Jonathan Alicea

This week, at the American Society of Gene & Cell Therapy (ASGCT) Virtual Meeting, investigators reported on the safety and potential efficacy of FX201 gene therapy for 

FX201, or humantakinogene hadenovec, is a helper-dependent adenovirus serotype 5 that expresses Interleukin (IL)-1 receptor (IL-1Ra) antagonist as an intra-articular gene therapy

“FX201 is designed to produce IL-1Ra in the presence of inflammation via a nuclear factor-kappa B-responsive promoter,” indicated the researchers, led by Scott Kelley, MD, Chief Medical Officer of Flexion Pharmaceuticals. “Previous work demonstrated safety and efficacy of FX201 in preclinical models of osteoarthritis.”

Kelley and team conducted a Phase 1 open-label, single ascending dose trial in order to assess the therapy’s safety, tolerability, biodistributions, and preliminary clinical activity in patients with moderate-to-severe osteoarthritis in the knee. This ongoing trial follows IND-enabling toxicology studies and clinical-scale cGMP production.

The most recent findings represent 24-week data from the low-dose cohort (n = 5). Patient ages ranged from 30-80 years old, and all had Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain scores ≥ 4.0 - ≤ 9.0.

Further, these patients had Kellgren-Lawrence Grade 2-3 radiographic severity and experienced failure of ≥2 other treatments.

As such, a dose of 1.4E10 genome copies of FX201 was administered to the knee in question via ultrasound-guided intra-articular injection. The investigators assessed systemic biodistribution and shedding through quantification of vector copies in plasma, urine, and injection site swabs.

“No evidence of systemic biodistribution in plasma or shedding in urine or skin samples was observed in any patient,” they reported.

Clinical activity of the gene therapy was evaluated through measurements of changes in pain (WOMAC-A) and function (Knee Injury and Osteoarthritis Outcome Score [KOOS] Function in daily living).

Kelley’s team thus observed variable clinical activity with reduction in pain and improvement in activity. Nonetheless, 3 patients experienced substantial improvements in WOMAC-A pain intensity (as assessed by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials [IMMPACT])) at week 8, and 2 patients had similar improvements at weeks 12 and 24.

“Substantial pain relief persisting to 24 weeks following low-dose FX201 is encouraging and supports evaluating tolerability and responses with higher doses of FX2021,” they wrote.

Overall, the therapy was considered well-tolerated among the patients, with 2 patients experiencing self-limited Grade 2 index-knee adverse events (pain, swelling, effusion). The investigators indicated these events may have been possibly related to conservative treatment management.

The team is expected to update their results in the future, especially as follow-up of the mid-dose cohort nears completion.

The study, “Interim Data from the First-in-Human Phase 1 Trial of FX201, an Intra-Articular, Helper-Dependent Adenoviral Gene Therapy for Osteoarthritis - Safety, Tolerability, Biodistribution, and Preliminary Evaluation of Clinical Activity in 5 Patients,” was presented at ASGCT 2021.

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The therapy was generally well-tolerated and offered substantial pain relief in patients.

Intra-Articular FX201 Gene Therapy Shows Promise for Osteoarthritis

New data presented at the American Society of Gene & Cell Therapy (ASGCT) Virtual Meeting demonstrate the potential of ARU-1801 gene therapy for sickle cell disease (SCD).

A team led by Michael Grimley, MD, of Cincinnati Children’s Hospital Medical Center, reported on findings from the ongoing Phase 1/2 MOMENTUM study, which is evaluating the safety and efficacy of the new investigative gene therapy product among a sickle cell population. ARU-1801 consists of autologous CD34+ hematopoietic stem and progenitors (HSPCs) transduced with a lentiviral vector (LV) encoding a modified γ-globin

“Preliminary studies in SCD mice have suggested HbF

may have a more potent anti-sickling effect than wild-type HbF,” the team wrote. “As a high potency anti-sickling globin, HbF

 is believed to allow ARU-1801 to be effective with reduced intensity conditioning (RIC), resulting in fewer toxicities and lower resource utilization than myeloablative approaches, expanding access to gene therapy to a broader group of SCD patients.”

