Protalix: Fabry BRIGHT Trial Data May Not So Bright After All

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Introduction

On Friday, March 18, Protalix BioTherapeutics (NYSE: PLX) and their partner Chiesi announced the final results from their open-label, phase 3 BRIGHT trial studying PRX-102 in adult Fabry patients.

A description of BRIGHT:

The BRIGHT Phase III clinical trial (NCT03180840) was a … open-label, switch-over study designed to evaluate safety, efficacy and pharmacokinetics of treatment with 2 mg / kg of PRX-102 administered every FOUR weeks for 52 weeks (a total of 14 infusions). The study enrolled 30 adult patients with Fabry disease (24 males and 6 females) with mean age … of 40.5 … years, ranging from 19 to 58 years, who previously received an approved enzyme replacement therapy ((ERT)) for at least three years on a stable dose administered every two weeks (agalsidase alfa – Replagal® or agalsidase beta – Fabrazyme®). “

(Source: edited for brevity, emphasis added)

For anyone who is new to PLX’s story, an important term to know here is eGFR, stands for estimated Glomerular Filtration Rate (expressed as ml / min / 1.73m2).

In Fabry patients, their renal function gets worse each year (eGFR absolute values ​​decrease), therefore the Fabry trials measure the rate at which eGFR declines per year, or eGFR slope (expressed as a negative value in ml / min / 1.73m2/ year).

The more effective a Fabry drug candidate is, the less steep the decline in eGFR absolute value, or smaller value in eGFR slope should be observed.

From PLX’s BRIGHT trial, the company reported:

Mean (SAY) eGFR slopeat the end of the study, for the overall population, was ‑2.92 (1.05) mL / min / 1.73m2/ year “

(Source: emphasis added)

From this and other data, PLX believes that data from BRIGHT supports the potential of PRX-102 to treat adult Fabry patients in “both the regular 1 mg kg every two weeks as well as the 2 mg kg every four weeks regimen.”

It should be noted that BRIGHT, an open-label trial without placebo or active control, is the only one of three PLX’s Fabry trials that studies administering PRX-102 2mg / kg every four weeks.

This means that their other two trials, BRIDGE (another open-label) and BALANCE (using Fabrazyme as the active control) both study 1mg / kg every two weeks.

An eGFR slope of -2.92 indicates “stability” in renal function?

In the press release, PLX claims that an eGFR slope of -2.92 “indicating stability” in renal function for these Fabry patients.

It is a claim that I find un-supported in the scientific literature and PLX’s own BRIDGE data.

I will give three examples below.

Ex. I: An eGFR slope of -1.12 & -2.60 in Fabry male patients indicated significant annual deteriorations

This is from a 2020 paper that analyzes renal and cardiac outcomes of 560 male Fabry patients on Agalsidase Alfa ERT (Enzyme Replacement Therapy) for ≤10 years after ERT initiation.

These patients “were stratified into three cohorts by age at ERT initiation: ≤18 years (cohort 1),> 18 and ≤30 years (cohort 2), and> 30 years (cohort 3).”

This means that cohort 2 & 3 (ADULT male Fabry patients) are PRX-102’s addressable patients.

Please note:

  • The paper concludes that “For cohort 2, … eGFR significantly deteriorated annually (–1.12 mL / min / 1.73m2; P<0.001). Cohort 3 demonstrated significant annual deteriorations in eGFR (–2.60 mL / min / 1.73m2; P<0.001) "
  • Numerically, PLX’s -2.92 are worse than -2.60, and much worse than -1.12.

In summary: It’s hard to see how a worse / much worse eGFR slope indicates a better (stable vs. significantly deteriorated) kidney function.

Ex. II: For untreated Fabry patients, eGFR slope was −2.93 for males, and −1.02 for females

This is from a 2009 review that analyzes and reports clinical outcomes of 447 ADULT Fabry patients, with available data for a median of 12 years per patient.

This study’s pre-specified endpoints including “progression of renalcardiac and cerebrovascular involvement and / or death before the initiation of enzyme replacement therapy. “(emphasis added)

In other words, none of these adult Fabry patients were treated with any ERT.

The mean rate of estimated glomerular filtration rate (eGFR) decline for patients was −2.93 for males, and −1.02 ml / min / 1.73 m 2 / year for females.

In summary: for the untreated adult Fabry patients, the male showed a similar eGFR slope as PLX’s -2.92 and the females much better.

It’s hard to see what the treatment effect (renal efficacy) of a PRX-102 “2 mg kg every four weeks regimen” is, when the untreated Fabry patients have a similar or better eGFR slope.

Ex. III: From PLX’s own BRIDGE: An eGFR slope of -1.19 for all patients

PLX’s other open-label Fabry trial, BRIDGE, reported an eGFR slope of -1.19 for all patients (-1.73 for males and -0.21 for females).

Unlike BRIGHT, BRIDGE studies PRX-102 1mg / kg being administered every two (not four) weeks.

Numerically, BRIDGE data seems much better than BRIGHT’s data (-1.19 vs. -2.92).

However, there’s no comment in March 18 PR regarding the difference, nor any comment on how such a discrepancy may or may not support the renal efficacy of PRX-102’s 4-week regimen.

Concluding Thoughts

I do not believe that BRIGHT data supports a claim that a 2mg / kg PRX-102 every FOUR week for 52 weeks was shown to stabilize Fabry patients’ kidney function.

I also do not believe that BRIGHT’s data proves PRX-102’s 4-week regimen to be comparable with the 2week regimen in its potential renal efficacy.

In terms of supporting the potential market approval of PRX-102 in the treatment of Fabry, I think that data from BRIGHT probably does little or nothing to support the use of the 4-week regimen.

Even if PRX-102 is approved in the EU or in the US for being a non-inferior (2-week regime) ERT to the currently available ERT in both markets, I doubt its market competitiveness, as it is shown to be only a non-inferior (not superior) ERT.

Thanks for reading. All the best!

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