CAUTIONARY STATEMENT REGARDING FORWARD-LOOKING STATEMENTS
AND RISK FACTORS SUMMARY
You should read the following discussion and analysis of our financial condition
and results of operations together with our financial statements and the
consolidated financial statements and the related notes included elsewhere in
this Form 10-Q and in our Annual Report on Form 10-K for the year ended
Examples of the risks and uncertainties include, but are not limited to, the following:
?the risk that the FDA might not grant marketing approval for PRX-102, by the Prescription Drug User Fee Act (PDUFA) action date or at all, and other risks related to the timing, progress and likelihood of final approval by the FDA of the resubmitted PRX-102 BLA;
?risks related to the timing, progress and likelihood of approval by the EMA of the MAA for PRX-102, and of approvals by other applicable health regulatory authorities;
?the risk that a marketing approval of PRX-102 by either the FDA or the EMA will be conditioned on significant limitations on its use;
?whether, if approved by the FDA, EMA and other applicable health regulatory authorities, the use of PRX-102 will be commercially successful;
?the likelihood that the FDA, EMA or other applicable health regulatory authorities will approve an alternative dosing regimen;
?failure or delay in the commencement or completion of our preclinical studies and clinical trials, which may be caused by several factors, including: slower than expected rates of patient recruitment; unforeseen safety issues; determination of dosing issues; lack of effectiveness during clinical trials; inability to satisfactorily demonstrate non-inferiority to approved therapies; inability or unwillingness of medical investigators and institutional review boards to follow our clinical protocols; inability to monitor patients adequately during or after treatment; and/or lack of sufficient funding to finance our clinical trials;
?the risk that the FDA, EMA, or other foreign regulatory authorities may not accept or approve a marketing application we file for any of our product candidates, and other risks relating to the review process;
?risks associated with the novel coronavirus disease, or COVID-19, outbreak and variants, which may adversely impact our business;
?risks related to any transactions we may effect in the public or private equity markets to raise capital to finance future research and development activities, general and administrative expenses and working capital;
?risks relating to our evaluation and pursuit of strategic alternatives;
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?the risk that the results of our clinical trials will not support the applicable claims of safety or efficacy and that our product candidates will not have the desired effects or will be associated with undesirable side effects or other unexpected characteristics;
?risks relating to our ability to manage our relationship with our collaborators, distributors or partners, including, but not limited to, Pfizer and Chiesi;
?risks related to the amount and sufficiency of our cash and cash equivalents;
?risks relating to our ability to make scheduled payments of the principal of, to pay interest on or to refinance our outstanding notes or any other indebtedness;
?risks relating to changes to interim, topline or preliminary data from clinical trials that we announce or publish;
?risk of significant lawsuits, including stockholder litigation, which is common in the life sciences sector;
?our dependence on performance by third-party providers of services and supplies, including without limitation, clinical trial services;
?delays in our preparation and filing of applications for regulatory approval; the inherent risks and uncertainties in developing drug platforms and products of the type we are developing;
?the impact of development of competing therapies and/or technologies by other companies;
?risks related to our supply of drug product to Pfizer;
?risks related to our expectations with respect to the potential commercial value of our product and product candidates;
?risks relating to the compliance by Fiocruz, an arm of the Brazilian MoH, with its purchase obligations under our supply and technology transfer agreement, which may have a material adverse effect on us and may also result in the termination of such agreement;
?potential product liability risks, and risks of securing adequate levels of related insurance coverage;
?the possibility of infringing a third-party's patents or other intellectual property rights and the uncertainty of obtaining patents covering our products and processes and successfully enforcing our intellectual property rights against third-parties;
?risks relating to changes in healthcare laws, rules and regulations in
?and the possible disruption of our operations due to terrorist activities and armed conflict, including as a result of the disruption of the operations of certain regulatory authorities and of certain of our suppliers, collaborative partners, licensees, clinical trial sites, distributors and customers.
Given these uncertainties, you should not place undue reliance on these forward-looking statements. Companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in advanced or late-stage clinical trials, even after obtaining promising earlier trial results or preliminary findings for such clinical trials. Even if favorable testing data is generated from clinical trials of a drug product, the FDA or foreign regulatory authorities may not accept or approve a marketing application filed by a pharmaceutical or biotechnology company for the drug product.
Recent Company Developments
?On
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?On
In light of recent developments relating to the COVID-19 pandemic and the focus
of healthcare providers and hospitals on fighting the virus and its variants,
and consistent with the
We are in close contact with our principal investigators, clinical sites and
clinical research organizations, which are primarily located in
Delisting from Tel Aviv Stock Exchange
On
ProCellEx: Our Proprietary Protein Expression System
ProCellEx is our proprietary platform used to produce and manufacture recombinant proteins through plant cell-based expressions in suspension. ProCellEx consists of a comprehensive set of proprietary technologies and capabilities, including the use of advanced genetic engineering and plant cell culture technology, enabling us to produce complex, proprietary, and biologically equivalent proteins for a variety of human diseases. Our protein expression system facilitates the creation and selection of high-expressing, genetically-stable cell lines capable of expressing recombinant proteins.