Thus, according to long-term clinical data, ARU-1801 demonstrated a favorable safety profile, and no treatment-related adverse events were reported. These were observed across 3 treated patients with >9 months of follow-up data.

The investigators noted that RIC led to neutrophil engraftment within 7-9 days (median, 7) of infusion and platelet engraftment within 6-12 days (median, 7).

Under the initial manufacturing, Patient 1 demonstrated a steady vector copy number of 0.2, in addition to stable expression of 20% HbF

 and 31% total anti-sickling globin (ASG). As noted by the investigators, ASG was composed of endogenous HbF, HbA2 and ARU-1801-derived HbF

Further, the patients showed 64% F-cells 2 years following gene therapy infusion.

Grimley’s team indicated that Patient 2 had a sub-therapeutic exposure to melphalan secondary to renal hyperfiltration and rapid clearance of melphalan — as such, this resulted in engraftment (VCN, 0.1) and thus lower HBF

Nevertheless, ASG expression was notably stable at 22%, as were F-cells at 36% 2 years post-infusion. This stability was due to sustained increases in endogenous HbF and HbA2.

Patient 3 had 10-month follow-up data (representative of the new manufacturing process) that showed a stable VCN of 0.7 with 41% ASG expression and 27% HbF

at month 10. Additionally, the patient had 92% F-reticulocytes at month 6, which indicates near pan-cellular expression of HbF.

All 3 patients had a median of 21 vaso-occlusive episodes in the 24 months prior to treatment with ARU-1801. They were hospitalized for a median of 6 of those episodes.

However, through 24 months post-infusion, patient 1 had a 93% reduction in the number of vaso-occlusive episodes, and patient 2 had an 85% reduction in the number of episodes. Through 10-months of follow-up, patient 3 experienced 0 vaso-occlusive episodes, thus demonstrating a 100% reduction.

Even more, the cumulative days spent in hospital from these episodes decreased from a median of 15 to a median of 0 days, showing an average of a 93.8% reduction.

“Treatment with ARU-1801 has resulted in remarkable improvement in clinical outcomes,” Grimely and team wrote.

“These results are an encouraging sign of the therapeutic benefit of ARU-1801 with RIC for patients with SCD,” they concluded.

The study, “Early Results from a Phase 1/2 Study of ARU-1801 Gene Therapy for Sickle Cell Disease (SCD): Safety and Efficacy of a Modified Gamma Globin Lentivirus Vector and Reduced Intensity Conditioning Transplant,” was presented at ASGCT 2021.

Early results from the MOMENTUM study show that treated patients experienced fewer vaso-occlusive episodes and related hospital admissions. 


ARU-1801 Improves Clinical Outcomes in Sickle Cell Disease

Association for Research in Vision and Ophthalmology (ARVO) Virtual Meeting

 demonstrates safety and efficacy of gene therapy ADVM-022 in patients with 

neovascular age-related macular degeneration (nAMD)

These findings are from the Phase 1 OPTIC trial, an open-label, multicenter, dose-ranging study designed to evaluate the safety, efficacy, and tolerability in patients who have previously received and shown response to anti-VEGF therapy.

“Intravitreal gene therapy has the potential to significantly reduce treatment burden and improve vision outcomes in patients with neovascular AMD,” noted the study investigators.

Led by Brandon Busbee, MD, of Tennessee Retina, the investigative team administered 2 different intravitreal doses of the gene therapy across 4 cohorts. Furthermore, they measured incidence and severity of adverse events, change in visual acuity (BCVA), change in central retinal thickness (CST), as well as need for and number of supplemental aflibercept injections.

