Diffusphere Intraarticular Injectable Technology

Sponsor(s)

No sponsor indicated

Partnerships

No partner indicated

Type of technology

Polymer-based particles

Administration route

Intra-articular, Intra-vitreal

Development state and regulatory approval

fluticasone

Phase II

FDA 505(b)(2) approval pathway

Description

Diffusphere is a polymer-based, long-acting injectable designed primarily for intra-articular administration. It consists of a polymeric shell encapsulating a crystalline drug core. The shell is immiscible with the API, protecting the drug core from the body's fluidic environment. Diffusphere can encapsulate more than one API when the core microparticles are heated between 210°C and 230°C. It offers a controlled release profile, delivering the drug over a period of 2 to 12 months while maintaining therapeutic concentrations at the target site.

Technology highlight

1) No/ Low Initial burst release 2) Zero order/ pseudo-zero order kinetics (concentration gradient is maintained with a constant release of drug) 3) Biodegradable thermally cured polyvinyl alcohol (PVA) is used 4) Low systemic toxicity

Technology main components

1. Cross-linked polymeric shell (thickness in microns), such as poly(vinyl alcohol) (PVA), poly(p-xylylene), poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PVL), poly(p-dioxanone) (PDS), poly(hydroxyvalerate) (PHV), poly(hydroxybutyrate) (PHB), and poly(malic acid) (PMLA), incorporating cross-linking groups like vinyl, allyl, acrylate, cinnamate, diacrylate, or oligoacrylate. The polymeric shell (2-10% w/w of polymeric shell) typically has a thickness measured in microns. 2. Crystalline API core, composed of a pharmaceutically acceptable salt or ester, which may exist either as a single large crystal or as multiple smaller crystals.

Information on the raw materials sourcing, availability and anticipated price

Not provided

Delivery device(s)

No delivery device

API desired features

Water-soluble molecules

Water-insoluble molecules

Small molecules

Diffusphere focuses on developing corticosteroids, including different salt forms of fluticasone, and aminoamide anesthetics like ropivacaine, articaine, and bupivacaine, among others. They also work with aminoester local anesthetics, such as procaine and benzocaine. Recently, Diffusphere has expanded its applications to disease-specific therapeutics, including oncology.

Additional solubility data

Not provided

Additional stability data

Not provided

API loading: Maximum drug quantity to be loaded

< 70 wt%

API co-administration

2 different APIs : API core to be heated at 210-250 °C

LogP

Max: 5
Fluticasone LogP = 3.2

Scale-up prospects

With a patent for manufacturing filed in 2019, the production facility is projected to achieve commercial-scale operations optimized for low cost of goods. Euphraxia has allocated a budget of 2.8 million Canadian dollars for the development of this manufacturing unit.

Tentative equipment list for manufacturing

Not provided

Manufacturing

Manufacturing (ISO 14644-1; Grade 8 cleanroom) involves: 1) Forming API microparticles (using any 1 method) a. Solvent Evaporation/ extraction techniques b. In-water drying technique c. Organic phase separation technique d. Air suspension technique e. Dip coating technique 2) Coating of the API core with the polymeric shell using the dip coating technique with Multifunctional multi-polymeric continuous composition spectrum surfactant 3) Microparticles are agitated with PVA polymer via stirring. 4) Vacuum filtration 5) Heated at 220 ºC for a period of at least 1 hour

Specific analytical instrument required for characterization of formulation

1) The dissolution Test is performed using a US Pharmacopoeia Type II apparatus where the condition is standardized at 3mg of microparticles in 200 ml of dissolution medium (70% methanol + 30% water) at 25 °C. The dissolution rate of the microparticles is observed at 160° C, 190° C, 220° C, and 250° C. 2) PVA content analysis using NMR spectroscopy 3) Drug content analysis using NMR system - Bruker Spectrospin 300 MHz magnet , Bruker B - ACS 120 autosampler , Bruker Avance II 300 console , and a Bruker BBO 300 MHz Si 5 mm with Z gradient probe. 4) Praticle transfer efficiency measured by HPLC

STEPUP

Identifier

NCT02609126

Link

https://clinicaltrials.gov/study/NCT02609126

Phase

Phase I

Status

Completed

Sponsor

Eupraxia Pharmaceuticals Inc.

