−Removed: We are a biopharmaceutical company focused on the formulation, development, and commercialization of innovative therapies for diseases and conditions of the eye using our proprietary bioresorbable hydrogel-based formulation technology.
−Removed: Our mission is to build an ophthalmology-focused biopharmaceutical company that capitalizes on the gaps that we believe increasingly exist in the ophthalmology sector between single product companies and large, multi-product pharmaceutical companies.
−Removed: Our current products and product candidates in clinical development incorporate therapeutic agents that have previously received regulatory approval from the U.S.
−Removed: Food and Drug Administration, or FDA, including small molecules, into our proprietary bioresorbable hydrogel-based formulation technology in our internal drug development activities, with the goal of providing local programmed release to tailor the duration and amount of drug to be delivered to the eye.
−Removed: We believe that our local programmed-release drug delivery technology has the potential to enable the treatment of conditions and diseases of both the front and the back of the eye and can be administered through a range of different modalities including intravitreal implants, intracameral implants and intracanalicular inserts.
−Removed: We are currently commercializing DEXTENZA, an intracanalicular insert for the treatment of both post-surgical ocular inflammation and pain and ocular itching associated with allergic conjunctivitis, in the United States.
−Removed: We also have product candidates in preclinical and clinical development:
−Removed: ● OTX-TKI, an axitinib intravitreal implant being developed for the treatment of wet age-related macular degeneration, or wet AMD, diabetic retinopathy and other retinal diseases;
−Removed: ● OTX-TIC, a travoprost intracameral implant being developed for the reduction of intraocular pressure, or IOP, in patients with primary open-angle glaucoma or ocular hypertension;
−Removed: ● OTX-DED, a dexamethasone intracanalicular insert being developed for the short-term treatment of the signs and symptoms of dry eye disease;
−Removed: ● OTX-CSI, a cyclosporine intracanalicular insert being developed for the chronic treatment of dry eye disease;
−Removed: ● A complement inhibitor program in preclinical development for the treatment of dry age-related macular degeneration, or dry AMD;
−Removed: ● A gene delivery program in preclinical development using our hydrogel technology to control the release of vectors such as adeno-associated virus , or AAV, to ocular tissues for the treatment of inherited and acquired ocular diseases, including dry or wet AMD.
+Added: We are a biopharmaceutical company committed to enhancing people’s vision and quality of life through the development and commercialization of innovative therapies for diseases and conditions of the eye, with a specific focus on retinal disease.
+Added: Our program for retinal disease is led by AXPAXLI (axitinib intravitreal implant, also known as OTX-TKI), which is based on our ELUTYX proprietary bioresorbable hydrogel-based formulation technology.
+Added: We are currently conducting a pivotal Phase 3 clinical trial to evaluate AXPAXLI for the treatment of wet age-related macular degeneration, or wet AMD, which we refer to as the SOL-1 trial, and a Phase 1 clinical trial for the treatment of diabetic retinopathy.
+Added: Our clinical portfolio also includes PAXTRAVA (travoprost intracameral implant, also known as OTX-TIC), which is currently in Phase 2 clinical development for the treatment of primary open-angle glaucoma, or OAG, or ocular hypertension, or OHT.
+Added: Our expertise in the formulation, development and commercialization of innovative therapies and our ELUTYX platform supported the development and launch of our first commercial drug product, DEXTENZA, a corticosteroid approved by the U.S.
+Added: Food and Drug Administration, or FDA, for the treatment of ocular inflammation and pain following ophthalmic surgery and ocular itching associated with allergic conjunctivitis.
+Added: We are also developing two other clinical-stage assets, OTX-DED (dexamethasone intracanalicular insert) for the short-term treatment of the signs and symptoms of dry eye disease, and OTX-CSI (cyclosporine intracanalicular insert) for the chronic treatment of dry eye disease, which we collectively refer to as our Dry Eye Programs, and several preclinical programs.
+Added: Our current products and product candidates in clinical development generally incorporate therapeutic agents that have previously received regulatory approval from the FDA, including small molecules, into ELUTYX, with the goal of providing local programmed release to tailor the duration and amount of the therapeutic agent to be delivered to the eye.
+Added: We believe that our local programmed-release drug delivery technology has the potential to enable the treatment of conditions and diseases of both the front and the back of the eye and can be administered through a range of ocular modalities including intravitreal implants, intracameral implants, and intracanalicular inserts.
+Added: The hydrogel technology that underpins ELUTYX has been used in the human body since 1992 and has demonstrated its safety and effectiveness in over five million patients across five FDA-approved devices since that time.
+Added: Our own approved product DEXTENZA, the first and only drug-eluting intracanalicular insert approved by the FDA, has been used in nearly 400,000 eyes since launch with reported adverse events in less than 1 in 10,000 patients.
+Added: As a result, we believe that the ELUTYX technology is well tolerated.
+Added: We believe the ELUTYX technology can provide delivery solutions for durable therapies for wet AMD, non-proliferative diabetic retinopathy, or NPDR, and other diseases and conditions of the eye.
+Added: The only factors that regulate the bioresorption of our ELUTYX polymer are temperature and pH of the aqueous environment.
+Added: As body temperature and pH of the human aqueous environment are within a typical range for each human, and since water levels in the vitreous humor are more than sufficient to saturate our polymer matrix, we believe we can program our products and product candidates so that the polymer will be intact long-enough to deliver the active pharmaceutical ingredient and then be fully bio-resorbed when re-dosing is required.
+Added: That ELUTYX does not create an acidic microenvironment, is easily eliminated from the vitreous, leaving behind no harmful byproducts, and has soft gel properties provides further support for the ELUTYX safety profile.
We currently focus on some of the largest markets in ophthalmology.
−Removed: According to the Market Scope 2022-2023 reports, our product candidates seek to address select indications within segments of ophthalmology that, in the aggregate, account for approximately $25 billion in global annual sales.
−Removed: The following table summarizes the status of DEXTENZA, our primary marketed product, and our key product candidates and development programs.
−Removed: We hold worldwide exclusive commercial rights to the core technology underlying all of our product candidates in development and have not granted commercial rights to any marketing
−Removed: partners other than a license agreement and collaboration with AffaMed for the development and commercialization of DEXTENZA and OTX-TIC in the geographies agreed to between the parties .
+Added: According to the Market Scope 2022-2023 reports, our product candidates seek to address select indications within the retina, glaucoma, and dry eye disease areas of ophthalmology.
+Added: These areas, in the aggregate, account for approximately $25.6 billion in global annual sales.
+Added: The following table summarizes the status of our key product candidates and development programs, as well as DEXTENZA.
+Added: We hold worldwide exclusive commercial rights to the core technology underlying all of our product candidates in development and have not granted commercial rights to any marketing partners other than a license agreement and collaboration with AffaMed Therapeutics Limited, or AffaMed, for the development and commercialization of DEXTENZA and PAXTRAVA in the geographies agreed to between the parties.
PIPELINE AT A GLANCE
−Removed: Our mission is to build an ophthalmology-focused biopharmaceutical company that capitalizes on the gaps that we believe increasingly exist in the ophthalmology sector between single product companies and large, multi-product pharmaceutical companies.
−Removed: Our strategy is to continue to build upon our experience in commercializing ophthalmology products that can be administered primarily in the surgical and/or office settings and to continue to develop a clinical pipeline of innovative ophthalmology products that address large areas of unmet need.