In the study, cohorts 1 (n = 6) and 4 (n = 9) received 6x10

 vg/eye while cohorts 2 (n = 6) and 3 (n = 9) received 2x10

 vg/eye. Patients in cohort 1 were followed up for a median of 86 weeks, patients in cohort 2 for a median of 64 weeks, cohort 3 for a median of 48 weeks, and cohort 4 for a median of 16 weeks.

All patient across cohorts received mean 7.1-9.2 injections of anti-VEGF in the 12 months prior to the study. Notably, such injections led to decent baseline BCVA (mean, 65.0-65.9 letters) before commencing ADVM-022 treatment.

Thus, Busbee and team reported that the gene therapy was well-tolerated across cohorts; it further demonstrated a favorable safety profile.

Reported ocular events related to the therapy were rated as mild in 78% of cases and moderate in 22% of cases. Any ocular inflammation was shown to subside with steroid eye drops. The investigators also reported no cases of retinal involvement.

As for general efficacy, both doses of gene therapy were linked with a significant reduction in anti-VEGF injection burden. Of the 15 who received the higher dose and 15 who received the lower dose, 14 and 10, respectively, did not require anti-VEGF supplementation.

Even more, mean annualized anti-VEGF injection frequency was reduced by 99% in the higher dose cohorts and 85% in the lower dose cohorts after treatment.

In cohorts 1-3, BCVA was maintained with an overall mean age change from -2.5 to 0.5 ETDRS letters. Patients demonstrated a CST mean change from -19.7 to -132.7 µm. Data from cohort 4 is currently pending.

“Over 80% of patients with nAMD treated with a single injection of ADVM-022 in OPTIC have not needed any supplemental anti-VEGF injections up to 92 weeks follow-up,” Busbee and colleagues emphasized. “ADVM-022 has the potential to reduce treatment burden and improve patient vision outcomes.”

Phase 1 Study of Intravitreal Gene Therapy with ADVM-022 for neovascular AMD (OPTIC Trial)

Despite these promising results, the future for ADVM-022 remains unclear. In late April, Adverum, the company developing the gene therapy, 

announced the discovery of a suspected unexpected serious adverse reaction

 of hypotony with panuveitis and loss of vision in a patient with diabetic macular edema treated in the phase 2 INFINITY trial. This adverse event is currently under exploration to uncover a potential cause.

The single-injection investigative gene therapy may help with providing continuous expression of aflibercept. 

ADVM-022 Gene Therapy for nAMD May Reduce Anti-VEGF Injection Burden 

Investigative gene therapy BIIB112 was shown to lead to durable improvements in patients with 

, a group of rare diseases marked by progressive vision loss leading to blindness.

“BIIB112 (NSR-RPGR) is an AAV8 vector–based gene therapy that uses codon optimization to express the full-length, correctly sequenced retinitis pigmentosa GTPase regulator (RPGR) protein in the photoreceptors of individuals with XLRP caused by mutations in RPGR,” noted the University of Oxford investigators, led by Robert MacLaren, FMedSci, FRCOphth.

The estimated prevalence of retinitis pigmentosa in the United States is between 1 in 3500 or 1 in 4000 individuals. Currently, the US Food and Drug Administration (FDA) has approved only 1 therapy — an adeno-associated virus vector-based gene therapy, which is indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy.

Therefore, newer therapeutic options—particularly investigative, efficacious, and safe gene therapies—are warranted.

, MacLaren's team presented their findings from 2 ongoing trials — the Phase 1 dose-escalation Xirius study and Xolaris, a natural disease progression study.

As such, the team evaluated 18 patients from the Xirius study who were treated with BIIB112. All patients were ≥18 years of age. They also looked at a subgroup of patients from Xolaris (N = 69) who met the inclusion criteria for Part I of Xirius and completed 12 months of follow-up.

For the purposes of their analysis, they defined retinal sensitivity responder as an achievement of ≥7 dB improvement from baseline at ≥5 loci.

