Background Analysis: US FDA Advisory Committee to Review Bronchitol Resubmission – MAY 8, 2019 (PADAC)

Announcement

The US FDA has scheduled a Pulmonary-Allergy Drugs Advisory Committee (PADAC) for Wednesday, May 8, 2019. The committee will discuss a new drug application (NDA) resubmission for Bronchitol (mannitol inhalation powder for oral inhalation), made by Chiesi USA, Inc. (Chiesi), for the proposed indication of the management of cystic fibrosis (CF) to improve pulmonary function in patients 18 years of age and older, in conjunction with standard therapy. Chiesi is a licensee of Pharmaxis Ltd. (Pharmaxis). Chiesi is responsible for US regulatory approval and commercialization. Pharmaxis is the supplier. Pharmaxis is also supporting Chiesi in their preparations for the upcoming advisory committee meeting.

Indication Background

Cystic fibrosis (CF) is a rare genetic disease that affects approximately 70,000 people worldwide (30,000 US). It is characterized by a buildup of thick, sticky mucus that hinders the body’s respiratory, digestive and reproductive systems. Disease severity depends on the type of genetic mutations present and other modifying factors. The median life-span for those with the disease is 37 years. Death typically occurs as a result of respiratory failure due to chronic obtrusive lung disease and/or chronic pulmonary infection.

Treatments for lung problems associated with CF include the following: antibiotics and vaccines to prevent and treat lung and sinus infections; inhaled medicines to help open the airways; mucus thinners; oxygen therapy; and lung transplantation.

Patients with certain genetic mutations of the CF transmembrane conductance regulator (CFTR) are candidates for therapy with CFTR potentiators/correctors [Kalydeco (ivacaftor), Orkambi (ivacaftor/lumacaftor), Symdeko (ivacaftor/tezacaftor)].

Product Background

Bronchitol is composed of an inhaler that delivers mannitol powder. The intent of mannitol is to hydrate the lungs and airways and promote coughing in patients with CF.

In May 2012, Pharmaxis submitted an initial Bronchitol NDA for the management of CF in patients aged 6 years and older. The company announced the receipt of a Response Letter (CRL) in March 2013. They said that the CRL referred to inadequacies with the clinical data, noting particularly that the Agency cited the following issues: 1) frequent and early dropouts in one of the two pivotal trials; 2) failure to reach statistical significance on the primary efficacy endpoint in the second pivotal trial; and 3) safety concerns about hemoptysis in pediatric patients.

In December 2018, the company announced that they resubmitted the NDA with new results from an additional clinical trial that was designed in “extensive consultation” with the FDA to support approval. The resubmission also revises the proposed use to the management of CF in adults only, and in conjunction with standard therapy.

Tarius notes that although the PADAC did not favor approval for the proposed use in 2013, at the time several committee members expressed having more confidence in the data to support adult use than pediatric use.

Clinical Trials

Comprehensive data from the clinical development program for Bronchitol, including detailed analyses by the company and by the FDA, will be presented in briefing materials that will be posted by the FDA ahead of the meeting. These briefing materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary. Presented below is a summary of topline results from the new clinical trial (Trial CF303) that was included in the NDA resubmission, based on information provided in Pharmaxis press releases.

Trial CF303 was a 26‐week randomized, double‐blind, parallel group investigation of Bronchitol administered twice daily in adults with all grades of CF disease who were already on the best standard of care. Management of the trial was outsourced to INC, a global contract research organization that Pharmaxis says has significant experience running international trials in the CF community. The trial was designed to assess improvements in lung function and other parameters, as well as safety. A total of 423 patients were recruited across 126 sites in 21 countries, including North and South America, Western and Eastern Europe, and Australasia. More than a quarter of patients were from the US.

According to Pharmaxis, the trial demonstrated superiority of Bronchitol versus the comparator on the primary endpoint, which was the change in forced expiratory volume of air in one second (FEV1) from baseline over 26 weeks, with an effect of 54 ml (p=0.020), corresponding to a 2.2% relative change (p=0.025). The company acknowledges that the lung function improvement seen in this trial was less than that seen in adults in previously reported phase 3 trials. In addition, no statistically significant differences were seen between treatment groups on the secondary endpoints. However, they note that a trend favoring Bronchitol was observed for the forced vital capacity (FVC), or the total amount of air exhaled during the FEV test. Related to the NDA resubmission, the company’s CEO has emphasized the following points: 1) The trial was high-quality; 2) Withdrawal rates were low; 3) Incremental improvements over standard of care in CF disease have resulted in longer life expectancy; 4) Many adults, who comprise 50% of the CF population, have deteriorating health or difficulty in complying with existing treatment options and need new options; and 5) Good benefit, on top of existing treatment, and good safety was demonstrated.

Results from trial CF303 have not been posted to ClinicalTrials.Gov, but elements of the trial design and other details are provided (ID: NCT02134353).

Regulatory Background

US Regulatory Background

Second half of 2019 – PDUFA date

December 20, 2018 –Pharmaxis announced the NDA resubmission (NDA 202049).

March 2013 – Pharmaxis announced receipt of the CRL in response to the initial NDA.

January 30, 2013 – The PADAC did not support approval of the initially proposed use, by a unanimous committee vote of 14-0.

May 2012 – The initial NDA was submitted.

November 11, 2004 –The Investigational New Drug (IND 70,277) was opened.

Fast Track Designation (Initial NDA), Orphan Drug Designation

European Regulatory Background

April 2012 – European Medicines Agency (EMA) Approval, via centralized procedure

Approved Indication: Bronchitol is indicated for the treatment of cystic fibrosis (CF) in adults aged 18 years and above as an add-on therapy to best standard of care.

Orphan Drug Designation

Australian Regulatory Background

February 2011 – Approval

Approved Indication: Bronchitol is indicated for the treatment of cystic fibrosis (CF) in both paediatric and adult populations six years and above as either an add-on therapy to dornase alfa or in patients intolerant to, or inadequately responsive to dornase alfa.

Orphan Drug Designation

Russian Regulatory Background

September 2016 – Approval

Approved Indication: Patients with CF cystic fibrosis aged 6 years and older (general indication, not verbatim)

Orphan Drug Designation

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Chiesi USA, Inc. Drug Name: mannitol inhalation powder for oral inhalation Drug Class: osmotic agent Indication: cystic fibrosis

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.