+Added: Our strategy is to advance our pipeline of clinical assets, focusing specifically on our programs for wet AMD and NPDR, while we continue to build upon our experience in commercializing ophthalmology products.
The key tactics of our strategy are:
+Added: ● Advance our AXPAXLI clinical development programs.
+Added: Complete enrollment of the SOL-1 trial, our first pivotal Phase 3 clinical trial of AXPAXLI for the treatment of wet AMD by the end of the first quarter of 2025.
+Added: Subject to agreement with the FDA, we intend to commence screening of a second pivotal Phase 3 clinical trial, which we refer to as the SOL-2 trial, by the first quarter of 2025.
+Added: Deliver topline data from our Phase 1 clinical trial of AXPAXLI for the treatment of NPDR, which we refer to as the HELIOS trial, in the second quarter of 2024.
+Added: Subject to favorable topline data and agreement with the FDA, we intend to commence a pivotal Phase 3 clinical trial as a next step of clinical development.
+Added: ● Deliver topline data from our U.S.-based Phase 2 clinical trial of PAXTRAVA for the reduction of intraocular pressure, or IOP, in patients with OAG or OHT in the second quarter of 2024.
● Grow DEXTENZA revenues primarily through sales for the treatment of ocular inflammation and pain following ophthalmic surgery.
−Removed: ● Advance our clinical development programs.
−Removed: be prepared to initiate a pivotal clinical trial as early as the third quarter of 2023, subject to ongoing discussions with the FDA and obtaining the necessary financing to fund the trial, which could be provided through a strategic alliance.
−Removed: o Diabetic Retinopathy:
−Removed: be positioned to initiate a pivotal clinical trial as early as the first quarter of 2024 subject to favorable interim results from our ongoing Phase 1 clinical trial, discussions with the FDA and obtaining the necessary financing to fund the trial.
−Removed: continue to enroll our U.S.-based Phase 2 clinical trial for the treatment of open-angle glaucoma or ocular hypertension and plan to provide topline data from the trial in the fourth quarter of 2023.
−Removed: ● Dry Eye Disease – OTX-DED and OTX-CSI:
−Removed: initiate a small trial of OTX-DED in the first half of 2023 to identify a proper placebo control for any future trials of these product candidates.
−Removed: ● Leverage our commercial infrastructure for additional ophthalmology products for both the surgical and office settings.
−Removed: ● Continue to develop experience and expertise with buy-and-bill products.
−Removed: DEXTENZA and all of our product candidates are designed to be medical-benefit “buy-and-bill” products with associated procedure codes.
−Removed: Products with these characteristics are designed to be attractive not only to physicians, optometrists and patients but also to the sites of care that participate in utilization.
−Removed: ● Apply our local programmed-release hydrogel-based formulation technology to create additional proprietary solutions for additional ophthalmic diseases and conditions.
−Removed: ● Address rest-of-world commercial opportunities through licensing and collaboration agreements.
+Added: ● Deliver topline data from our ongoing trial to evaluate OTX-DED in the fourth quarter of 2024.
Limitations of Current Drug Delivery in Ophthalmology
25 unchanged sentences
Intravitreal injections are used to administer medications to treat a variety of chronic conditions;
−Removed: wet AMD, diabetic retinopathy, diabetic retinal edema, or DME, and retinal vein
−Removed: occlusion, or RVO, are among the most common conditions treated with intravitreal anti-VEGF drugs.
+Added: wet AMD, diabetic retinopathy, diabetic retinal edema, or DME, and retinal vein occlusion, or RVO, are among the most common conditions treated with intravitreal anti-VEGF (vascular endothelial growth factor, or VEGFs) drugs.
Anti-VEGF drugs and steroids help to reduce fluid leakage associated with these disorders.
4 unchanged sentences
These patients may not be mobile enough to travel to the office on their own and therefore require not only the assistance of a caregiver but also transportation to and from the office.
−Removed: Finally, while intravitreal injections are typically safe, there is the potential risk of endophthalmitis (infection in the eye), inflammation, bleeding into the vitreous gel and retinal detachment that comes with injections.
+Added: These patients may also be younger, part of the active workforce and therefore unwilling or unable to take personal time off to receive frequent injections.
+Added: Furthermore, injecting high doses of drug to the back of the eye every four to six weeks can result in the macula constantly alternating between a thicker and a thinner state, which may lead to fibrosis presenting as scarring and atrophy.
+Added: Finally, while intravitreal injections are
+Added: typically safe, there is the potential risk of endophthalmitis (infection in the eye), inflammation, bleeding into the vitreous gel and retinal detachment that comes with injections.
As a result of these limitations, there is a significant unmet need for technologies that will allow for a longer duration of effect and an overall reduced number of injections.
The Ocular Therapeutix Approach
−Removed: Our Hydrogel-Based Formulation Technology
−Removed: We apply our expertise with an established bioresorbable hydrogel-based formulation technology to the development of products for local programmed-release of known, FDA-approved therapeutic agents for a variety of ophthalmic diseases and conditions and to ophthalmic wound closure.
−Removed: Our bioresorbable hydrogel-based formulation technology is based on the use of a proprietary form of PEG.
+Added: Our Hydrogel-Based Formulation Technology ELUTYX
+Added: We apply our expertise with ELUTYX to the development of products for local programmed-release of known, FDA-approved therapeutic agents for a variety of ophthalmic diseases and conditions and to ophthalmic wound closure.
+Added: ELUTYX is based on the use of a proprietary form of PEG.
Our technical capabilities include a deep understanding of the polymer chemistry of PEG-based hydrogels and the design of the highly specialized manufacturing processes required to achieve a reliable, preservative-free and pure product.
11 unchanged sentences
We consider the following selection criteria:
−Removed: ● prior approval by the FDA for the targeted ophthalmic indication, except for our OTX-TKI program in which the active pharmaceutical ingredient, axitinib, is not currently approved for an ophthalmic indication;
+Added: ● prior approval by the FDA for the targeted ophthalmic indication, except for our AXPAXLI program in which the active pharmaceutical ingredient, axitinib, is not currently approved for an ophthalmic indication;
● expiration of relevant patent protection prior to or within our anticipated development timeline;
28 unchanged sentences
The implants are designed to be held in place by currents and gravity present in the anterior chamber of an eye.
−Removed: In the case of OTX-TIC, the implant is designed to infuse with liquid, settle into the inferior angle of the eye and demonstrate little to no movement.
+Added: In the case of PAXTRAVA, the implant is designed to infuse with liquid, settle into the inferior angle of the eye and demonstrate little to no movement.
The implants are preferably polymeric, biodegradable and provide sustained release of at least one therapeutic agent to both the trabecular meshwork and associated ocular tissue and the fluids within the anterior chamber of an eye.
1 unchanged sentence
We are engaged in the clinical development of our hydrogel administered via intravitreal injection to address the large and growing markets for diseases and conditions of the back of the eye.
−Removed: Our intravitreal implant product candidates, such as OTX-TKI, consist of a PEG-based hydrogel suspension, which contains embedded micronized particles of active drug.
+Added: Our intravitreal implant product candidates, such as AXPAXLI, consist of a PEG-based hydrogel suspension, which contains embedded micronized particles of active drug.
