Protalix Biotherapeutics (PLX) offers great potential in the coming months. The NYSE-traded, Israel-based biopharma has a pipeline of "proprietary, potentially clinically superior versions of recombinant therapeutic proteins that target established pharmaceutical markets" that is looking increasingly robust - particularly its lead candidate, PRX-102 (Pegunigalsidase alfa). Even amidst the pandemic, the company has managed to stay on track - the fast track, in fact, that was granted in 2018 by the FDA - submitting its Biologics Licensing Application (BLA) for accelerated approval in late May 2020, as well as completing one Phase III study.

PRX-102 is a therapy for Fabry Disease, a rare genetic disorder that nonetheless generates $1B for Sanofi with its drug Fabrazyme. Not only is PRX-102 years newer than Fabrazyme, but new standards are in place for approval that should give prescribers more confidence with the newer medication. 

According to the company:

"Fabry disease is an X-linked inherited disease that results from abnormal deposits of a fatty substance called globotriaosylceramide (Gb3) in blood vessel walls throughout a person’s body. Fabry disease occurs in one person per 40,000. Fabry patients inherit a deficiency of the enzyme alpha-galactosidase-A, which is normally responsible for the breakdown of Gb3. The abnormal storage of Gb3 increases with time and, accordingly, Gb3 accumulates, primarily in the blood and in the blood vessel walls. The channels of blood vessels narrow, leading to decreased blood flow and decreased tissue nourishment. The ultimate consequences of Gb3 deposition range from episodes of pain and impaired peripheral sensation to end-organ failure—particularly of the kidneys, but also of the heart and the cerebrovascular system. Fabry disease is generally treated with enzyme replacement therapy (ERT), meaning the replacement of the missing alpha-Galactosidase-A enzyme with a recombinant form of the protein via intravenous infusion once every two weeks."

PLX-102 is designed to be a plant cell culture-expressed, and a chemically modified version of, the recombinant alpha-Galactosidase-A protein. The Fabry disease community is expressing great interest in treatment that avoids certain side effects such as the kidney issues recently discussed in a nephrology paper by Dr. David Warnock et al., in which PLX-102 is said to "meet an unmet medical need" in Fabry patients compared to existing therapies. Its longer half-life could also potentially enable a treatment option of once-monthly infusions as opposed to bi-weekly infusions.

For the accelerated approval process, the first of the phase 3 studies, known as BRIDGE, has successfully met its safety and efficacy endpoints. This study basically was a 12-month open-label single arm switch over study. About 22 patients were previously treated with agalsidase alfa (Replagal) and then switched over to1 mg/kg infusion of PLX-102 once every 2 weeks. These patients were treated for up to two years and on a stable dose for 6 months on previous ERT before switch. In essence, those who switched from Replagal to PLX-102 had a substantial improvement in renal function as measured by annualized estimated Glomerular Filtration Rate (eGFR slope). Safety was also good in nature as adverse events with treatment of PLX-102 were transient and without sequelae. Basically, sequelae means that the patient recovers but ends up with an additional problem as a result of a prior disease in question. In this study, patients were without sequelae from adverse events. Additional results submitted as part of the BLA include biomarkers like Gb3 levels from biopsies and supportive data. 

Next up is the randomized phase III BALANCE study: "The ongoing BALANCE study is a fully enrolled, randomized, double blind, head-to-head, active control study which aims to demonstrate PRX‑102's superiority in renal function as measured by the comparison of the mean annualized change (slope) in estimated glomerular filtration rate (eGFR_CKD-EPI) between treatment groups over 24 months of treatment as compared to agalsidase beta, marketed by Sanofi Genzyme as Fabrazyme." (biospace.com)

Can Protalix receive Accelerated Approval for PLX-102 without the active controlled phase 3 BALANCE study included as part of the package? Yes. Protalix has met with the FDA in a few Type C meetings and a PreBLA meeting. It was clear from the FDA that no randomized study would be needed to seek and file for Accelerated Approval for PLX-102 in Fabry Disease. Instead, the phase 3 randomized BALANCE study will serve as a confirmatory study, which means that in order to change PLX-102 from Accelerated Approval to full approval, the confirmatory BALANCE study will be needed. As long as that study confirms findings from the prior studies, then the AA converts to full approval. 

Safety and Efficacy Biomarkers Are In Good Shape

As noted above, the FDA was in agreement that a randomized study would not be necessary in terms of accelerated approval for PLX-102 for the treatment of patients with Fabry Disease. This boils down to everyone agreeing that subjecting patients to a placebo arm would not be ideal. Especially, since there have been many other studies since incorporating a placebo arm. In all previous Fabry Disease studies, it was noted that there was no spontaneous reduction of Gb3. The bottom-line is that the FDA only needs to see biomarkers and safety to determine Accelerated Approval for PLX-102. The phase 3 BALANCE study to be readout sometime possibly in 1st half of 2022 will only serve as a confirmatory study for full approval. This was according to the FDA meeting minutes with Protalix. 

Conclusion

Protalix BioTherapeutics offers massive potential in the coming year. Protalix’s PLX-102 has a good chance to compete against Sanofi’s Fabrazyme, which generates roughly $1 billion in sales per year. In terms of cash, Protalix is good for 2 years at least. It had just completed a private placement of cash totaling roughly $44 million. With a burn rate of about $7.5 million per quarter, it has plenty of cash on hand to get through the potential Accelerated Approval of PLX-102 for Fabry Disease. Its partner Chiesi is due to provide a $7M milestone payment when accelerated approval kicks in. I believe that while there is risk involved for the review of the BLA for Accelerated Approval for PLX-102, there is a good chance it should make it through the finish line. 

Protalix's competitors, in addition to Sanofi (SNY), are BioLineRx (BLRX), Brainstorm Cell Therapeutics (BCLI), Bellorophon Therapeutics (BLPH), Pluristem Therapeutics (PSTI), and Itamar Medical (ITMR).

Related Article: There Is Beta In Protalix Stock Due To PRX-102