PLX: Final Results for BRIDGE and A Letter to Shareholders

By John Vandermosten, CFA

NYSE:PLX

READ THE FULL PLX RESEARCH REPORT

On December 30, 2020, Protalix BioTherapeutics, Inc. PLX announced final results of its BRIDGE Phase III open-label, switch-over clinical trial of lead candidate pegunigalsidase alfa (PRX-102) in Fabry Disease. Protalix President and CEO, Dror Bashan simultaneously issued its 2020 Letter to Shareholders. This is the first update since our initiation on Protalix on December 7, 2020.

Protalix uses a plant-based protein expression system, ProCellEx, to produce its biologics. In 2012, Protalix successfully gained FDA approval for Elelyso making it the first FDA approved biologic expressed with a plant-based system. While Elelyso is already approved, Protalix has additional, clinical-stage candidates including PRX-102 which is under review by the FDA with a target action date of April 27, 2021.

Protalix Clinical Development Pipeline (1)

PRX–102 is a recombinant α-Galactosidase-A enzyme. Protalix uses its ProCellEx platform to express the enzyme and then chemically modifies it via surface pegylation. Protein sub-units are covalently bound via chemical cross-linking using short PEG moieties, resulting in a molecule with unique pharmacokinetic parameters. In clinical studies, PRX–102 has demonstrated a circulatory half-life of approximately 80 hours. Due to the chronic nature of Fabry, patients must receive IV infusion of enzyme replacement therapy every two weeks, which is a significant burden. PRX-102, with its extended half-life, aims not only to be more effective, but also reduce the frequency of doctors' visits by Fabry patients.

Three Phase III studies were launched to support regulatory approval of PRX-102 around the globe, designated BRIDGE, BALANCE and BRIGHT. After a release of topline results in May 2020, the BRIDGE trial provided final results on December 30, reiterating its findings of a substantial improvement in renal function.

BRIDGE was a 12-month open-label, single arm switch-over study evaluating the efficacy of 1 mg/kg of pegunigalsidase alfa infused every two weeks. The 22 Fabry patients in the trial had been previously treated with agalsidase alfa (Replagal) for at least two years and had been stable on this drug for at least six months.

The study found a mean annualized estimated glomerular filtration rate (eGFR) slope of the study participants improvement from -5.90 mL/min/1.73m^2/year while on agalsidase alfa to -1.19 mL/min/1.73m²/year on PRX-102 in all patients. Male patients improved from -6.36 mL/min/1.73m^2/year to -1.73 mL/min/1.73m²/year and female patients improved from -5.03 mL/min/1.73m²/year to -0.21 mL/min/1.73m²/year.

Baseline characteristics of the 20 completed patients, ranging from ages 28 to 60 years, were as follows: mean eGFR 75.87 in males and 86.14 in females and plasma lyso-GL-3 (2) mean levels were 51.8 nM and 13.8 nM in males and females, respectively. While lyso-GL-3 levels remained somewhat high, particularly within the male cohort, continuous reduction in lyso-GL-3 levels was observed of 19.55 nM (32.35%) in males and 4.57 nM (29.81%) in females. Lyso-GL-3 is a biomarker that indicates the status of the patient and whether or not they are improving but is not related to a patient's clinical symptoms.

The shift to PRX-102 resulted in a decrease of kidney disease progression and most patients were stable after the change. PRX-102 was well tolerated during the study. All adverse events were transient without sequelae. Of the 22 patients enrolled, the majority of treatment emergent adverse events (TEAE) were mild or moderate. Two patients (9.1%) withdrew from therapy due to hypersensitivity reaction that resolved. The most common TEAEs were nasopharyngitis, headache and dyspnea.