We design the intravitreal implant to be injected and retained in the vitreous humor to provide local programmed-release intravitreal delivery of anti-VEGF compounds.
1 unchanged sentence
Retinal Diseases
−Removed: Age-related macular degeneration, or AMD, and diabetic retinopathy are the most common retinal diseases, affecting approximately 207.6 million and 141.2 million, respectively, worldwide, according to the Market Scope 2022 Retinal Pharmaceuticals Report.
+Added: Age-related macular degeneration, or AMD, and diabetic retinopathy are the most common retinal diseases, affecting approximately 212.0 million and 146.4 million, respectively, worldwide, according to the Market Scope 2023 Retinal Pharmaceuticals Market Report.
In the United States, Market Scope estimates that there are approximately 17.9 million suffering from some form of AMD.
11 unchanged sentences
DR can take time to develop.
−Removed: Nonproliferative DR, sometimes called background retinopathy, is usually mild and may go unnoticed.
−Removed: Proliferative DR is the most serious stage of the disease and develops when areas of the retina are starved for nourishment and oxygen, triggering the proliferation of new blood vessels via secretions of vascular endothelial growth factor (VEGF).
−Removed: The current standard of care for DR at the nonproliferative stage is watchful waiting, with the use of anti-VEGFs when the disease has progressed to the proliferative stage.
−Removed: It is estimated that there were 8.4 million cases of DR in the United States in 2022 according to Market Scope, of which 3.3 million cases were moderate to severe non-proliferative DR, growing at an approximately 2% compound annual growth rate through 2027.
+Added: NPDR, sometimes called background retinopathy, is usually mild and may go unnoticed.
+Added: Proliferative DR is the most serious stage of the disease and develops when areas of the retina are starved for nourishment and oxygen, triggering the proliferation of new blood vessels via secretions of VEGFs.
+Added: The current standard of care for DR at the non-proliferative stage is watchful waiting, with the use of anti-VEGFs when the disease has progressed to the proliferative stage.
+Added: It is estimated that there were 8.6 million cases of DR in the United States in 2023 according to the Market Scope 2023 Retinal Pharmaceuticals Market Report, of which 3.4 million cases were moderate to severe NPDR, growing at an approximately 1.8% compound annual growth rate through 2028.
Overall, there are an estimated 146.4 million cases of DR globally, growing at a compound annual growth rate of 3.1%.
The global market for retinal disease inclusive of wet AMD and DR was approximately $16.5 billion in 2023 and is estimated to grow at approximately 6.1% per year through 2028 according to Market Scope.
−Removed: market accounted for just over 50% of the global market or $8.5 billion in 2022 and is expected to grow at approximately 7% through 2027.
+Added: market accounted for approximately 58% of the global market or $9.5 billion in 2023 and is expected to grow at approximately 5.6% through 2028.
The anti-VEGF market for the treatment of wet AMD consists predominantly of three drugs that are approved for marketing and primarily prescribed for the treatment of wet AMD:
1 unchanged sentence
Lucentis, marketed in the United States by Genentech;
−Removed: and bevacizumab, an anti-VEGF therapy approved for the treatment of certain cancers, used off-label in ophthalmology.
−Removed: A new anti-VEGF, Vabysmo, launched by Genentech in 2022, has penetrated the market rapidly and is expected to gain significant market share in the future.
−Removed: Retinal Disease Programs
−Removed: OTX-TKI (axitinib intravitreal implant)
−Removed: Our product candidate OTX-TKI is a preformed, bioresorbable hydrogel fiber implant incorporating axitinib, a small molecule TKI with anti-angiogenic properties delivered by intravitreal injection and designed for a duration of six months or longer.
−Removed: We are conducting a Phase 1 clinical trial in Australia and a Phase 1 clinical trial in the United States to evaluate OTX-TKI for the treatment of wet AMD.
−Removed: Our initial implants have delivered anti-VEGF compounds in vitro over a targeted nine to twelve month period, which we believe could make it possible to reduce patients’ treatment burden by reducing the frequency of the current monthly or bi-monthly intravitreal injection regimen for wet AMD.
−Removed: We are also conducting a Phase 1 clinical trial in the United States to evaluate OTX-TKI for the treatment of DR.
+Added: and Vabysmo, launched in 2022 and marketed in the United States by Genentech.
+Added: Bevacizumab, also known as Avastin, an anti-VEGF therapy approved for the treatment of certain cancers, is also used off-label in ophthalmology.
+Added: Retinal Programs
+Added: AXPAXLI (axitinib intravitreal implant)
+Added: Our product candidate AXPAXLI is a preformed, bioresorbable hydrogel fiber implant based on our ELUTYX technology incorporating axitinib, a small molecule TKI with anti-angiogenic properties.
+Added: AXPAXLI is delivered by intravitreal injection and is designed for a duration of six months or longer.
+Added: We are conducting the SOL-1 trial to evaluate AXPAXLI for the treatment of wet AMD in the United States, Argentina, and several other countries.
+Added: Subject to agreement with the FDA, we intend to commence screening of the SOL-2 trial by the first quarter of 2025.
+Added: We have also conducted a Phase 1 clinical trial in Australia and a Phase 1 clinical trial in the United States to evaluate AXPAXLI for the treatment of wet AMD.
+Added: We are also conducting the HELIOS trial in the United States to evaluate AXPAXLI for the treatment of NPDR.
+Added: Subject to favorable topline data from the HELIOS trial and agreement with the FDA, we intend to commence a pivotal Phase 3 clinical trial of AXAPXLI for the treatment of NPDR as a next step of clinical development.
We believe axitinib is well suited for use with our platform given its high potency, multi-target capability, and compatibility with a hydrogel vehicle.
1 unchanged sentence
We believe our local programmed-release drug delivery technology gives us potential advantages in this regard.
−Removed: We have conducted two Phase 1 trials of OTX-TKI for the treatment of wet AMD, with different formulations of axitinib.
−Removed: We currently intend to move forward into pivotal trials with our single 600 µg axitinib implant formulation of OTX-TKI for both the treatment of wet AMD and the treatment of diabetic retinopathy.
−Removed: As we have previously disclosed, we are also developing a second formulation of OTX-TKI that could be used in future trials of retinal indications.
−Removed: Currently, we do not believe any additional development work is required to advance to pivotal trials in either wet AMD or diabetic retinopathy.
+Added: Our initial implants have delivered anti-VEGF compounds in vitro over a targeted nine-to-twelve-month period, which we believe could make it possible to reduce patients’ treatment burden by reducing the frequency of the current monthly or bi-monthly intravitreal injection regimen for wet AMD.
+Added: We conducted the two Phase 1 trials of AXPAXLI for the treatment of wet AMD with different formulations of axitinib.
+Added: We are conducting the SOL-1 trial, and intend to conduct the SOL-2 trial and any pivotal trials for the treatment of NPDR, with a single 450 µg axitinib implant formulation of AXPAXLI, which is a different formulation than we used in either of the two Phase 1 trials.
Wet Age-Related Macular Degeneration (wet AMD)
+Added: The SOL-1 Trial
+Added: We initiated the SOL-1 trial, our first pivotal Phase 3 clinical trial of AXPAXLI for the treatment of wet AMD, in September 2023 with the activation of the trial’s first clinical site.
+Added: The SOL-1 trial is designed as a prospective, multi-center, randomized, parallel-group trial that will be run primarily at U.S.