Our ProCellEx technology allows for many unique advantages, including: biologic optimization; an ability to handle complex protein expressions; flexible manufacturing with improvements through efficiencies, enhancements and/or rapid horizontal scale-ups; a simplified production process; elimination of the risk of viral contaminations from mammalian components; and intellectual property advantages.
We are the first and only company to gain FDA approval of a protein produced through plant cell-based expression. Our ProCellEx platform uses flexible polyethylene disposable bioreactors and is optimized for plant cell cultures. As opposed to the large stainless-steel bioreactors commonly used for recombinant protein production, our ProCellEx bioreactors are easy to use and maintain and allow for the major advantage of rapid horizontal scale-up.
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Plant Cell Production Advantages
[[Image Removed: Graphic]]
ProCellEx®:
[[Image Removed: Graphic]] 16 Table of Contents Product Pipeline [[Image Removed: Graphic]]
Pegunigalsidase Alfa (PRX-102) for the Treatment of Fabry Disease
PRX-102, our lead product candidate, is a late-stage clinical asset in development for the treatment of Fabry disease. We expect PRX-102 to be the primary subject of our development efforts in the short-term. It is our proprietary, investigational, plant cell culture expressed enzyme, and a chemically modified stabilized version of, the recombinant ?-Galactosidase-A protein, a lysosomal enzyme, under development for the treatment of Fabry disease. Fabry disease is a serious life-threatening rare genetic disorder. Fabry patients lack or have low levels of ?-galactosidase-A resulting in the progressive accumulation of abnormal deposits of a fatty substance called globotriaosylceramide, or Gb3, in blood vessel walls throughout their body. 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 occurs in one person per 40,000 to 60,000 males.
The global market for Fabry disease, that includes Sanofi's Fabrazyme®, Shire's
(acquired by Takeda Pharmaceutical Company Limited) Replagal®, and Amicus
Therapeutics' Galafold®, among others, was
Our phase III clinical program included three separate clinical trials which are
referred to as the BALANCE study, the BRIDGE study and the BRIGHT study, all of
which have been completed. In addition, the phase III clinical program included
two extension studies in which subjects that participated in our phase I/II
clinical trials and our phase III clinical trials were given the opportunity to
enroll and continue to be treated with PRX-102. As of
The FDA has indicated that the BLA for PRX-102 for the potential treatment of
adult patients with Fabry disease that we, together with Chiesi, resubmitted on
On
The MAA submission includes a comprehensive set of preclinical, clinical and
manufacturing data compiled from our completed and ongoing clinical studies
evaluating PRX-102 as a potential alternative treatment for adult patients with
Fabry disease, including data from our completed 12-month switch-over phase III
BRIGHT clinical trial in adult patients with Fabry disease treated with a
2 mg/kg every four weeks dosage to support an additional potential treatment
regimen for Fabry patients. As part of the EMA review process, we and Chiesi
responded to the Day 120 list of questions in
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On
In
Chiesi, together with
Key Trials and Design
Our clinical development program is designed to show that PRX-102 has a
potential clinical benefit in all adult Fabry patient populations when compared
to currently marketed Fabry disease enzymes, agalsidase beta (Fabrazyme®;
marketed by Sanofi (acquired
Our phase III clinical program of PRX-102 for the treatment of Fabry disease includes three individual studies; the BALANCE study, the BRIDGE study and the BRIGHT study, all of which have been completed. In 2016, we completed a phase I/II clinical trial of PRX-102, which was a dose range finding study in ERT-naïve adult Fabry patients. In the phase III clinical program overall, two potential dosing regimens for PRX-102 were analyzed; 1 mg/kg every two weeks, with the potential for improved efficacy and safety offering a potential alternative to existing enzyme replacement therapies, and 2 mg/kg every four weeks, which has the potential to lower treatment burden versus existing treatments and potentially provide a better quality of life for a subset of adult Fabry patients.
Patients who completed the BALANCE, BRIDGE and BRIGHT studies, and the extension
of the phase I/II study, were offered the opportunity to continue PRX-102
treatment in one of two long-term open-label extension studies. Currently, 126
subjects who participated in our PRX-102 clinical program have opted, with the
advice of the treating physician, to continue PRX-102 treatment in one of our
long-term, open label, extension studies. Such extension studies include 97
patients in the 1 mg/kg every two weeks extension study (PB-102-F60) with a
total cumulative exposure of approximately 400 patient years (10 subjects who
completed an extension study from the phase I/II study, 18 subjects who
completed the BRIDGE study; 69 subjects who completed the BALANCE study), and 29
subjects who completed the BRIGHT study, in the 2 mg/kg every four weeks
extension study (PB-102-F51) with a total cumulative exposure of approximately
110 patient years. Two of such subjects are being treated with 1 mg/kg every two
weeks. As of
In
Phase III BALANCE Study
The pivotal BALANCE study was a 24-month, randomized, double blind, active
control study of PRX-102 in adult Fabry patients with deteriorating renal
function that was designed to evaluate the safety and efficacy of 1 mg/kg of
PRX-102 administered every two weeks compared to agalsidase beta. Topline
results from the completed study were announced in
The primary endpoint of the BALANCE study is the comparison in the annualized rate of decline of estimated Glomerular Filtration Rate, or eGFR, slope between the agalsidase beta and PRX-102 treatment arms. eGFR is considered a reliable and accepted test to
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measure kidney function and stage of kidney disease. Additional parameters evaluated include: cardiac assessment, Lyso-Gb3 (a biomarker for monitoring Fabry patients during therapy), pain, quality of life, immunogenicity, Fabry Clinical Events, pharmacokinetics and other parameters.
