of the UK (sometimes referred to as “compassionate use” or “pre-approval access”).