+Added: sites, as well as sites in Argentina and several other countries.
+Added: The SOL-1 trial is designed as a superiority trial comparing a single optimized implant of AXPAXLI with a drug load of 450 µg of a more soluble form of axitinib to a single injection of aflibercept and assessing the safety and efficacy of AXPAXLI in subjects with wet AMD by measuring Best Corrected Visual Accuity, or BCVA, and central subfield thickness, or CSFT.
+Added: We plan to enroll approximately 300 evaluable wet AMD subjects who are treatment naïve in the study eye with good visual acuity and a diagnosis of choroidal neovascularization or sub-foveal neovascularization at screening in the SOL-1 trial.
+Added: Every enrolled subject will receive two aflibercept injections between the initial screening visit and day 1:
+Added: one at week -8 and another at week -4.
+Added: Subjects reaching approximately 20/20 vision or experiencing an improvement of 10 Early Treatment of Diabetic Retinopathy Study, or ETDRS, letters after these injections, in addition to satisfying other enrollment criteria, will then be randomized in the trial at baseline to receive either one implant of AXPAXLI in the investigational arm or one injection of aflibercept in the control arm, followed every month and rescued as needed with supplemental anti-VEGF treatment based on pre-specified criteria.
+Added: The primary endpoint is the proportion of subjects who maintained visual acuity, defined as a BCVA loss of less than 15 letters on the ETDRS chart at week 36.
+Added: Our pre-specified rescue criteria are a loss of 15 or more letters on the ETDRS chart compared to baseline, or a new hemorrhage that is deemed to be likely to cause irreversible vision loss.
+Added: A loss of 15 letters or more on the ETDRS chart at any time in the trial would be considered as having met the endpoint as a treatment failure.
+Added: In September 2023, we submitted a request for a Special Protocol Assessment, or SPA, to the FDA to determine whether the proposed clinical protocol and the statistical analysis plan for the SOL-1 trial adequately addressed scientific and regulatory requirements for a clinical trial that could support a marketing application.
+Added: We received an agreement letter regarding the overall trial design from the FDA under the SPA on October 30, 2023.
+Added: In December 2023, we
+Added: submitted the SPA Agreement Modification to the FDA to broaden the inclusion criteria for subjects in the SOL-1 trial and to reflect our intention to evaluate a single optimized implant of AXPAXLI with a drug load of 450 µg of a more soluble form of axitinib in the trial.
+Added: This optimized configuration is expected to provide for a slightly increased daily release of the drug and is designed to improve synchronization of axitinib drug depletion with hydrogel bioresorption.
+Added: We received an agreement letter regarding the SPA Agreement Modification from the FDA on January 22, 2024.
+Added: The SPA Agreement Modification enables the trial to include treatment-naïve wet AMD subjects with visual acuity of approximately 20/80 or better at the initial screening visit.
+Added: The first three subjects in the SOL-1 trial were screened and received their first aflibercept injection in February 2024.
+Added: We expect to complete enrollment of the SOL-1 trial by the end of the first quarter of 2025.
Phase 1 Clinical Trial (Australia)
−Removed: We are conducting an open-label, multi-center, proof-of-concept, dose-escalation Phase 1 clinical trial of OTX-TKI for the treatment of patients with wet AMD caused by excessive blood vessel growth in the back of the eye due to VEGF.
−Removed: This Phase 1 clinical trial is designed to evaluate the safety, durability and tolerability of OTX-TKI.
−Removed: The Phase 1 clinical trial was submitted to the Therapeutic Goods Administration, Australia’s regulatory authority for therapeutic goods, in July 2018 and is being conducted at multiple sites in Australia.
−Removed: Our Phase 1 clinical trial of OTX-TKI in Australia is comprised of four cohorts consisting of subjects with pre-existing intraretinal and/or subretinal fluid:
+Added: We have conducted an open-label, multi-center, proof-of-concept, dose-escalation Phase 1 clinical trial of AXPAXLI for the treatment of patients with wet AMD caused by excessive blood vessel growth in the back of the eye due to VEGF.
+Added: This Phase 1 clinical trial was designed to evaluate the safety, durability and tolerability of AXPAXLI.
+Added: All subjects have exited this Phase 1 clinical trial and we are in the process of closing all clinical sites.
+Added: Our Phase 1 clinical trial of AXPAXLI in Australia was submitted to the Therapeutic Goods Administration, Australia’s regulatory authority for therapeutic goods, in July 2018 and was being conducted at multiple sites in Australia.
+Added: The Phase 1 clinical trial was comprised of four cohorts consisting of subjects with pre-existing intraretinal and/or subretinal fluid:
a lower dose cohort of 200 µg with six subjects;
a higher dose cohort of 400 µg with seven subjects;
−Removed: a third cohort with two parallel arms, one arm of six subjects receiving a concomitant anti-VEGF injection with 400 µg of OTX-TKI and the other arm of six subjects receiving a 600 µg of OTX-TKI with no anti-VEGF injection;
−Removed: and a fourth cohort with two parallel arms, one arm of six subjects receiving a 600 µg single implant of OTX-TKI and the other arm of six subjects receiving a 600 µg single implant of OTX-TKI with anti-VEGF injection.
−Removed: In this trial, we are evaluating whether OTX-TKI can reduce existing fluid levels.
−Removed: This trial’s enrollment is complete.
−Removed: We plan to continue to follow subjects at least until their respective seventeen-month anniversaries of initial dosing, in accordance with the clinical trial protocol.
−Removed: In the Phase 1 clinical trial of OTX-TKI, we are evaluating biological activity by measuring central subfield thickness, or CSFT, using spectral domain optical coherence tomography, or OCT, and following visual acuity over time as measured by Best Corrected Visual Acuity, or BCVA.
−Removed: In February 2022, interim data as of January 11, 2022 from this Phase 1 clinical trial of OTX-TKI was presented at the Angiogenesis, Exudation and Degeneration Virtual Symposium.
−Removed: In subjects with subretinal and/or intraretinal fluid
−Removed: due to wet AMD, OTX-TKI was observed to be generally well tolerated.
+Added: a third cohort with two parallel arms, one arm of four subjects receiving a concomitant anti-VEGF injection with 400 µg of AXPAXLI and the other arm of six subjects receiving a 600 µg of AXPAXLI with no anti-VEGF injection;
+Added: and a fourth cohort with two parallel arms, one arm of one subject receiving a 600 µg single implant of AXPAXLI and the other arm of five subjects receiving a 600 µg single implant of AXPAXLI with anti-VEGF injection.
+Added: In this trial, we evaluated whether AXPAXLI can reduce existing fluid levels.
+Added: In the Phase 1 clinical trial of AXPAXLI conducted in Australia, we evaluated biological activity by measuring CSFT, using spectral domain optical coherence tomography, or OCT, and following visual acuity over time as measured by BCVA.
+Added: In February 2022, data as of January 11, 2022 from this Phase 1 clinical trial of AXPAXLI was presented at the Angiogenesis, Exudation and Degeneration Virtual Symposium.
+Added: In subjects with subretinal and/or intraretinal fluid due to wet AMD, AXPAXLI was observed to be generally well tolerated.
No ocular serious adverse events were reported in treatment naïve or previously treated wet AMD subjects.