Given the changed regulatory landscape in
The median (95% confidence interval) of the eGFR slope in the PRX-102 arm was -2.514 mL/min/1.73m2/year (-3.788, -1.240) and -2.155 mL/min/1.73m2/year (-3.805, -0.505) in the agalsidase beta arm, demonstrating a large overlap in the confidence intervals of the two arms. The difference in medians (95% confidence interval) is -0.359 mL/min/1.73m2/year (-2.444, 1.726). The prespecified non-inferiority margin was met. The final results of the per-protocol analysis set (72 patients) are consistent with the ITT results, with an even smaller difference in medians (95% confidence interval); -0.118 mL/min/1.73m2/year (-2.450, 2.213). Additional sensitivity and supportive analyses investigated mean eGFR slopes using other statistical models. These models yielded results similar to the primary analysis and confirming non-inferiority of PRX-102 to agalsidase beta. These results supported the robustness of the methodology used for comparisons of treatment effects in the BALANCE study.
The study population (ITT analysis set) was composed of 47 males (61.0%) and 30 females (39.0%), with a mean (range) age of 44.3 (18-60) years. The mean duration of prior treatment with agalsidase beta was approximately six years. At baseline, mean (SD) eGFR was 73.69 ml/min/1.73m2 (20.32) and median eGFR was 74.51 ml/min/1.73m2; mean (SD) eGFR slope was -8.10 mL/min/1.73m2/year (5.92) and median eGFR slope was -7.25 ml/min/1.73m2/year.
A consistent efficacy response was also observed across biomarkers and functional systems relevant to Fabry disease, as demonstrated via secondary endpoints, where in some cases the trend was in favor of PRX-102 and in some in favor of agalsidase beta, but the actual difference between the two arms is always clinically small, supporting the comparability of the two treatments.
Key secondary endpoints included Urine protein creatinine ratio (UPCR) as indicator of proteinuria, plasma levels of lyso -Gb3, imaging marker of cardiac remodeling (Left Ventricular Mass Index, LVMI, by cardiac MRI), disease severity (by Mainz Severity Score Index, MSSI), pain severity (Short Form Brief Pain Inventory, BPI) and quality of life (EQ-5D-5L). Both treatments showed either a stabilization of clinical parameters (e.g., for eGFR, eGFR slope and UPCR) or prevention of further progression of Fabry disease (e.g., LVMI, MSSI).
?Secondary measures of kidney function. In addition to eGFR levels and slope, the proportion of patients categorized as having severe proteinuria (UPCR ? 1 gr/gr) in the PRX-102 arm remained stable during the study (at baseline, 7/52 [13.5%] and 6/45 [13.3%] 24-month), while in the agalsidase beta arm, the proportion increased slightly with 3/25 (12.0%) and 4/24 (16.7%), respectively. Mean (SE) UPCR data (post-hoc analysis) for the entire study population remained stable throughout the study with a slight advantage for PRX-102 at 24-months compared to agalsidase beta (Table 1).
?Biomarkers of Fabry disease. Mean (SE) and median (range) plasma lyso-Gb3 change from baseline to 24 months of treatment in the PRX-102 arm were 3.30 (1.38) and 1.15 (-32.2 to 32.7) nM for PRX-102, and -8.74 (4.85) and -1.50 (-102.3 to 2.4) nM for agalsidase beta. As expected, a gender difference was noted, with female Fabry patients exhibiting lower values at baseline and no remarkable changes during the study. Overall, the absolute changes of the Fabry biomarkers were minor in both treatment arms and were considered not clinically significant since there was no indication of Gb3 re-accumulation nor of disease progression.
?Measures of cardiac disease. LVMi was centrally evaluated based on cardiac MRI. An increase in LVMi is indicative of progressing cardiomyopathy, hence preventing an increase in LVMI represents a therapeutic goal in Fabry patients. In the BALANCE study, the change from baseline in both treatment arms was analyzed by absence/presence of hypertrophy at baseline (defined as a LVMI above 91 g/m2 for males and LVMI above 77 g/m2 for females at baseline) and by gender (Kawel-Boehm 2015). Similar results were achieved in the two treatment arms after 24 months, with a slight reduction in the mean (SE) LVMi values in the PRX-102 arm -4.238 (5.731) and a small increase in the agalsidase beta arm 2.417 (9.620) for patients with hypertrophy at baseline. Small differences were observed also in those patients without hypertrophy at baseline in both treatment arms.
