A description of BRIGHT:
The BRIGHT Phase III clinical trial (NCT03180840) was a...open-label, switch-over study designed to evaluate the 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: Company press release - 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 in 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 (SE) eGFR slope, at the end of the study, for the overall population, was ‑2.92 (1.05) mL/min/1.73m2/year"
(Source: Company press release - 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.
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.
This is from a 2020 paper that analyses 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 the cohort 2 & 3 (ADULT male Fabry patients) are PRX-102's addressable patients.
In summary: It's hard to see how a worse/much worse eGFR slope indicates a better (stable vs. significantly deteriorated) kidney function.
This is from a 2009 review that analyses 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 renal, cardiac 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 m2 /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.
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.
I don't believe that BRIGHT data supports a claim that a 2mg/kg PRX-102 every FOUR weeks for 52 weeks was shown to stabilize Fabry patients' kidney function.
I also don't believe that BRIGHT's data proves PRX-102's 4-week regime to be comparable with the 2-week regime 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 competitivity, as it is shown to be only a non-inferior (not superior) ERT.
Thanks for reading. All the best!
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Additional disclosure: I own shares in ACLX, ATRA, AVRO, AVXL, CYTH, KRYS, LOGC, LRMR, MNKKQ, ORTH, PASG, SIOX, STOK, XCUR and I have put options in SAVA, VXRT