More details

The main purpose of this study is to understand the pharmacokinetics of EP-104IAR and to determine whether it is safe to use in patients with osteoarthritis (OA) of the knee. The study will also provide some preliminary insights into whether the experimental treatment reduces pain in the knee. Osteoarthritis is the most common joint disease, affecting over 20 million people in the US alone. Currently, pain treatments that are injected directly into the knee often work for only a short time and may also have side effects within the rest of the body. The experimental treatment is a steroid that is in the same family of drugs as the most common current injectable treatments for knee osteoarthritis. For this study, the drug is coated with a polymer intended to prolong the time it stays inside

Purpose

Safety Study of a Long-Acting Injectable Steroid to Treat Knee Osteoarthritis

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2016-04-01

Anticipated Date of Last Follow-up
2021-08-30

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2017-12-28

Actual Completion Date
2017-12-28

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: * OA of Index Knee * Kellgren Lawrence Grade 2 or 3 * Patient-reported pain (PtPain) of Index Knee ≥4 but ≤9 * PtPain of non-Index Knee \<6 * BMI ≦ 40 kg/m2 Exclusion Criteria: * Intra-articular joint injection in the Index Knee within the past 8 weeks for glucocorticoids and 6 months for hyaluronic acid * Insulin-dependent diabetes * Active infection * Pregnant or breast feeding

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

32

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Double-blind masking

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

SPRINGBOARD

Identifier

NCT04120402

Link

https://clinicaltrials.gov/study/NCT04120402

Phase

Phase II

Status

Completed

Sponsor

Eupraxia Pharmaceuticals Inc.

More details

The purpose of this study is to evaluate the safety, efficacy and pharmacokinetics (PK) of EP-104IAR in patients with osteoarthritis (OA) of the knee

Purpose

Study to Evaluate the Efficacy and Safety of EP-104IAR in Patients With Osteoarthritis of the Knee

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2021-09-10

Anticipated Date of Last Follow-up
2024-05-29

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2023-05-17

Actual Completion Date
2023-06-01

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Key Inclusion Criteria: * Males or females, aged ≥40 years * Body Mass Index (BMI) ≤ 40.0 kg/m2 * Diagnosis of primary OA of the Index knee, with symptoms present for at least 6 months * OA severity Grade 2 or 3 (based on Kellgren Lawrence Grading Scale) * Unsatisfactory pain relief from at least 2 prior standard OA treatments * Qualifying pain in the Index knee during the baseline period * Ambulatory (without the need for a cane/other walking aide) * Female subjects willing to use highly effective birth control methods to prevent pregnancy * Willing and able to comply with study procedures and restrictions, including abstaining from use of restricted medications. Key Exclusion Criteria: * OA of the Index knee due to acute injury or trauma, or unstable joint

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

318

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Quadruple-blind masking

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

RESOLVE

Identifier

NCT05608681

Link

https://clinicaltrials.gov/study/NCT05608681

Phase

Phase I/II

Status

Recruiting

Sponsor

Eupraxia Pharmaceuticals Inc.

More details

An open-label, dose-escalation study to explore the safety, tolerability and pharmacokinetics of EP-104IAR in adults with eosinophilic esophagitis (EoE). Endoscopic and histologic assessments will also be evaluated to understand the local effects of EP-104IAR on eosinophilic EoE disease activity. Approximately 27 to 33 participants will be enrolled in dose escalation: 3-6 participants per dose cohort in approximately 9 cohorts. The number of participants enrolled in escalation will depend on the number of dose escalation cohorts evaluated, and dose cohorts needing to be expanded. An additional 10-24 participants will be enrolled in 1 or 2 cohorts of 10-12 participants each at tolerable dose regimen(s) selected based on the accumulated clinical data to identify the recommended phase 2 dos

Purpose

A Trial to Evaluate EP-104IAR in Adults With Eosinophilic Esophagitis (EoE).