MacLaren and colleagues reported that treatment with the 4 highest doses (n = 12) resulted in early and durable improvements in central retinal sensitivity. As such, 6 participants showed response at month 1, and 4 maintained response through month 12.

Furthermore, none of the selected participants from Xolaris (untreated eyes) achieved central retinal sensitivity response at any point through month 12.

The team also assessed low-luminance visual acuity (LLVA), defining improvements as gain of ≥15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Thus, they observed improvements in treated eyes as early as Month 1 as well as maintenance through 12 months of follow-up (3/11 participants). There were no untreated eyes that achieved improvements.

Most of the associated reported adverse events were considered mild and resolved. Additionally, there were no dose-limiting toxicities that occurred at any of the studied doses. Inflammation mostly occurred at higher doses, but treatment with oral corticosteroids was considered efficacious and useful.

"Treatment with BIIB112 was well tolerated and, in cohorts 3-6, led to early and durable improvements in 2 measures of visual function," the investigators concluded.

Visual function improvements with BIIB112 (NSR-RPGR) in X-linked retinitis pigmentosa: XIRIUS (dose-expansion) and XOLARIS (natural disease progression) studies

The AAV8 vector–based gene therapy was associated with improvements in 2 measures of visual function. 

Gene Therapy BIIB112 Promising for X-Linked Retinitis Pigmentosa

has been found to occur roughly in 1 in 10,000 individuals in the United States. However, issues related to screening and diagnosis persist, which ultimately can affect ascertainment of the disease’s overall prevalence.

Fabry is caused by a mutation of the α-galactosidase A (GLA) gene, which debilitates lysosomal function, thus causing the build-up of compounds and intracellular structures throughout the body. As such, this can have devasting and chronic effects on organs such as the heart and kidney, among others.

podcast, Eric Wallace, MD, Director of Telehealth, University of Alabama at Birmingham answered 8 questions about the disease—all related to its prevalence, treatment options, and research landscape.

Below are key quotes and takeaways regarding the monogenic disease.

Tell me how and why you got into this clinical domain?

“The best part of taking care of any rare genetic kidney disease, or any genetic kidney disease, is that you end up taking care of that patient, that patient’s children, that patient’s children’s children. And it becomes part of the family. […] The continuity of care that I needed was in Fabry disease. It just so happens it was with a fascinating pathophysiology as well.”

What is Fabry Disease? What are it clinical presentations?

“Imagine every cell in the body has this buildup of trash that has been building up since birth. Well, now, later on in life, the organs don’t work as well. […] Patients actually can have early stroke, they can have white matter disease, early dementia. Those are the big ones on the CNS side. They can cause cardiac issues. […] A significant portion of our patients end up on dialysis, [receive a kidney] transplant, etcetera.”

What populations does it typically affect?

“There are patients with Fabry disease on every continent. At least in our experience, there seems to be a predominance in the Caucasian population, but that doesn’t mean if a patient is African American, Asian, etc., that they can’t have it. […] One of the highest incidences of Fabry disease is actually in south-east Asia. So, it doesn’t spare anybody as far as race.

Now, the question isn’t, ‘are there ways you can predict who may or may not have it?’. The answer is, ‘probably not.’ But there are enriched populations.”

Where should we be at with screening for Fabry disease?

“It is unreasonable for us to think that every physician or provider is going to know every single rare disease. That’s not a tenable solution. So, what we have to do is to get the screening so easy you can’t miss it. This is where the gene panels come in.”

What does the treatment landscape look like for this disease?

“Enzyme replacement treatment — and there are multiple — [has] really changed the outcomes, primarily on the kidney. There are some unmet needs as it relates to cardiac outcomes and CNS outcomes. […] We have Galafold, a chaperone therapy, which had been shown to help in patients who make a full-length protein that doesn’t fold correctly, for instance. [….] There’s been a lot that’s gone around in adjunctive therapies.”