−Removed: Plasma concentrations of the active drug (axitinib) were measured to be below the limit of quantification of assay, or BLQ < 0.1 ng/ml, at all sampled time points for all patients in cohorts 1, 2, 3a and 3b.
+Added: Plasma concentrations of the active drug (axitinib) were measured to be below the limit of quantification of assay, or BLQ < 0.1 ng/ml, at all sampled time points for all subjects in cohorts 1, 2, 3a and 3b.
This assessment indicated that there was no measurable systemic exposure to axitinib.
3 unchanged sentences
We observed extended duration of activity of six months or more for over 60% of subjects across all cohorts and for over 80% of subjects in cohort 3a, in which we administered a 600 μg dose.
−Removed: In addition, the OTX-TKI implants in cohort 1 (single implant) were observed to have biodegraded in all subjects within nine to 10.5 months of injection.
−Removed: It has also been observed in the trial that the implants were able to be adequately monitored and that there was limited to no movement of the implant in the anterior segment of the eye.
+Added: In addition, the AXPAXLI implants in cohort 1 (single implant) were observed to have biodegraded in all subjects within nine to 10.5 months of injection.
+Added: It has also been observed in the trial that the implants were able to be adequately monitored and that there was limited to no movement of the implant.
Phase 1 Clinical Trial (United States)
−Removed: In July 2021, we announced that we had dosed the first patient in a prospective, multi-center, randomized, controlled Phase 1 clinical trial in the United States under an exploratory investigational new drug, or eIND, application to evaluate a single implant 600 µg dose of OTX-TKI with an anti-VEGF injection in comparison with a 2 mg dose of aflibercept.
−Removed: The population we are studying in this U.S.-based clinical trial is different than the population we are studying in our ongoing Phase 1 clinical trial of OTX-TKI in Australia.
−Removed: In this trial, we are evaluating how long we are able to maintain subjects who have been previously treated with anti-VEGF therapy without the need for retreatment.
+Added: We have conducted a prospective, multi-center, randomized, controlled Phase 1 clinical trial in the United States under an exploratory investigational new drug, or eIND, application to evaluate a single implant 600 µg dose of AXPAXLI with an anti-VEGF injection in comparison with a 2 mg dose of aflibercept.
+Added: The population we studied in this U.S.-based clinical trial was different than the population we studied in our Phase 1 clinical trial of AXPAXLI in Australia.
+Added: In this trial, we evaluated how long we are able to maintain subjects who have been previously treated with
+Added: anti-VEGF therapy without the need for retreatment.
+Added: All subjects have exited this Phase 1 clinical trial and we are in the process of closing all clinical sites.
The trial enrolled a total of 21 subjects at six clinical sites, comprising two arms consisting of subjects previously treated with, and responsive to, standard of care anti-VEGF therapy:
−Removed: a 16-subject arm receiving OTX-TKI in combination with a single anti-VEGF injection at month one and a five-subject arm receiving on-label aflibercept at eight-week intervals.
−Removed: The trial is designed to assess the safety, durability and tolerability of OTX-TKI as well as to assess preliminary biological activity in subjects by measuring anatomical and functional changes.
−Removed: This trial was fully enrolled as of February 2022.
−Removed: In February 2023, we announced interim 10-month data from the ongoing Phase 1 clinical trial of OTX-TKI in the United States at the Angiogenesis, Exudation, and Degeneration 2023 Annual Meeting.
−Removed: As of the December 12, 2022 cut-off date, the interim data showed that the single 600 µg OTX-TKI implant was generally well tolerated with no drug-related ocular or systemic serious adverse events, or SAEs, observed through 10 months.
−Removed: One SAE of endophthalmitis was observed in the OTX-TKI arm which occurred following the aflibercept injection required by the clinical trial protocol at month one and was assessed by the investigator as related to the injection procedure.
−Removed: There were no instances of elevated IOP, retinal detachment, retinal vasculitis, or implant migration into the anterior chamber observed in the OTX-TKI arm, and no subjects had dropped out of either arm as of the data cutoff.
−Removed: The interim results showed subjects treated with a single OTX-TKI implant demonstrated stable and sustained BCVA (mean change from baseline of -0.3 letters) and CSFT (mean change from baseline of -1.3 µm) in the OTX-TKI arm at 10 months, which was comparable with the aflibercept arm (mean change from BCVA baseline of -0.8 letters;
+Added: a 16-subject arm receiving AXPAXLI in combination with a single anti-VEGF injection at month one and a five-subject arm receiving on-label aflibercept at eight-week intervals.
+Added: The trial was designed to assess the safety, durability and tolerability of AXPAXLI as well as to assess preliminary biological activity in subjects by measuring anatomical and functional changes.
+Added: In February 2023, we announced interim 10-month data from the Phase 1 clinical trial of AXPAXLI in the United States at the Angiogenesis, Exudation, and Degeneration 2023 Annual Meeting.
+Added: As of the December 12, 2022 cut-off date, the interim data showed that the single 600 µg AXPAXLI implant was generally well tolerated with no drug-related ocular or systemic serious adverse events, or SAEs, observed through 10 months.
+Added: One SAE of endophthalmitis was observed in the AXPAXLI arm which occurred following the aflibercept injection required by the clinical trial protocol at month one and was assessed by the investigator as related to the injection procedure.
+Added: There were no instances of elevated IOP, retinal detachment, retinal vasculitis, or implant migration into the anterior chamber observed in the AXPAXLI arm, and no subjects had dropped out of either arm as of the data cutoff.
+Added: The interim results showed subjects treated with a single AXPAXLI implant demonstrated stable and sustained BCVA (mean change from baseline of -0.3 letters) and CSFT (mean change from baseline of -1.3 µm) in the AXPAXLI arm at 10 months, which was comparable with the aflibercept arm (mean change from BCVA baseline of -0.8 letters;
mean change from CSFT baseline of -4.5 µm).
Up to Month 10, 73% of subjects remained rescue-free.
−Removed: Overall, a 92% reduction in treatment burden (average percent decrease in injections over the period compared to a standard monthly injection regimen) was observed in OTX-TKI treated subjects for up to 10 months.
−Removed: Four subjects were rescued in the OTX-TKI arm up to Month 10.
+Added: Overall, a 92% reduction in treatment burden (average percent decrease in injections over the period compared to a standard monthly injection regimen) was observed in AXPAXLI treated subjects for up to 10 months.
+Added: Four subjects were rescued in the AXPAXLI arm up to Month 10.
One subject, the subject who experienced endophthalmitis, was rescued twice.
1 unchanged sentence
One additional subject, who met the established rescue criteria at such subject’s Month 10 visit, was rescued at the end of Month 10.
−Removed: There was one subject randomized to the OTX-TKI arm who was inadvertently given aflibercept instead of sham injections at the subject’s month three and month five visits.
−Removed: Since this subject was not treated according to protocol, the subject was excluded from the analysis of biological activity, which comprised 15 out of the 16 subjects in the OTX-TKI
−Removed: arm and all five subjects in the aflibercept arm, but the subject was included in the safety analysis which comprised all 16 subjects in the OTX-TKI arm and all five subjects in the aflibercept arm.
−Removed: Per protocol, we will continue to follow subjects in the Phase 1 trial at least until their respective one-year anniversaries of initial dosing.
−Removed: Regulatory Pathway
−Removed: We are in active discussions with the FDA regarding the regulatory pathway for OTX-TKI for the treatment of wet AMD and potential future clinical trial requirements.
