Image Source: Protalix.com

Protalix BioTherapeutics (PLX) is an Israel-origin developer of recombinant therapeutic proteins using its proprietary plant-cell based protein expression platform. The company has a corporate presence in New Jersey and trades on the NYSE under the ticker symbol PLX. Their PROCELLEX platform is validated by the 2012 approval of ELELYSO  for long-term enzyme replacement therapy (ERT) for patients with type 1 Gaucher disease. PRX-102 is their second candidate, an ERT targeting Fabry Disease. On January 27, 2021, PRX-102 had a PDUFA date stemming from an accelerated approval; however, this molecule has had a spate of bad luck.

In November, the FDA extended the review period of PRX-102 by three months, with a new date of April 27, 2021. However, on that date, the FDA handed a Complete Response Letter (CRL) to the company, citing its own inability to inspect a manufacturing facility based in Carmiel, Israel, due to Covid-19 restrictions. 

This would have been a minor issue but for the fact that in March, 2021, the FDA gave full approval to Genzyme’s Fabrazyme, which is an ERT which was being used to treat Fabry Disease since its accelerated approval 17 years ago. This caused a whole lot of problems for Protalix, because Protalix was also aiming for an accelerated approval of PRX-102, and an accelerated approval is no longer possible for the molecule since another drug candidate now has full approval in Fabry Disease. 

The sequence of events turned out to be a little unfair to Protalix. So they had a product candidate which had an FDA review date that was delayed due to no fault of the company, and during those additional three months of delay, the FDA went ahead and approved another product which had not been given full approval for 17 years. Now PRX-102 cannot get accelerated approval any longer, but has to complete the BALANCE trial, which directly compares PRX-102 with Fabrazyme, in order to be approved. 

Recall that the BLA for the accelerated approval was based on data from the BRIDGE and the BRIGHT studies, none of which were directly comparing PRX-102, or pegunigalsidase alfa, with Fabrazyme, or agalsidase beta. Both these studies were single arm studies, meaning they did not compare PRX-102 with any other drug directly. BALANCE, however, is a blinded, two-arm study with an active control, agalsidase beta, and complete topline data from this study is now required to refile a BLA seeking full approval of PRX-102. 

BALANCE was designed as a superiority study comparing differences in change in eGFR slope between PRX-102 and Fabrazyme patients. However, some experts including a former FDA official have opined that BALANCE may just be too small or of a too short duration, and even too heterogeneous, to decidedly demonstrate efficacy superiority. We reached out to Protalix management seeking comments on this aspect. CEO Dror Bashan and Mr Eyal Rubin, Senior Vice President and Chief Financial Officer at Protalix, responded to our emails. According to Mr Rubin, given the full approval of Fabrazyme in the US, the regulatory environment has changed, and demonstrating superiority is no longer required. The company and the agency have agreed to the data package necessary for the BLA resubmission, and this includes the BALANCE 2-year data analysis. 

This is interesting because, as we noted elsewhere, the open label BRIGHT study, which analyzes the safety, pharmacokinetic and efficacy of PRX-102 in patients previously treated with Fabrazyme, may be an important part of the BLA supporting full approval based on providing two alternative dosing options for treating Fabry patients. Recall that PRX-102 was differentiated from Fabrazyme in terms of a longer half-life (80 hours vs. 2 hour), which may enable lower frequency doses of PRX-102 compared to Fabrazyme, potentially reducing safety concerns. This, and not demonstrated efficacy superiority, could be the key to full approval for PRX-102. Mr Rubin’s statement seems to support that idea.

The company has guided for a 2H 2022 BLA resubmission, which will take into account the BALANCE data to be read out in 1H. If approved, PRX-102 could become a market leader in Fabry Disease, a multibillion dollar market, and effectively bolster Protalix’ unremarkable sales of ELELYSO.

Protalix has full rights to ELELYSO in Brazil, where the molecule has sold much better than ex-Brazil, where Pfizer holds commercial rights. According to Mr Rubin, ELELYSO has sold very well in Brazil despite Covid, and has exceeded initial expectations. However, the company seems dissatisfied with Pfizer’s efforts so far. They think Pfizer could have done more to increase market share. 

The company, according to Mr Rubin, is adequately funded for “7-8 quarters” which will be enough to see PRX-102 through the finish line. The company has reallocated most of their resources on the PRX-102 program, and the rest of its pipeline, including PRX-110, seems to be on the backburner.

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