“Finally, I’m really excited about all the clinical trials going on — specifically one in substrate reduction therapy […] and gene therapy.”

What about ongoing research? What have been the challenges associated with it?

“One of the great things is that there’s a lot of research going on. One of the problems with a lot of research going on all at once is that there’s a limited amount of patients. [One of the reasons for this is that] we do a poor job of diagnosing Fabry disease.”

Can you add further insight into the quality of life for these patients?

“It’s a tough disease. It hurts. That’s the biggest thing. These patients are in pain a significant portion of their lives. In fact, they almost get to the point where they just think pain is normal, and that’s sad. The other thing, for the medical group in the room, is that we miss it all the time.”

Do you have any final thoughts you want to offer about Fabry disease?

“If you’re already working with patients with Fabry disease, you need to know that the field is changing very very quickly. I mean, it’s hard for me to keep up with field: mosaicism of females that are not carriers and all the work that has been done in lyonization, antibodies to enzyme, inhibitory antibodies. This is a disease you can spend your entire career on.”

Quotations have been edited for clarity. 

As a multi-systemic disorder, Fabry disease can impact the functions of various organs. As a genetic disorder, Fabry can impact the offsprings, parents, and relatives of the patient. Therefore, its effects are far-reaching. 

Understanding Fabry Disease: Perspectives from a Nephrologist

New data from GenSight Biologics showed promising results for lenadogene nolparvovec (LUMVOQ), an intravitreal gene therapy for 

 caused by mutations in the mitochondrial ND4 gene.

Overall, the therapy was well-tolerated in patients, had a favorable safety profile, and was shown that it may lead to clinically meaningful improvements.

A team, led by Catherine Vignal-Clermont, MD, Rothschild Foundation Hospital, Paris, France, conducted an open-label, single-center, dose-escalation study that primarily assessed safety and tolerability of the gene therapy among 15 patients with LHON.

“Therapeutic options for adolescent and adult patients with LHON are currently limited to idebenone (Raxone®), a synthetic analog of coenzyme Q10, which is approved only in Europe under exceptional circumstances for treatment of LHON,” Vignal-Clermont and team wrote.

They further acknowledged that no approved treatment exists in the United States.

Among the exclusion criteria were vision loss in the fellow eye, glaucoma, diabetic retinopathy, macula edema, vitreoretinal disease, pathology of the retina or the optic nerve, retinal vein occlusion, narrow angles, optic neuropathy for other causes, or any other disease that would have an effect on visual function.

Eligible patients were divided into a dosing cohort to receive a single injection and then were followed-up immediately at day 3 for safety and efficacy assessments.

The investigators pursued further follow-up at weeks 1, 2, 4, 8, 12, 24, 36, and 48 post-treatment. Additional follow-up was performed at years 1.5, 2, 2.5, 3, 4, and 5.

The study’s primary endpoint was the overall incidences of adverse events up to 5 years post-treatments for each dosing level and for the treatment as a whole.

Secondary endpoints included best corrected visual acuity (BCVA; calculated as logarithm of the minimal angle of resolution [LogMAR])

Throughout the follow-up period, the investigators noted no serious adverse events that were considered related to treatments.

Furthermore, patients did not experience unexpected adverse events nor grades 3 or 4 Common Terminology Criteria for Adverse Events.

“Anterior chamber inflammation and vitritis were mostly managed with topical steroids, and ocular inflammation was considered to be dose limiting by the independent data safety monitoring board based on the benefits/risks for the subjects,” the investigators wrote.

In terms of efficacy, the team reported that analysis of the LogMAR BCVA in both treated and untreated eyes showed clinically relevant and durable improvements compared with baseline.

As such, the mean improvement for the treated eye was -0.44 LogMAR and for the untreated eye was -0.49.

Thus, at 5 years post-treatment, the final value of LogMAR was +1.96 and +1.85, respectively, for the treated and untreated eyes.