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?Measures of systemic disease burden (MSSI). Further evidence of the stabilization of the disease is provided by the MSSI overall scores, which remained stable throughout the BALANCE study in both arms, with the baseline score in both groups at the low end of the moderate range (means of 23.18 points in the PRX-102 arm and 25.16 points in the agalsidase beta arm), that slightly decreased (improvement by -2.1 points) in the PRX-102 arm and slightly increased in the agalsidase beta arm (+2.0 points). In this case, the CI of the difference in mean changes did not contain 0, suggesting a difference between the two arms in favor of PRX-102.
?Patient reported outcomes. With regards to the patient-reported outcomes (BPI and EQ-5D-5L), the two treatments showed very similar results, with the majority of patients reporting an improvement or no change in both groups, for each domain.
For an overview of primary and secondary endpoints collected in the BALANCE study, please refer to the Table 1 below.
Table 1: Summary Table of Comparison of Treatment Benefit Data in the BALANCE Study, (Mean (SE) [median]), Efficacy Population
Parameter PRX-102 (N = 52) Agalsidase beta (N = 25) eGFR n n (ml/min/1.73m2) Baseline 52 73.46 (2.80) 25 74.16 (4.19) [73.45] [74.85] Month 24 47 70.53 (3.19) 24 72.05 (4.69) [69.35] [74.48] Change from 47 -3.60 (1.58) 24 -1.97 (1.51) Baseline [-2.39] [-3.20] eGFR slope Baseline 52 -8.03 25 -8.25 (ml/min/1.73m2/yr) (0.92) (0.85) [-6.70] [-7.84] Range: Range: -30.5; -20.3; 6.3 -2.8 Month 24 51 -2.38 (1.25) 25 -2.31 (0.71) [-2.51] [-2.16] Q1; Q3: -4.8; Q1; Q3: -4.6; 0.8 -0.5 Reaching kidney Month 24 52 41 25 20 therapeutic goala patients patients (80.4%) (80.0%) UPCR Baseline 52 0.441 25 0.284 (0.084) (0.097) Month 24 45 0.480 (0.118) 24 0.489 (0.162) Change from 45 0.088 (0.067) 24 0.197 (0.085) Baseline Plasma lyso-Gb3 Baseline 52 26.22 25 32.14 (nM) (3.78) (7.08) [15.20] [17.60] Month 24 46 29.22 (4.48) 22 19.65 (3.60) [18.80] [15.30] Change from 46 3.30 (1.38) 22 -8.74 (4.85) Baseline [1.15] [-1.50] LVMI (g/m2) Baseline 40 75.97 22 82.22 (5.13) (6.34) Month 24 35 71.56 (5.20) 20 82.43 (8.39) Change from 28 -0.64 (2.69) 19 0.29 (3.73) Baseline MSSI (overall Baseline 49 23.18 25 25.16 score)a (1.42) (2.14) Month 24 46 22.11 (1.80) 23 27.09 (2.30) Change from 44 -2.07 (0.77) 23 2.04 (1.10) Baseline BPI (score for Baseline 52 3.5 25 2.6 pain at its (0.4) (0.6) worst)b Month 24 45 3.3 (0.5) 22 3.0 (0.7) Change from 45 -0.1 (0.5) 22 0.6 (0.6) Baseline
BPI=brief pain inventory; eGFR=estimated glomerular filtration rate; lyso-Gb3=globotriaosylsphingosine; LVMI=Left Ventricular Mass Index; MSSI=Mainz Severity Score Index; UPCR=Urine Protein Creatinine Ratio.
a Wanner 2018; b Higher scores indicate higher symptom severity.
Forty-seven (90.4%) patients in the PRX-102 arm experienced at least one treatment-emergent adverse event (TEAE) compared to 24 (96.0%) in the agalsidase beta arm. The number of events adjusted to 100 years of exposure is 572.36 events for the PRX-102 arm and 816.85 events for the agalsidase beta arm.
Treatment-related adverse events were reported for 21 (40.4%) patients in the PRX-102 arm compared to 11 (44.0%) in the agalsidase beta arm. The number of treatment-related events adjusted to 100 years of exposure is 42.85 events for the PRX-102 arm and 152.91 events for the agalsidase beta arm.
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Usage of infusion pre-medication was tapered down during the study, if possible, for all patients. At baseline, 21 (40.4%) patients in the PRX-102 arm used infusion premedication compared to 16 (64.0%) in the agalsidase beta arm. At the end of the study, only three out of 47 (6.4%) patients in the PRX-102 arm used infusion premedication compared to three out of 24 (12.5%) in the agalsidase beta arm. Even with this reduction in use of premedication, there were fewer reported infusion-related reactions with PRX-102: 11 (21.2%) patients in the PRX-102 arm experienced a total of 13 events compared to six (24.0%) patients experiencing a total of 51 events in the agalsidase beta arm. The number of infusion-related reactions adjusted to 100 infusions is 0.5 for the PRX-102 arm and 3.9 for the agalsidase beta arm.
