PLX: Type A Meeting Provides Clarity

By John Vandermosten, CFA

NYSE:PLX

READ THE FULL PLX RESEARCH REPORT

Type A Meeting Update

Protalix Biotherapeutics, Inc. (NYSE:PLX) updated stakeholders on the regulatory pathway forward for PRX-102. The company is advancing the candidate indicated for Fabry Disease in both the US and the EU. In the United States, PRX-102 was submitted to the FDA in May 2020 using the accelerated approval pathway. The FDA returned a complete response letter (CRL) in April 2021. Following an internal review of the FDA’s response, Protalix requested a Type A meeting with the agency to obtain additional information on the deficiencies listed in the CRL and to identify items required for a resubmission to the agency. In an October press release, details regarding the process were provided. The Type A meeting was held on September 9th and provided written notes regarding resubmission requirements. The FDA noted that the regulatory environment had changed since the original submission of PRX-102 with the March 2021 grant of traditional approval to Fabrazyme. Under these new circumstances, additional data was requested and the resubmission will include the final two year analyses of the Phase III BALANCE clinical trial.

The October press release also provided an update on progress with the European Medicines Agency (EMA). On October 8, Protalix, Chiesi and the EMA rapporteur and co-rapporteur held a meeting to discuss the planned marketing authorization application (MAA) submission. The EMA representatives were generally supportive of the submission which is planned for 1Q:22.

The detail from the FDA’s Type A meeting provides more clarity on the pathway forward for resubmission and we update our model accordingly. Below is our estimate of the timeline for the FDA resubmission and related events:

➢ Type A Meeting – September 2021

➢ Type A Meeting Notes – October 2021

➢ Last patient completion of BALANCE trial – October 2021

➢ Availability of full data package for BALANCE – 1H:22

➢ Resubmission of BLA for PRX-102 – prior to end of 1H:22

➢ On-site inspection of drug substance and/or fill and finish facilities – 2H:22

➢ Completion of 6-month resubmission review – prior to year-end 2022

➢ PRX-102 commercialization – 2023

PRX-102 Background

Following the anticipated April 27th target action date for its investigational candidate, Protalix announced that the FDA had issued a Complete Response Letter (CRL) related to the submission of PRX-102.1 Protalix and Chiesi Global Rare Disease had submitted the associated Biologics License Application (BLA) for the PEGylated enzyme and received acceptance of receipt in August 2020. Priority review was granted which normally provides for a six month appraisal of the BLA. Initially, the FDA issued a target action date of January 27, 2021, but in late November extended the date to April 27.

An ongoing outstanding item related to PRX-102 approval has been the required inspection for Protalix’ manufacturing facility and that of a third party that performs fill and finish processes. Due to pandemic-related travel restrictions, inspections have been delayed, especially those performed overseas. Prior to the issuance of the CRL, it had been unclear if the agency would temporarily waive the inspection due to the unmet need for Fabry patients and the agency’s backlog on account of the pandemic.

In a follow up press release on April 28th, Protalix provided additional details on the contents of the CRL. The FDA did not raise any issues related to the safety or efficacy of the drug, but rather attributed the unfortunate letter to the FDA’s own inability to conduct an on-site inspection for the manufacturing facility in Israel and ongoing review of the third-party facility in Europe.

Protalix’ April 28th communication indicated that primary competitor Fabrazyme was recently converted to full approval, which, for nearly 20 years, was approved based on surrogate endpoints. The change is important as it led the FDA to withdraw PRX-102’s priority review designation – a status granted to drugs that offer major advances in treatment or provide a treatment where no adequate therapy exists. Priority review is provided to drug candidates that show evidence of significant improvements in safety or effectiveness when compared to standard of care.

Post-CRL Milestones

Following the issuance of a CRL, there are several steps that are common to all candidates. The sponsor has 90 days following the issuance of a CRL to schedule a Type A meeting with the FDA to cover any questions related to the letter. When the sponsor makes the request, the FDA has 30 days to hold the meeting, after which notes from the gathering will be provided. Explained in the CRL and clarified in the meeting, the FDA outlines the steps needed to address the discrepancies presented. In general, these could include additional trials, further questions and bridging studies among other needs. When the requested deliverables are ready, the sponsor may then resubmit the application which will then be considered a Class 1 or Class 2 resubmission. A Class 1 resubmission offers a two month turnaround time and generally deals with simpler issues such as labeling, stability and safety updates, discussion of post-marketing requirements, assay validation data, minor reanalysis, final release testing or other minor issues. A Class 2 resubmission is any item that does not fall under Class 1 and/or requires presentation to an advisory committee and requires a six month turnaround time.

Milestones

➢ BRIDGE Final results – 4Q:20

➢ Partnership with Sarcomed for PRX-110 in respiratory disease – February 2021

➢ BRIGHT Top line results – February 2021

➢ PRX-102 Target Action Date – April 27, 2021

➢ PRX-102 CRL Announced – April 28, 2021

➢ Receipt of notes from FDA regarding CRL – May 2021

➢ Oral presentation on PRX-102 in females by Dr. Camilla Tøndel at ERA-EDTA Congress – June 2021

➢ BALANCE Interim results – June 2021

➢ ATM Agreement with HCW – July 2021

➢ Request Type A meeting regarding PRX-102 – August 2021

➢ Attend Type A meeting regarding PRX-102 – September 2021

➢ EMA submission of PRX-102 – 1H:22

➢ BALANCE final results – 1H:22

➢ Resubmission of BLA for PRX-102 – prior to end of 1H:22

➢ On-site inspection of drug substance and/or fill and finish facilities – 2H:22

➢ Completion of 6-month resubmission review – prior to year-end 2022

➢ EMA approval and EU commercialization of PRX-102 – 1H:23

➢ PRX-102 commercialization – 2023

Valuation

We adjust our valuation to reflect a delay in first sales of PRX-102 from 2022 to 2023 based on the timeline we outline in this report. The change reduces our price target from $12.50 to $11.00.

Summary

In a press release earlier this week, Protalix provided an update on its meetings with regulatory agencies in the US and EU. We now have better resolution on the regulatory pathway forward. In Europe, submission plans are further established after meetings with EMA representatives. The first half of 2022 is expected to see a package submitted to both agencies and a potential approval around year end. We expect to see additional preparation efforts over the next few months and into next year.

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1. Also referred to by its generic name, pegunigalsidase alfa.

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