−Removed: Subject to those discussions and obtaining the necessary financing, which could be provided through a strategic alliance, we aim to be prepared to initiate a pivotal clinical trial for the treatment of wet AMD in the third quarter of 2023.
−Removed: If we were to obtain favorable results from two pivotal clinical trials, we expect that we would submit an NDA under Section 505(b)(2) of the FDCA.
+Added: There was one subject randomized to the AXPAXLI arm who was inadvertently given aflibercept instead of sham injections at the subject’s month three and month five visits.
+Added: Since this subject was not treated according to protocol, the subject was excluded from the analysis of biological activity, which comprised 15 out of the 16 subjects in the AXPAXLI arm and all five subjects in the aflibercept arm, but the subject was included in the safety analysis which comprised all 16 subjects in the AXPAXLI arm and all five subjects in the aflibercept arm.
+Added: In April 2023, we presented data regarding the preclinical pharmacokinetics, or PK, of AXPAXLI and a review of the 10-month interim data from the ongoing Phase 1 clinical trial of AXPAXLI in the United States, including AXPAXLI implant resorption data to date.
+Added: We augmented the results from our ongoing clinical trial with PK data in two animal models showing the uptake of axitinib from our hydrogel implant in the choroid and retinal pigment epithelium, or RPE, cells, where axitinib acts intra-cellularly to exert its VEGF receptor inhibiting effect.
+Added: That data showed that clinically representative formulations of AXPAXLI delivered sustained axitinib concentrations through 12 months that were well above the IC50 for VEGFR-2 (vascular endothelial growth factor receptor) in cynomolgus monkey retina tissue and choroid/RPE tissues.
+Added: This preclinical PK data aligns with the pharmacodynamics data we have observed to date in our ongoing U.S.
+Added: clinical trial, namely the high proportion of rescue-free subjects up to Month 10 and suggests that AXPAXLI may provide continuous VEGF receptor inhibition, which, in turn, may support this new treatment paradigm, Treat to Maintain, in wet AMD care.
+Added: In June 2023, we presented 12-month data from the ongoing Phase 1 clinical trial of AXPAXLI in the United States at the Clinical Trials at the Summit 2023 conference sponsored by the American Society of Retina Specialists.
+Added: As of the April 14, 2023 cut-off date, there were no drug-related ocular or systemic SAEs observed in the AXPAXLI arm except for the one SAE of endophthalmitis following the aflibercept injection at month one that we announced at the 10-month data readout in February 2023 and was assessed by the investigator as related to the injection procedure.
+Added: There were no retinal detachment, retinal vasculitis, or implant migration into the anterior chamber adverse events observed in the AXPAXLI arm, and no subjects had dropped out of either arm as of the data cut-off.
+Added: The results showed subjects treated with a single AXPAXLI implant continued to demonstrate sustained BCVA (mean change from baseline of -1.0 letters) and CSFT (mean change from baseline of +20.2 μm) in the AXPAXLI arm at 12 months, which was comparable
+Added: with the aflibercept arm (mean change from BCVA baseline of +2.0 letters;
+Added: mean change from CSFT baseline of -2.2 μm).
+Added: Sixty percent of AXPAXLI subjects were rescue-free up to Month 12.
+Added: At the Month 12 visit, an additional four of the subjects were rescued.
+Added: Overall, an 89% reduction in treatment burden was observed in AXPAXLI treated subjects at 12 months.
+Added: These results align with our expectation that we would see a reactivation of disease in some subjects, which we believe indicates that AXPAXLI continues to function as designed with axitinib concentrations beginning to fall below therapeutic levels after the implant bioresorbs.
+Added: Subject to agreement with the FDA, we intend to commence screening of the SOL-2 trial by the first quarter of 2025.
+Added: The SOL-2 trial design is expected to be substantially similar to the design of the SOL-1 trial.
+Added: If we were to obtain favorable results from the SOL-1 trial and the planned SOL-2 trial evaluating AXPAXLI for the treatment of wet AMD, we expect that we would submit an NDA under Section 505(b)(2) of the FDCA.
See “—Government Regulation—Section 505(b)(2) NDAs” for additional information.
−Removed: Diabetic Retinopathy (DR)
+Added: Non-Proliferative Diabetic Retinopathy (NPDR)
Phase 1 Clinical Trial
−Removed: Given our belief in the potential applicability of OTX-TKI to other retinal diseases, we initiated a Phase 1 U.S.-based clinical trial to evaluate OTX-TKI for the treatment of DR in the fourth quarter of 2022 and dosed our first patient in February 2023.
−Removed: We are conducting the Phase 1 clinical trial initially under an eIND.
−Removed: The trial is designed to include approximately 21 subjects with diabetic retinopathy secondary to type 1 or type 2 diabetes who had not had an anti-VEGF injection in the prior 12 months or DME in the prior six months, randomized 2:1 to either a single 600 µg implant of OTX-TKI or sham control across approximately 10 sites.
−Removed: We anticipate disclosing topline results as early as the fourth quarter of 2023.
−Removed: Regulatory Pathway
−Removed: We are in active discussions with the FDA regarding the clinical development of OTX-TKI.
−Removed: Assuming positive topline data results from the Phase 1 clinical trial, the finalization of the design of our clinical development program reflecting of our ongoing discussions with the FDA, and additional financing to fund the trials, we believe we could be in a position to initiate our first pivotal trial of OTX-TKI for the treatment of DR as early as the first quarter of 2024 and a second pivotal trial shortly thereafter.
−Removed: If we were to obtain favorable results from these two pivotal clinical trials, we expect that we would submit an NDA under Section 505(b)(2) of the FDCA.
−Removed: See “—Government Regulation—Section 505(b)(2) NDAs” for additional information.
+Added: Given our belief in the potential applicability of AXPAXLI to other retinal diseases, we initiated the HELIOS trial to evaluate AXPAXLI for the treatment of NPDR in the fourth quarter of 2022.
+Added: The HELIOS trial is a U.S.-based, multicenter, double-masked, randomized, parallel group study evaluating the safety, tolerability and biological activity of AXPAXLI in patients with moderately severe to severe NPDR without DME.
+Added: We dosed our first subject in February 2023.
+Added: We are conducting the Phase 1 clinical trial initially under an eIND and are in the process of converting this to a regular IND.
+Added: We have enrolled 22 subjects with diabetic retinopathy secondary to type 1 or type 2 diabetes who had not had an anti-VEGF injection in the prior 12 months or diabetic macular edema in the prior six months, randomized 2:1 to either a single implant of AXPAXLI containing 600 µg of axitinib or sham control.
+Added: We announced the completion of enrollment in the HELIOS trial in June 2023 and expect to provide 9-month topline data in the second quarter of 2024.
+Added: We have had discussions with the FDA with respect to the clinical development of AXPAXLI for the treatment of NPDR and have a potential pivotal clinical trial design that is consistent with guidance from the FDA.
+Added: Subject to favorable topline data from the ongoing HELIOS trial and agreement with the FDA, we intend to commence a pivotal Phase 3 clinical trial evaluating AXPAXLI for the treatment of NPDR as a next step of clinical development.
Glaucoma is a progressive and highly individualized disease in which elevated levels of IOP are associated with damage to the optic nerve, which results in irreversible vision loss.