Assessment of immunogenicity, that is, the existence and development of anti
PRX-102 antibodies or anti-agalsidase beta antibodies, in the study indicated
that for the PRX-102 arm, 18 (34.6%) patients were
Out of the 78 randomized patients, six patients discontinued the study: out of the five (9.4%) from the PRX-102 arm, one patient withdrew consent prior to the first infusion, two discontinued due to personal reasons, and two due to adverse events (one due to an unrelated adverse event and one due to a treatment related adverse event); one (4%) patient from the agalsidase beta arm discontinued for personal reasons. There were no deaths in this study.
Considering that in the trial, patients in the PRX-102 arm were exposed for the first time to the novel enzyme, tolerability data appear favorable for PRX-102 and in line with what was observed in the previous clinical studies of PRX-102.
Of the patients who completed the trial from both the PRX-102 and agalsidase beta treatment arms, 69 have opted, with the advice of the treating physician, to receive PRX-102 1 mg/kg every two weeks in the long-term open-label extension study which is now sponsored by Chiesi.
The results of the direct, blinded comparison of PRX-102 to agalsidase beta, for the primary efficacy renal endpoints (i.e., eGFR change, eGFR slope) and for the main secondary endpoints (e.g., urine protein to creatinine ratio [UPCR] LVMI, MSSI, BPI) strongly suggest comparability in treatment effects between the two treatments.
At the same time a potentially favorable safety profile was identified based on
lower rates of IRR, lower
Phase III BRIDGE Study
The BRIDGE study was a 12-month open-label, single arm switch-over study
evaluating the safety and efficacy of pegunigalsidase alfa, 1 mg/kg infused
every two weeks, in up to 22 Fabry patients previously treated with agalsidase
alfa for at least two years and on a stable dose for at least six months. The
trial was completed in
Final results of the data generated in the BRIDGE study showed substantial
improvement in renal function as measured by mean annualized eGFR slope in both
male and female patients. Twenty of 22 patients completed the 12-month treatment
duration. Eighteen of the patients who completed the study opted to roll over to
a long-term extension study and continue to be treated with PRX-102. In the
study, the mean annualized eGFR slope of the study participants improved from
-5.90 mL/min/1.73m2/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/1.73m2/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. Following the switch to
PRX-102, there was a decrease in patients with progressing or fast progressing
kidney disease which is consistent with the therapeutic goals for Fabry disease,
as identified by
PRX-102 was well-tolerated in the BRIDGE study, with all adverse events being transient in nature without sequelae. Of the 22 patients enrolled in the BRIDGE study, the majority of TEAEs were mild or moderate in severity, with two patients (9.1%) withdrawing from the therapy due to hypersensitivity reaction that was resolved. The most common moderate TEAEs were nasopharyngitis, headache and dyspnea.
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An immunogenicity assessment indicated that four out of 20 patients (20%) developed persistent ADAs over the course of the study, of which two had neutralizing activity.
Baseline characteristics of the 20 patients who completed the study, ranging from ages 28 to 60 years, were as follows: mean eGFR 75.87 mL/min/1.73m2 in males, and 86.14 mL/min/1.73m2 in females and plasma lyso-Gb3 were 51.81 nM and 13.81 nM in males and females, respectively. While lyso-Gb3 levels remain slightly high, particularly within the male cohort, continuous reduction in lyso-Gb3 levels was observed of 19.55 nM (32.35%) in males and 4.57 nM (29.81%) in females.
Of the patients who completed the trial, 18 have opted, with the advice of the treating physician, to continue receiving PRX-102 1 mg/kg every two weeks in a long-term open-label extension study which now sponsored by Chiesi.
Phase III BRIGHT Study
The BRIGHT study was a multicenter, multinational 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 trial, which was completed in
We announced final results from the BRIGHT study in
All 30 patients received at least one dose of PRX-102, and 29 patients completed the one-year study. Of these 29 patients, 28 received the intended regimen of 2 mg/kg every four weeks throughout the entire study, while one patient was switched to 1 mg/kg PRX-102 every two weeks per protocol at the 11th infusion. One patient withdrew from the study after the first infusion due to a traffic accident.
First infusions of PRX-102 were administered under controlled conditions at the investigation site. Based on the protocol-specified criteria, patients were able to receive their PRX-102 infusions at a home care setup once the applicable Investigator and Sponsor Medical Monitor agreed that it was safe to do so. Safety and efficacy exploratory endpoints were assessed throughout the 52-week study.
Overall, 33 of 183 total TEAEs reported in nine (30.0%) of the patients were considered treatment related; all were mild or moderate in severity and the majority were resolved at the end of the study. There were no serious or severe treatment-related TEAEs and no TEAEs led to death or study withdrawal. Of the treatment-related TEAEs, 27 were infusion-related reactions (IRRs) and the remainder were single events of diarrhea, erythema, fatigue, influenza-like illness, increases urine protein/creatinine ratio, and urine positive for white blood cells. The 27 IRRs were reported in five (16.7%) patients, all male. All IRRs occurred during the infusion or within two hours post-infusion; no events were recorded between two and 24 hours post-infusion.