As for those treated with the optimal dose level of 9 × 10

viral genomes/eye (n = 6), the mean visual acuity improvement from baseline was −0.68 LogMAR for treated eyes and −0.64 LogMAR for untreated eyes.

The final mean value for the treated and untreated eyes were LogMAR +1.77 and +1.78, respectively.

“While there was a meaningful improvement in visual acuity for REVEAL subjects, the final visual acuity was less favorable than that seen in the two subsequent pivotal phase III studies in which subjects were treated earlier during the course of their disease,” Vignal-Clermont and colleagues wrote.

Nevertheless, the team acknowledged that these findings are a promising prelude to the Phase III RESCUE and REVERSE studies, which are running in tandem and currently assessing the efficacy of the single injection of the gene therapy in a larger population.

Safety of Intravitreal Gene Therapy for Treatment of Subjects with Leber Hereditary Optic Neuropathy due to Mutations in the Mitochondrial ND4 Gene: The REVEAL Study,

No approved treatment for leber hereditary optic neuropathy is currently available in the United States. 

Gene Therapy GS010 Safe, Well-Tolerated for LHON

 (SCD) gene therapy resulted in near pancellular β

expression and reduced HbS among affected patients.

The investigators also observed reduced hemolysis, increased total hemoglobin, and a complete resolution of vaso-occlusive crises and acute chest syndrome (ACS) in nearly all patients.

These findings were presented at the 2021 Transplantation & Cellular Therapy (TCT) Meetings Digital Experience.

Led by Mark Walters, MD, UCSF Benioff Children's Hospital, Oakland, the study evaluated the efficacy and safety of LentiGlobin for SCD gene therapy, which uses a modified human β-globin gene that produces GT-derived anti-sickling hemoglobin (HbA

The team enrolled patients aged ≥12 and ≤50 years of age with SCD and severe vaso-occlusive events. Included in the study were those with acute episodes of pain and ACS.

Walters and team collected CD34+ cells using plerixafor mobilization/apheresis. The cells were then tranduced with BB305 LVV. 

Following infusion of LentiGlobin after myeloablative busulfan conditioning, patients were assessed for laboratory evaluations, SCD-related outcomes, and adverse events.

According to the team’s Group C data, 40 patients (median, 23.5 years) initiated cell collection and underwent a median of 2 mobilization cycles. Furthermore, 25 of the 40 patients were treated with LentiGlobin.

Red blood cell transfusions were stopped among all patients up to 90 days following treatment.

“In 16 evaluable patients with ≥6 months of follow-up, total Hb at last visit was 11.5 g/dL, with HbA

 contribution of 5.2 g/dL, HbS of 6.1 (g/dL, and median HbS ≤60% of total Hb,” wrote the investigators.

“Exploratory assays showed near pancellular expression of HbA

 ≥6 months post-treatment with ~90% of RBCs containing β

Their data also reported that, at last visit, hemolysis markers were trending toward normalization in 25 patients.

Furthermore, the team evaluated 14 patients with ≥6 months of follow-up and history of vaso-occlusive crisis or ACS. The annualized combined vaso-occlusive crisis and ACS rate in this population was a median of 4 in the 2 years preceding treatment.

However, there were no noted ACS or serious vaso-occlusive crises post-treatment — save for 1 non-serious Grade 2 vaso-occlusive crisis, which occurred about 3.5 months after treatment.

Stomatitis occurred in 15 patients and febrile neutropenia in 11 patients—both of which were considered the most common non-hematologic ≥ Grade 3 adverse events following treatment.

The serious adverse events that occurred in ≥2 patients post-treatment were nausea, opioid withdrawal syndrome, and vomiting (n = 2 in all). No treatment-related serious adverse events have been reported so far.

Additionally, no events of graft failure, vector-mediated replication-competent lentivirus, or clonal dominance have been observed.