According to the World Health Organization, glaucoma is the second leading cause of blindness in the world.
−Removed: Ocular hypertension is characterized by elevated levels of IOP without any optic nerve damage.
−Removed: Patients with ocular hypertension are at high risk of developing glaucoma.
+Added: OHT is characterized by elevated levels of IOP without any optic nerve damage.
+Added: Patients with OHT are at high risk of developing glaucoma.
In a healthy eye, fluid is continuously produced and drained to maintain pressure equilibrium and provide nutrients to the ocular tissue.
2 unchanged sentences
Once glaucoma develops, it is a chronic condition that requires life-long treatment.
−Removed: According to Market Scope, it is estimated that there were 172.0 million people globally in 2023 with primary open-angle glaucoma or ocular hypertension.
−Removed: In the United States, it is estimated there are 6.8 million and 3.7 million who had primary open-angle glaucoma or ocular hypertension, respectively.
+Added: According to the Market Scope 2023 Glaucoma Pharmaceuticals Market Report, it is estimated that there were 126.6 million people globally in 2023 with primary OAG or OHT.
+Added: In the United States, it is estimated there are 6.8 million and 3.7 million who had primary OAG or OHT, respectively.
Both groups are estimated to grow by 1.3% and 2.4% annually through 2026, respectively.
1 unchanged sentence
Importantly, however, adherence to current topical glaucoma therapies is known to be particularly poor with reported rates of non-adherence from 30% to 80%.
−Removed: These low compliance rates may be associated with disease progression and loss of vision and may be part of the reason that glaucoma is a leading cause of blindness in people over 60 years of age.
+Added: These low compliance rates may be associated with disease progression and loss of vision and may be part of the
+Added: reason that glaucoma is a leading cause of blindness in people over 60 years of age.
Prostaglandins are the most commonly used class of medications to treat patients with glaucoma and are administered via daily eye drops as the current standard of care.
7 unchanged sentences
Branded products have maintained premium pricing and significant market share.
−Removed: These products include Lumigan (bimatoprost) marketed by Allergan, Travatan Z (travoprost) marketed by Novartis and Tapros marketed by Santen.
+Added: These products include Lumigan (bimatoprost) marketed by Allergan, Travatan Z (travoprost) marketed by Novartis, Tapros marketed by Santen, and recently approved Miebo ( perfluorohexyloctane ophthalmic solution) marketed by Bausch + Lomb.
Commonly used generic drugs include latanoprost and timolol.
Glaucoma Program
−Removed: OTX-TIC (travoprost intracameral implant)
−Removed: Our product candidate OTX-TIC is a bioresorbable hydrogel implant incorporating travoprost, an FDA-approved prostaglandin analog designed to lower elevated IOP, that is designed to be administered by a physician as an intracameral injection with an initial target duration of drug release of four to six months with a single treatment.
+Added: PAXTRAVA (travoprost intracameral implant)
+Added: Our product candidate PAXTRAVA is a bioresorbable hydrogel implant based on ELUTYX, incorporating travoprost, an FDA-approved prostaglandin analog designed to lower elevated IOP, that is designed to be administered by a physician as an intracameral injection with an initial target duration of drug release of four to six months with a single treatment.
+Added: Phase 2 Clinical Trial
+Added: We are conducting a U.S.-based Phase 2 prospective, multi-center, randomized, controlled clinical trial evaluating the safety, tolerability and efficacy of PAXTRAVA for the treatment of patients with primary OAG or OHT under an IND.
+Added: The Phase 2 clinical trial was initially designed to include approximately 105 subjects at 15 to 20 sites between three arms of approximately 35 subjects each to evaluate two formulations of PAXTRAVA for the treatment of OAG or OHT in subjects compared to DURYSTA.
+Added: The non-study eye of each subject receives a topical prostaglandin daily.
+Added: The primary efficacy endpoint is measured by diurnal IOP mean change from baseline (8 a.m., 10 a.m.
+Added: and 4 p.m.) at two, six and 12 weeks.
+Added: The active comparator control arm receives one injection of DURYSTA in one eye and a topical prostaglandin daily in the non-study eye.
+Added: We initiated the Phase 2 clinical trial in the fourth quarter of 2021 and dosed the first subject in the first quarter of 2022.
+Added: One arm in the Phase 2 clinical trial is receiving the same formulation used in cohort 2 of the Phase 1 clinical trial of PAXTRAVA that we conducted, containing a 26 µg dose of drug and utilizing a standard implant.
+Added: The second arm was receiving the same formulation used in cohort 4 of the Phase 1 clinical trial, containing a 5 µg dose of drug and utilizing a fast-degrading implant.
+Added: Due to elevations in IOP observed approximately 12 weeks after enrollment in six subjects in the PAXTRAVA 5 µg arm of the trial, we terminated enrollment in the 5 µg arm of the trial in the fourth quarter of 2022 and continued with the PAXTRAVA 26 µg and DURYSTA arms of the trial.
+Added: The Phase 2 clinical trial consists of 86 subjects:
+Added: 35 subjects in the PAXTRAVA 26 µg treatment arm, 35 subjects in the DURYSTA arm and 16 subjects that were previously enrolled in the PAXTRAVA 5 µg treatment arm.
+Added: Enrollment of the Phase 2 clinical trial was completed in July 2023.
+Added: We have started a pilot repeat-dose sub-study in the Phase 2 clinical trial to evaluate the safety of a repeat, sustained release dose of PAXTRAVA 26 μg, in a small subset of subjects with OAG or OHT.
+Added: These subjects will be followed for at least six months after their enrollment in the sub-study to monitor and evaluate their endothelial cell health.
+Added: We plan to provide topline data from the single-dose portion of the Phase 2 clinical trial, assessing the safety, efficacy and durability of PAXTRAVA and whether the product candidate’s preservation of endothelial cell health could make the drug suitable for chronic dosing, at the American Society of Cataract and Refractive Surgery 2024 Annual Meeting in April 2024.
Phase 1 clinical development
−Removed: We submitted an IND for OTX-TIC in February 2018 and have completed a prospective, multi-center, open-label, dose-escalation, proof-of-concept Phase 1 clinical trial of OTX-TIC in the United States that we initiated in the second quarter of 2018 for the treatment of subjects with moderate to severe glaucoma or ocular hypertension.
−Removed: The clinical trial is designed to evaluate the safety, biological activity, durability and tolerability of OTX-TIC in subjects with controlled open-angle glaucoma or ocular hypertension.
−Removed: The clinical trial consisted of four patient cohorts:
+Added: We submitted an IND for PAXTRAVA in February 2018 and have completed a prospective, multi-center, open-label, dose-escalation, proof-of-concept Phase 1 clinical trial of PAXTRAVA in the United States that we initiated in the second quarter of 2018 for the treatment of subjects with moderate to severe glaucoma or OHT.
+Added: The clinical trial is designed to evaluate the safety, biological activity, durability and tolerability of PAXTRAVA in subjects with controlled OAG or OHT.
+Added: The clinical trial consisted of four subject cohorts:
cohort 1 included five subjects who received a 15 µg dose, cohort 2 included four subjects who received a 26 µg dose, cohort 3 included five subjects who received a 15 µg dose with a fast-degrading implant, and cohort 4 included five subjects who received a 5 µg dose with a fast-degrading implant.