Study outcome measures show that plasma lyso-Gb3 concentrations remained stable during the study with a mean change (±SE) of 3.01 nM (0.94) from baseline (19.36 nM ±3.35) to Week 52 (22.23 ±3.60 nM). Mean absolute eGFR values were stable during the 52-week treatment period, with a mean change from baseline of -1.27 mL/min/1.73m2 (1.39). Mean (SE) eGFR slope, at the end of the study, for the overall population, was -2.92 (1.05) mL/min/1.73m2/year indicating stability.
The study suggests that Fabry patients who are currently receiving ERT every two weeks may be successfully transitioned to PRX-102 2 mg/kg every four weeks as an effective and tolerable alternative treatment option. Additional long term data is being collected as part of the ongoing long term extension study of the 2 mg/kg PRX-102 every four weeks dose.
Following a survey of participants using the Quality of Life EQ-5D-5L questionnaire, responses indicate that patient perception of their own health remained high and stable throughout the 52-week study duration, with overall health mean (SE) scores of 78.3 (3.1) and 82.1 (2.9) at baseline and Week 52, respectively, in a 0 to 100 scale. Using the short-form Brief Pain Inventory, or questionnaire,
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approximately 75% of study participants had an improvement or no change in average pain severity at Week 52 (compared to baseline). The short-form BPI interference items also remained stable during the study. Pain-related results indicate that there was no increase and/or relapse in pain. No Fabry clinical events were reported during the study.
Open-Label Extension Studies
Our PRX-102 clinical program included two open-label extension studies; one of
the 1 mg/kg PRX-102 every two weeks dosage, which we refer to as the F60 Study
and the second of the 2 mg/kg PRX-102 every four weeks dosage, which we refer to
as the F51 Study. Patients who completed the BALANCE Study, the BRIDGE Study and
our phase I/II extension study were given the opportunity to enroll in the
F60 Study and patients who completed the BRIGHT Study were given the opportunity
to enroll in the F51 Study. Overall, 97 patients enrolled in the F60 Study;
69 patients from the BALANCE Study, 18 patients from the BRIDGE Study and
10 patients from the phase I/II study. In addition, 29 patients enrolled in the
F51 Study. As of
COVID-19 Impact on PRX-102 Clinical Trials
To date, the COVID-19 pandemic has had a minimal effect on the performance of the phase III clinical trials of PRX-102 as many of the patients were already treated in home care settings. We were able to complete all three studies. In a minimal amount of cases, patients who completed a trial were not able to be transferred into an extension study due to the pandemic restrictions, and, accordingly, the main trial was prolonged for the patients to permit the continuation of treatment.
Phase I/II Study
Our phase I/II clinical trial of PRX-102, which we completed in 2015, was a worldwide, multi-center, open-label, dose ranging study designed to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and efficacy parameters of PRX-102 in adult patients with Fabry disease. Sixteen adult, naïve Fabry patients (9 male and 7 female) completed the trial, each in one of three dosing groups, 0.2 mg/kg, 1 mg/kg and 2 mg/kg. Each patient received IV infusions of PRX-102 every two weeks for 12 weeks, with efficacy follow-up after six-month and twelve-month periods. A majority of the patients who completed the trial opted to continue receiving PRX-102 in an open-label, 60-month extension study under which all patients were switched to receive 1 mg/kg of the drug, the selected dose for our BALANCE and BRIDGE studies.
The adult symptomatic, ERT-naïve Fabry disease patients enrolled in the phase I/II study were evaluated for Gb3 levels in kidney biopsies and for plasma Lyso-Gb3 concentration by the quantitative BLISS methodology. Biopsies were available from 14 patients. The outcome of ? 50% reduction in the average number of Gb3 inclusions per kidney PTC from baseline to Month 6 was demonstrated in 11 of 14 (78.6%) of the patients treated with PRX-102. The overall results demonstrate that PRX-102 reaches the affected tissue and reduces kidney Gb3 inclusions burden and Lyso-Gb3 in the circulation. A high correlation was found between the two Fabry disease biomarkers, reduction of kidney Gb3 inclusions and the reduction of plasma Lyso-Gb3 over six months of treatment.
Data was recorded at 24 months from 11 patients who completed 12 months of the long-term open-label extension trial that succeeded the phase I/II study. Patients who did not continue in the extension trial included: female patients who became or planned to become pregnant and therefore were unable to continue in accordance with the study protocol; and patients who relocated to a location where treatment was not available under the clinical study.
Results show that Lyso-Gb3 levels decreased approximately 90% from baseline. Renal function remained stable with mean eGFR levels of 108.02 and 107.20 at baseline and 24 months, respectively, with a modest annual eGFR slope of -2.1. An improvement across all the gastrointestinal symptoms evaluated, including severity and frequency of abdominal pain and frequency of diarrhea, was noted. Cardiac parameters, including LVM, LVMI and EF, remained stable with no cardiac fibrosis development detected. In conclusion, an improvement of over 40% in disease severity was shown as measured by the Mainz Severity Score Index, or MSSI, a score compiling the different elements of the disease severity including neurological, renal and cardiovascular parameters. In addition, an improvement was noted in each of the individual parameters of the MSSI.