“The safety profile post-LentiGlobin remains generally consistent with myeloablative single-agent busulfan conditioning and underlying SCD,” Walters and team concluded.

Data from the ongoing HGB-206 study reports reduced hemolysis, increased total hemoglobin, and a complete resolution of vaso-occlusive crises among patients.

LentiGlobin Gene Therapy for Sickle Cell Demonstrates Therapeutic Potential

Biologic agents like adalimumab (HUMIRA) have proven to be efficacious and well-tolerated in patients with non-infectious 

 — and yet, a subset of patients fail to respond to these targeted immune therapies.

According to a late-breaking presentation given at 

the American Academy of Ophthalmology (AAO) 2020 Virtual Conference

, single-cell RNA sequencing has the potential to ultimately elucidate this treatment gap and provide insight into the driving factors behind the disease and immune response.

®, Lynn Hassman, MD, PhD, Assistant Professor, Ophthalmology and Visual Sciences, Washington University School of Medicine in St. Louis, discussed the need for this new technology as well as its clinical implications.

“As an immunologist, what that [treatment] gap tells me is that there are some patients whose immune response—and potentially some types of uveitis—may not be driven by TNF-α, the molecule targeted by Humira,” she said. “Therefore, Humira is probably never going to work for those patients.”

She explained how these responses (or non-responses) are determined through clinical trials. However, she stressed the necessity to predict response prior to treatment.

Her presentation focused on the ability of single-cell RNA sequencing to characterize differences between uveitis types and patients.

“This technology is revolutionizing our ability to study immune cells in the eye,” she said.

For example, she cited its power in producing a vast and deep amount of information from small amount of eye fluid, among other promising features.

So far, Hassman and her team have only studied a small number of patients. However, she has been encouraged by observed specifics of the disease made possible by the technology.

“The data that I present is not ready for [physicians] to change the way that they treat the vast majority of patients that they see,” she noted. “But, as we accumulate more data, and do more studies using this technology, we will start to find trends and patterns in the types of molecules that are expressed in different types of uveitis that are going to suggest treatments to try.”

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Lynn Hassman, MD, talks about a promising new technology that can optimize precision medicine in patients with uveitis.

Single-Cell RNA Sequencing May Improve Personalized Uveitis Therapy

According to late-breaking data presented at the virtual 

American Academy of Ophthalmology (AAO) 2020 Conference

, low and intermediate doses of the novel adeno-associated virus retinitis pigmentosa GTPase regulator (AVV-RPGR) was well-tolerated and demonstrated sustained or increased vision improvement in patients with

 previous 6-month data presented at the American Society of Retina Specialists (ASRS) 2020 virtual sessions earlier this year

The Phase 1/2 open-label, multi-center, dose-escalation trial, co-led by investigators from Janssen and MeiraGtx and presented by Michel Michaelides, MD, assessed the safety of the gene therapy (its primary endpoint) as well as changes in visual function across multiple metrics and modalities.

The ongoing trials consists of 3 phases: dose-escalation, dose-confirmation, and dose-expansion. Thus, in the dose-escalation phase, patients (n = 10) were administered low (n = 3), intermediate (n = 4), or high (n = 3) dose AVV-RPGR via subretinal injection.

The injection targeted the central retina in the eye that was more affected at baseline. Further, the investigators considered the untreated eye as a control.

Full-field static perimetry was performed for each patient at baseline, 3, 6, 9, and 12 months to assess baseline retinal function and change over time.

In the dose-escalation phase, 3 of the total patients who received low and intermediate dosage demonstrated improvement or stability in retinal sensitivity in the treated eye.

As noted in the intermediate cohort, there were observed statistically significant differences in mean retinal sensitivity between the treated and untreated eyes (1.05 decibel [dB]; 90% CI, 0.81-1.29).