Interventions

Intervention 1

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2023-03-31

Anticipated Date of Last Follow-up
2024-07-26

Estimated Primary Completion Date
2025-12-01

Estimated Completion Date
2025-12-01

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: * Symptomatic EoE; * For women of childbearing potential, a negative pregnancy test and willing to use a highly effective method of birth control until end of study; * Willing and able to adhere to study-related procedures and visit schedule; * Willing and able to provide informed consent. Exclusion Criteria: * Concomitant esophageal disease, relevant GI disease, or any condition, history, or laboratory abnormality that might interfere with the study; * Oral or esophageal mucosal infection of any type (bacterial, viral, or fungal); * Oropharyngeal or dental conditions that prevents normal eating; * Severe esophageal motility disorders other than EoE; * Contraindication to or factors that substantially increase risks associated with EGD or biopsy, or narrowing of the

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

57

Allocation

Not provided

Intervention model

Single group assignment

Intervention model description

Not provided

Masking

Open label

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

Proprietary excipients used

No proprietary excipient used

Novel excipients or existing excipients at a concentration above Inactive Ingredients Database (IID) for the specified route of administration

No novel excipient or existing excipient used

Residual solvents used

No residual solvent used

Other features of the technology

• Biodegradable
• Drug-eluting
• Monolithic
• Room temperature storage
• At least 1 year shelf life

Release properties

The drug is released at a constant rate following zero-order kinetics from the polymeric shell. Diffusphere has favorable PK parameters mainly because of the low/no initial burst. Clinical studies of EP104 showed that the plasma concentrations of fluticasone propionate (EP104) had a blunted initial peak with a terminal half-life of approximately 18–20 weeks.

Injectability

Diffusphere is an Intra-articular via ultrasound-guided injectable formulation that requires a 22-25 gauge needle with a length of 1-1.5 inches.

Safety

Based on the pharmacokinetic clinical trials of EP104, 57% of the treatment population had one or more Treatment Emerging Adverse Events (TEAE), However, the effects on serum glucose and cortisol concentrations were minimal.

Stability

At least 2 years of proven stability at room temperature storage.

Storage conditions and cold-chain related features

Diffusphere doesn't require cold chain storage or transport.

Therapeutic area(s)

Use case(s)

Use of technology

Description

Injectable sustained release composition and method of using the same for treating inflammation in joints and pain associated therewith

Brief description

Described herein are injectable corticosteroid-loaded microparticles, pharmaceutical composition thereof and methods for reducing inflammation or pain in a body compartment such as a joint, an epidural space, a vitreous body of an eye, a surgically created space, or a space adjacent to an implant.

Representative patent

US9987233B2

Category

Formulation composition

Patent holder

Eupraxia Pharmaceuticals USA LLC

Exclusivity

Not provided

Expiration date

March 21, 2034

Status

Active

Publications

<p><span style="color: rgb(33, 33, 33);">Malone, A., Kowalski, M. M., Helliwell, J., Lynggaard Boll, S., Rovsing, H., Moriat, K., Castillo Mondragón, A., Li, Y., Prener Miller, C., Reinstrup Bihlet, A., Dobek, C., Peck, V., Wilmink, M., Simon, L. S., &amp; Conaghan, P. G. (2024). Efficacy and safety of a diffusion-based extended-release fluticasone propionate intra-articular injection (EP-104IAR) in knee osteoarthritis (SPRINGBOARD): a 24-week, multicentre, randomised, double-blind, vehicle-controlled, phase 2 trial.&nbsp;</span><em style="color: rgb(33, 33, 33);">The Lancet. Rheumatology</em><span style="color: rgb(33, 33, 33);">, S2665-9913(24)00223-6. Advance online publication. </span><a href="https://doi.org/10.1016/S2665-9913(24)00223-6" rel="noopener noreferrer" target="_blank" style="color: rgb(33, 33, 33);">https://doi.org/10.1016/S2665-9913(24)00223-6</a></p>

Between Sept 10, 2021, and Nov 16, 2022, 1294 people were screened for eligibility, and 319 were randomly assigned to EP-104IAR (n=164) or vehicle control (n=155). One participant in the EP-104IAR group was excluded from all analyses because treatment was not administered due to an adverse event. 318 participants (135 [42%] male and 183 [58%] female, 315 [99%] White) received randomly assigned treatment and were included in the primary analysis and safety analysis (EP-104IAR, n=163; vehicle control, n=155). At week 12, least squares mean change in WOMAC pain score from baseline was -2·89 (95% CI -3·22 to -2·56) in the EP-104IAR group and -2·23 (-2·56 to -1·89) in the vehicle control group, with a between-group difference of -0·66 (-1·11 to -0·21; p=0·0044); a significant between-group difference persisted to week 14. 106 (65%) of 163 participants in the EP-104IAR group had one or more treatment-emergent adverse event compared with 89 (57%) of 155 participants in the vehicle control group. Effects on serum glucose and cortisol concentrations were minimal and transient. There were no treatment-emergent deaths or treatment-related serious adverse events. Plasma concentrations of fluticasone propionate showed a blunted initial peak with terminal half-life of approximately 18-20 weeks.