The majority of adverse events were mild-to-moderate in severity, and transient
in nature. During the first 12 months of treatment, only three of 16 patients
(less than 19%) formed ADAs of which two of these patients (less than 13%) had
neutralizing antibodies. Importantly, however, the ADAs turned negative for all
three of these patients following 12 months of treatment. The
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Commercialization Agreements with
We have entered into two exclusive global licensing and supply agreements for
PRX-102 for the treatment of Fabry disease with Chiesi. The agreements have
significant revenue potential for
On
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As of
Elelyso® for the Treatment of Gaucher Disease
Elelyso (taliglucerase alfa), our first commercial product, was approved by the
FDA in 2012 for injection as an enzyme replacement therapy (ERT) for the
long-term treatment of adult patients with a confirmed diagnosis of type 1
Gaucher disease. In
Gaucher disease, also known as glucocerebrosidase, or GCD, deficiency, is a rare genetic autosomal recessive disorder and one of the most common Lysosomal Storage Disorders, or LSDs, in the world. It is one of a group of disorders that affect specific enzymes that normally break down fatty substances for reuse in the cells. If the enzymes are missing or do not work properly, the substances can build up and become toxic. Gaucher disease occurs when a lipid called glucosylceramide accumulates in the cells of the bone marrow, lungs, spleen and liver, and sometimes the brain. Gaucher disease symptoms can include fatigue, anemia, easy bruising and bleeding, severe bone pain and easily broken bones, and distended stomach due to an enlarged spleen and thrombocytopenia. Epidemiology of Gaucher disease varies; recent literature provides that prevalence of Gaucher disease ranges from 0.70 to 1.75 per 100,000 in the
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general population. In people of Ashkenazi Jewish heritage, estimates of occurrence vary from approximately 1 in 400 to 1 in 850 people.
The global market for Gaucher disease, that includes Sanofi's Cerezyme®, Shire's
(acquired by Takeda Pharmaceutical Company Limited) Vpriv®, and Sanofi's
Cerdelga®, among others, was
Commercialization Agreements for Elelyso
We have licensed to Pfizer the global rights to Elelyso in all markets excluding
For the first 10-year period after the execution of our Amended Pfizer Agreement, we have agreed to sell drug substance to Pfizer for the production of Elelyso, and Pfizer maintains the right to extend the supply period for up to two additional 30-month periods subject to certain terms and conditions. In a subsequent amendment, we agreed that after the completion of the first 10-year supply period, the supply term would automatically extend for a five-year period.
We maintain distribution rights to Elelyso in
Uricase (PRX-115)
PRX-115 is our plant cell-expressed recombinant PEGylated uricase (urate oxidase) - a chemically modified enzyme under development for the potential treatment of severe gout. We use ProCellEx to express an optimized recombinant uricase enzyme under development for the potential treatment of severe gout which we are designing to lower uric acid levels while having low immunogenicity and increased half-life in the circulation. Pre-clinical data demonstrates stable PK profile and long half-life, low immunogenic risk and high specific activity which supports the potential of PRX-115 to be a safe and effective treatment for severe gout. Results from the one-month multiple dosing toxicity studies in two species demonstrate that PRX-115 is well tolerated.
On
Gout is the most common inflammatory arthritis in
Severe gout is generally described as a state of gout in which there is a presence of monosodium urate crystals with any of the following: frequent recurrent gout flares, chronic gouty arthritis, subcutaneous tophi or disease elements of gout seen via imaging. It is estimated that approximately 2% of the gout patient population is considered to have chronic refractory disease, and we believe the incidence of severe gout is higher.
Currently available urate-lowering therapies, or ULTs, can be effective in treating gout. However, we believe that new effective, safe therapies are needed to treat severe gout and chronic refractory gout regardless of treatment history. One treatment option may be a therapeutic use of the uricase enzyme which converts uric acid to allantoin, which is easily eliminated through urine. The uricase enzyme does not exist naturally in humans. To date, two variants of recombinant uricases are approved for marketing: (i) Krystexxa® (pegloticase) for treatment of chronic gout refractory to conventional therapy (gout patients who have contraindication/failure of other lowering uric acid treatments) and (ii) Elitek®, indicated for the treatment of tumor lysis syndrome but not gout. Both have a black box warning for anaphylaxis and other major side-effects. In particular, 89% of patients treated with Krystexxa developed an immunogenic response associated with a failure to maintain normalization of serum uric acid levels over a 6-month therapy cycle. In addition, a recent phase IV study demonstrates that co-treatment with Krystexxa and methotrexate prolongs efficacy and increases
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tolerability in patients with refractory gout. Krystexxa is no longer marketed
in the
PRX-119
PRX-119 is our plant cell-expressed PEGylated recombinant human DNase I product candidate being designed to elongate half-life in the circulation for NETs-related diseases. NETs, Neutrophil extracellular traps, are web-like structures, released by activated neutrophils that trap and kill a variety of microorganisms. NETs are composed of DNA, histones, antimicrobial and pro-inflammatory proteins. Excessive formation or ineffective clearance of NETs can cause different pathological effects. NETs formation has been observed in various autoimmune, inflammatory and fibrotic conditions, diverse forms of thrombosis, cancer and metastasis. According to scientific literature, animal studies have demonstrated that DNase treatment reduces NETs toxicity. Our proprietary modified DNase I design for long and customized systemically circulating in the bloodstream, may potentially enable effective treatment of acute and chronic conditions.