The final results provided an immunogenic analysis, adding to the details reported in May. Over the duration of the study, patient serum was collected at monthly frequency and screened for the presence and amount of immunoglobulin (antibodies) that were active against PRX-102. An immunogenicity assessment indicated that 4 out of 20 patients (20%) developed persisting antidrug antibodies over the study period, two of which had antibodies with neutralizing activity (3). However, two of the four patients were positive at baseline following treatment with Replagal, suggesting pre-existing antibodies that were cross-reactive with PRX-102. Furthermore, based on statistical analysis, efficacy and safety were unaffected by whether the patient was antibody positive or negative. This is likely due to remaining levels of PRX-102 that escaped antibody suppression and were sufficient to break down GL-3. Antibodies found were not anti-glycan nor anti-PEG but mostly directed toward the core of the enzyme. The 20% immunogenicity compares to Fabrazyme and Replagal at 79% (4) and 25%-45%, respectively. Antibodies are frequently cross reactive in patients that use both Fabrazyme and Replagal (5) but do not materially impact the efficacy of the drug.

Data from the interim analysis of the BRIDGE Study was included in the PRX-102 BLA submission to the FDA under the Accelerated Approval pathway. Now that final analysis is available, the data will be used to support a Marketing Authorization Application (MAA) with the EMA.

Shareholder Letter

On December 30, 2020, President and CEO of Protalix, Dror Bashan, issued a 2020 letter to shareholders. In the letter, he highlighted the progress made with partner Chiesi in submitting the BLA for PRX-102, and the FDA's acceptance and filing of the application under Accelerated Approval and granting of Priority Review designation. Bashan updated investors on the revised Prescription Drug User Fee Act (PDUFA) date to April 27, 2021 and reiterated the potential market for PRX-102 in Fabry and clinical progress, specifically final result reporting from BRIDGE, topline data expected from BRIGHT 1Q:21, and interim results from BALANCE in 1H:21. Finally, he guided toward the 2H:21 commercialization of PRX-102 pending BLA approval.

Bashan acknowledged the expansion of partnerships and collaborations. In July 2020, Protalix entered into a non-binding term sheet with SarcoMed USA Inc., which, if consummated, would support development and commercialization of PRX-110 in pulmonary sarcoidosis and related diseases. An update on this relationship may be available within the next few weeks. In March 2020, Protalix announced an agreement with Kirin Holdings Company, Ltd. to conduct feasibility study for production of a novel complex protein using ProCellEx.

The letter summarized the financing achieved during 2020 including a $44 million raise in March through the sale of common stock and warrants in private placement. Protalix established an at-the-market (ATM) facility through Bank of America Securities that provides the opportunity to raise up to $30 million. Dr. Yael Hayon was added to Protalix' senior executive management team as VP Research and Development.

Summary

We recently initiated on Protalix and expect to see additional data releases over the next months as well as approval and launch of PRX-102. Assuming FDA approval of PRX-102, sales of the enzyme should be underway by 2H:20. Below we summarize the key elements of our thesis:

‣ PRX-102 on cusp of commercialization

◦ Target action date: April 27, 2021

‣ Potential for superiority vs market leader Fabrazyme

◦ Improved efficacy

◦ Longer duration between infusions

‣ Existing sales and royalty revenues from taliglucerase alfa

◦ Pfizer, globally

◦ Fiocruz, Brazil

‣ Maintain regulatory approved plant based expression system

‣ Orphan indication for PRX-102

‣ Partnership with Chiesi for global commercialization of PRX-102 in Fabry Disease

‣ Rights to milestones and royalties

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1. Protalix Corporate Presentation September 2020

2. Lyso-GL-3, also referred to as Lyso-Gb3, is a biomarker with limited correlation to symptoms, but is highly sensitive as a therapeutic monitor.

3. Neutralizing antibodies are distinguished from binding antibodies in that neutralizing antibodies bind to sites (epitopes) directly involved in the activity of the antigen (such as a receptor), interfering with the activity of the antigen, while binding antibodies attach to non-critical portions of the antigen.

4. Provided in FDA Label for Fabrazyme.

5. Linthorst, G.E. et al. Enzyme therapy for Fabry disease: Neutralizing antibodies toward agalsidase alpha and beta. Kidney International; Volume 66, Issue 4, October 2004, Pages 1589-1595