<p><span style="color: rgb(34, 34, 34);">Malone, A., Helliwell, J., Kowalski, M., Rovsing, H., Boll, S. L., Moriat, K., ... &amp; Conaghan, P. G. (2024). OP0247 EFFICACY OF A NOVEL LONG-ACTING FLUTICASONE PROPIONATE INTRA ARTICULAR INJECTION (EP-104IAR) IN KNEE OSTEOARTHRITIS: PER-PROTOCOL ANALYSIS OF A RANDOMISED, DOUBLE-BLIND, PHASE 2 TRIAL OF EP-104IAR VS VEHICLE PLACEBO (SPRINGBOARD).</span></p>

Least-squares mean (LSM) change from baseline for WOMAC total score and subscales are shown in Figure 1. LSM change from baseline to Week 12 was significantly better for EP-104IAR vs vehicle for each of the WOMAC subscales: pain (-2.97 vs -2.24; p=0.003), function (-2.64 vs -1.99; p=0.005) and stiffness (-2.85 vs -2.05; p=0.001). Stiffness and function maintained p<0.05 to the Week 20 assessment and pain to Week 15. Total WOMAC score at Week 12 was significantly better for EP-104IAR vs vehicle (-2.79 vs -2.07; p=0.002) and this difference persisted with p<0.05 to the Week 20 assessment. The proportion of OMERACT-OARSI strict pain responders, defined as ≥50% decrease from baseline with absolute decrease ≥2 on the 10-point WOMAC pain scale was calculated for each week. The proportion of strict pain responders at Week 12 was 55.3% for EP-104IAR vs 39.5% for vehicle (p=0.013). This difference persisted with p<0.05 to the Week 15 assessment. The proportion of subjects with 70% reduction in pain score at Week 12 was 34.4% for EP-104IAR vs 14.6% for vehicle (p<0.001). This difference persisted with p<0.05 to the Week 21 assessment at all but one timepoint. The observed C_max of FP in the full study population (n=163) was 90pg/mL with a terminal phase half-life of 18-20 weeks.

<p><span style="color: rgb(34, 34, 34);">Helliwell, J., Malone, A., Bredenoord, A. J., Nguyen, N., Ko, H. H., Dobek, C., ... &amp; Dellon, E. S. (2024). 265. INITIAL RESULTS FROM RESOLVE, A PHASE 1B DOSE-ESCALATION STUDY OF EP-104GI (EXTENDED-RELEASE FLUTICASONE PROPIONATE INTRA-ESOPHAGEAL INJECTION) FOR EOSINOPHILIC ESOPHAGITIS.&nbsp;</span><em style="color: rgb(34, 34, 34);">Diseases of the Esophagus</em><span style="color: rgb(34, 34, 34);">,&nbsp;</span><em style="color: rgb(34, 34, 34);">37</em><span style="color: rgb(34, 34, 34);">(Supplement_1), doae057-044. </span><a href="https://doi.org/10.1093/dote/doae057.044" rel="noopener noreferrer" target="_blank" style="color: rgb(0, 111, 183); background-color: rgb(255, 255, 255);">https://doi.org/10.1093/dote/doae057.044</a></p>

All subjects demonstrated decreased symptom scores compared to baseline, with generally greater responses at the higher EP-104GI dose in Cohort 2 (Fig 1). Histologically, all Cohort 2 patients showed decreases in EoEHSS scores with 2/3 having ≈50% decrease in total grade score and ≈35% decrease in total stage score at Week 4, also, eosinophil counts were reduced by ≈35% at Week 4 and ≈40% at Week 12.

Findings from Cohorts 1 and 2 of the ongoing trial include mild-moderate treatment-emergent AEs, the majority occurring on the day of treatment. No AEs were related to EP-104GI.

Additional documents

• EP-104 Poster

Useful links

There are no additional links

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