In both low and intermediate dosage cohorts, statistically significant differences were observed in central visual field progression rate between the treated and untreated eyes (low: 1.10 dB-sr/year; 90% CI, 0.10-2.10; intermediate: 1.26 dB-sr/year; 90% CI, 0.65-1.86).

Furthermore, the investigators observed efficacy signals at the 1st post-treatment assessments at 3 months. Improvements were sustained or increased at 12 months.

The study also reported on vision-guided mobility data. At baseline and 9 months, patients performed a vision-guided mobility maze in order to assess their ability to navigate across a broad range of controlled light levels (with 1 lux being equated to deep twilight and 256 lux being equated to an office work setting).

Thus, in the 9-month analysis, 5 of 6 patients demonstrated improvements in mobility at lux levels 1, 4, or 16. Furthermore, there was a significant improvement between treated and untreated eyes in the low and intermediate cohorts (n = 6) at 1 lux (-16.1 second; 90% CI, -9.91 to -22.1) and 4 lux (-3.71 second; 90% CI; -2.83 to -4.96).

However, the mobility test was not conducted for the high-dose cohort.

The most common adverse events associated with the therapy were related to the surgical procedure—which were considered transient and resolved without intervention.

Inflammation was reported in 2 patients in the high-dose cohort, and measures of visual function did not improve.

 had the opportunity to speak with Michaelides about the significance of these findings.

“Not long ago, the majority of specialists and these types of patients would have been delighted at these types of therapy to slow the rate of visual loss,” he said. “The fact that we’re actually seeing improvements in vision is very unexpected in many ways, but clearly game changing.”

He also commented on the larger advancements of gene therapy within the field of ophthalmology, which he considered to be staggering and encouraging.

“I don’t expect it to slow any time soon,” Michaelides noted. “It’s certainly at the forefront of providing therapies for our patients with inherited retinal diseases.”

The study presented at AAO provides an update on previously shared 6-month data from earlier this year.

New Data Shows Promise for Investigative XLRP Gene Therapy 

 have expanded over the past years, the clinical complications of the condition as well as the limitations of these pharmacotherapies have called for an urgent need to implement a personalized treatment strategy for patients that is based on risk stratification.

In a recent article, Emily Meier, MD, of the Indiana Hemophilia and Thrombosis Center, elucidated on the key considerations in the prescribing of such therapies as well as the current barriers that preclude healthcare providers from achieving an optimal treatment strategy for these patients.

“With increasing therapeutic options, the ideal scenario for children with SCA would be one similar to childhood acute lymphoblastic leukemia (ALL) risk stratification: treatment intensity varies with risk level,” Meier wrote.

Thus, children who are at low risk for sickle cell anemia complications would receive less intense therapies, which includes a continuation of hydroxyurea. On the other hand, those with the highest risk would be recommended to immediately receive one or more curative therapies, such as hematopoietic stem cell transplant, gene therapy, transfusion therapy, voxelotor, and/or crizanlizumab.

Of course, as Meier noted, there are certain limitations that must be considered before implementing such a strategy.

For one, crizanlizumab and voxelotor are approved for ages ≥16 and 12 years, respectively. According to the risk based therapy model, high-risk patients should only use both therapies once age appropriate.

Similarly, patients with medium risk of complications should only use L-glutamine once they reach the appropriate age of ≥5 years.

Additionally, there is no validated predictor for the overall severity of the disease prior to the onset of associated complications. Currently available predictors of a severe outcome is an abnormal velocity on transcranial Doppler ultrasonography. These predictors identity children at highest risk for stroke.

Meier noted that there are no predictors for vaso-occlusive episodes or acute chest syndrome.

Furthermore, there is no unanimous agreement of what constitutes severe sickle cell anemia. However, the inclusion criteria for hematopoietic stem cell transplant is considered a promising start.

Overall, Meier suggested that hydroxyurea should be the standard of care in pediatric and adult patients, regardless of disease severity.

The complexities associated with the disease and lack of validated risk predictors makes such a model challenging to implement.