Intellectual Property
A key element of our overall strategy is to establish a broad portfolio of
patents to protect our proprietary technology, proprietary product and product
candidates and their methods of use. As of
Scientific Presentations
We hosted an informational booth at the 19th Annual WORLDSymposium™ 2023, which
took place
"First results of a head-to-head trial of pegunigalsidase alfa vs. agalsidase
beta in Fabry disease: 2-year results of the phase 3 randomized, double-blind,
BALANCE study," an abstract (lead author
"Long-term safety and efficacy of pegunigalsidase alfa administered every 4
weeks in patients with Fabry disease: two-year interim results from the ongoing
phase 3 BRIGHT51 open-label extension study," an abstract presented by
Both of the abstracts were also available during the symposium as poster presentations. Copies of presentations are available on our website under the Presentation tab in the Investors section.
Research & Development
We continuously work on the further development of our ProCellEx plant cell expression technology and bioreactor system. In addition, we are working on the development of new products, each in different initial stages of development, for specific products for which there are unmet needs in terms of efficacy and safety. Our development strategy focuses on the utilization of different modification approaches and development improvements, customized for each protein product, in all stages of expression and development.
Critical Accounting Policies
Our significant accounting policies are more fully described in Note 1 to our
consolidated financial statements appearing in this Quarterly Report. There have
been no material changes to our critical accounting policies since we filed our
Annual Report on Form 10-K for the year ended
The discussion and analysis of our financial condition and results of operations
is based on our financial statements, which we prepared in accordance with
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basis for making judgments about the carrying value of assets and liabilities that are not readily apparent from other sources. Actual results may differ from these estimates under different assumptions or conditions.
Results of Operations
Three months ended
Revenues from Selling Goods
We recorded revenues from selling goods of
Revenues from License and R&D Services
We recorded revenues from license and R&D services of
Cost of Goods Sold
Cost of goods sold was
Research and Development Expenses
For the three months ended
Total decrease in research and developments expenses was
We expect research and development expenses to continue to be our primary expense as we enter into a more advanced stage of preclinical and clinical trials for certain of our product candidates.
Selling, General and Administrative Expenses
Selling, general and administrative expenses were
Financial Expenses, Net
Financial expenses, net were
Income taxes
Section 174 of the Tax Cuts and Jobs Act, which was enacted in
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Liquidity and Capital Resources
Our sources of liquidity includes our cash and cash equivalents balance. At
During the year ended
On
The 2024 Notes were issued pursuant to the Indenture dated as of
We believe that our cash and cash equivalents as of
Cash Flows
Net cash used in operations was
Net cash used in operations was
Future Funding Requirements
As a result of our significant research and development expenditures and the
lack of significant revenue from sales of taliglucerase alfa, we have generated
operating losses from our continuing operations since our inception. Our
outstanding 2024 Notes are secured by a perfected lien on all of our assets.
Under the terms of the 2024 Indenture, we are required to comply with certain
covenants, including the requirement to maintain a minimum cash balance of at
least
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We expect to continue to incur significant expenditures in the near future as we increase our research and developments efforts with respect to our product candidates. We cannot anticipate the costs or the timing of the occurrence of such costs. To the extent we need to obtain additional financing, it may be more difficult for us to do so given the volatility of the price of our common stock. Our material cash needs for the next 24 months will include, among other expenses, (i) costs of preclinical and clinical trials, (ii) employee salaries, (iii) payments for rent and operation of our manufacturing facilities, (iv) fees to our consultants and legal advisors, patent advisors and fees for service providers in connection with our research and development efforts and (v) payments of principal and interest on our outstanding 2024 Notes. We believe that the funds currently available to us are sufficient to satisfy our capital needs for at least 12 months.
As discussed above, we may be required to raise additional capital to develop our product candidates and continue research and development activities. Our ability to raise capital, and the amounts of necessary capital, will depend on many other factors, including:
? the duration and cost of discovery and preclinical development and laboratory
testing and clinical trials for our product candidates;
? our progress in commercializing BioManguinhos alfataliglicerase in
? the timing and outcome of regulatory review of our product candidates;
? the costs involved in preparing, filing, prosecuting, maintaining, defending
and enforcing patent claims and other intellectual property rights; and
? the costs associated with any litigation claims.
We expect to finance our future cash needs through corporate collaborations,
licensing or similar arrangements, public or private equity offerings and/or
debt financings. We currently do not have any commitments for future external
funding, except with respect to the development-related payments and milestone
payments that may become payable under the Chiesi Agreements. As of
Effects of Currency Fluctuations
Currency fluctuations could affect us through increased or decreased acquisition
costs for certain goods and services and salaries expenses. We do not believe
currency fluctuations have had a material effect on our results of operations
during the three months ended
Off-Balance Sheet Arrangements
We have no off-balance sheet arrangements as of each of
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