In February 2022, at the Glaucoma 360 virtual meeting, we presented interim results from all four subject cohorts in the Phase 1 clinical trial.
−Removed: We believe, based on these results, that OTX-TIC shows potential as a sustained-release therapy with a long duration of action.
−Removed: In the Phase 1 clinical trial, at least one subject in each of the four cohorts receiving OTX-TIC were observed to experience a mean change in IOP from baseline as measured at 8:00 am, 10:00 a.m.
+Added: We believe, based on these results, that PAXTRAVA shows potential as a sustained-release therapy with a long duration of action.
+Added: In the Phase 1 clinical trial, at least one subject in each of the four cohorts receiving PAXTRAVA were observed to experience a mean change in IOP from baseline as measured at 8:00 am, 10:00 a.m.
and 4:00 p.m.
2 unchanged sentences
IOP lowering effects lasted more than six months in subjects in cohorts 1 and 2 and three to six months in subjects in cohorts 3 and 4.
−Removed: The OTX-TIC implant was observed to biodegrade in between five and seven months in subjects in cohorts 1 and 2.
+Added: The PAXTRAVA implant was observed to biodegrade in between five and seven months in subjects in cohorts 1 and 2.
In subjects in cohorts 3 and 4, the fast-degrading implants biodegraded between three and five months.
2 unchanged sentences
IOP elevation was observed in three subjects in cohort 3 at the approximate time of the implant resorption.
−Removed: Phase 2 Clinical Trial
−Removed: We are conducting a U.S.-based Phase 2 prospective, multi-center, randomized, controlled clinical trial evaluating the safety, tolerability and efficacy of OTX-TIC for the treatment of patients with primary open-angle glaucoma or ocular hypertension.
−Removed: The Phase 2 clinical trial was designed to include approximately 105 subjects at 15 to 20 sites
−Removed: between three arms of approximately 35 subjects each to evaluate two formulations of OTX-TIC for the treatment of open-angle glaucoma or ocular hypertension in subjects compared to DURYSTA.
−Removed: The non-study eye of each subject will receive a topical prostaglandin daily.
−Removed: The primary efficacy endpoint is measured by diurnal IOP mean change from baseline (8 a.m., 10 a.m.
−Removed: and 4 p.m.) at two, six and 12 weeks.
−Removed: The active comparator control arm will receive one injection of DURYSTA in one eye and a topical prostaglandin daily in the non-study eye.
−Removed: We initiated the Phase 2 clinical trial in the fourth quarter of 2021 and dosed the first subject in the first quarter of 2022.
−Removed: One arm in the Phase 2 clinical trial is receiving the same formulation used in cohort 2 of the Phase 1 clinical trial, containing a 26 µg dose of drug and utilizing a standard implant.
−Removed: The second arm was receiving the same formulation used in cohort 4 of the Phase 1 clinical trial, containing a 5 µg dose of drug and utilizing a fast-degrading implant.
−Removed: Due to elevations in IOP observed approximately 12 weeks after enrollment in six subjects in the OTX-TIC 5 µg arm of the trial, we terminated enrollment in the 5 µg arm of the trial in the fourth quarter of 2022 and are continuing forward with the OTX-TIC 26 µg and DURYSTA arms of the trial.
−Removed: We expect that the Phase 2 clinical trial will consist of approximately 86 patients:
−Removed: approximately 35 patients in the OTX-TIC 26 µg treatment arm, 35 patients in the DURYSTA arm and approximately 16 patients that were previously enrolled in the OTX-TIC 5 µg treatment arm.
−Removed: Enrollment is ongoing.
−Removed: We plan to provide topline data from the trial in the fourth quarter of 2023.
−Removed: Regulatory Pathway
−Removed: If our Phase 2 clinical trial is successful and subject to obtaining the necessary financing, we would then be required to successfully complete two well-controlled pivotal clinical trials conducted under an IND to obtain marketing approval from the FDA.
−Removed: If we were to obtain favorable results from these two pivotal clinical trials, we expect that we would submit an NDA to the FDA for marketing approval of OTX-TIC under Section 505(b)(2) of the FDCA.
−Removed: See “—Government Regulation—Section 505(b)(2) NDAs.”
+Added: If the data from our Phase 2 clinical trial is favorable, we intend to evaluate our strategic alternatives for advancing the development of PAXTRAVA to pivotal Phase 3 clinical trials.
+Added: If we were to decide to move the PAXTRAVA program into pivotal Phase 3 clinical trials, we would be required to successfully complete two well-controlled pivotal clinical trials conducted under an IND to seek marketing approval from the FDA.
+Added: If our development efforts are successful, we expect that we would submit an NDA under Section 505(b)(2) of the FDCA.
+Added: See “—Government Regulation—Section 505(b)(2) NDAs” for additional information.
Ocular Surface Diseases
12 unchanged sentences
Cequa for increasing tear production, marketed by Sun Ophthalmics in the United States;
−Removed: lifitegrast, for the treatment of the signs and symptoms of dry eye disease, marketed by Novartis under the brand name Xiidra;
+Added: lifitegrast, for the treatment of the signs and symptoms of dry eye disease, marketed by Bausch & Lomb (previously marketed by Novartis) under the brand name Xiidra;
and off-label use of corticosteroids.
14 unchanged sentences
Market Scope has estimated that approximately 9.8 million ocular surgeries were performed in the United States in 2023, an increase of approximately 3.5% over 2022.
−Removed: Market Scope further estimates that approximately 4.6 million are estimated to have been cataract surgeries, an increase of 3.1% over 2021.
+Added: According to the Market Scope 2023 US and Western Europe Cataract Pharmaceuticals Market Report, there were an estimated 4.7 million cataract surgeries in the United States in 2023, an increase of 3.0% over 2022.
We currently focus our sales efforts for DEXTENZA for the treatment of inflammation and pain on patients covered by Medicare Part B which accounts for roughly 50% of all cataract surgeries or approximately 2 million surgeries annually.
11 unchanged sentences
These treatments act to reduce the signs and symptoms of the early phase allergic reaction.
−Removed: For the subset of patients with chronic or more severe forms of allergic conjunctivitis, anti-histamines and mast cell stabilizers are often not sufficient to treat their signs and symptoms.
+Added: For the subset of patients with chronic or more severe forms of allergic conjunctivitis, anti-histamines and mast
+Added: cell stabilizers are often not sufficient to treat their signs and symptoms.
These refractory patients are frequently treated with topical corticosteroids administered by prescription eye drops.
2 unchanged sentences
data, approximately 4.6 million anti-allergy eye drop prescriptions were filled in the United States in 2023, resulting in sales of approximately $257.0 million.
−Removed: The market to treat allergic conjunctivitis
−Removed: consists of antihistamines, mast-cell stabilizers and steroid eye drops and consists of both branded and generic products.
−Removed: Branded steroids include Lotemax and Alrex (loteprednol etabonate) marketed by Bausch & Lomb, and Durezol (difluprednate) marketed by Alcon.
+Added: The market to treat allergic conjunctivitis consists of antihistamines, mast-cell stabilizers and steroid eye drops and consists of both branded and generic products.
+Added: Commonly used branded steroids include Lotemax and Alrex (loteprednol etabonate) marketed by Bausch & Lomb, and Durezol (difluprednate) marketed by Alcon.
Commonly used generic steroids include prednisolone, dexamethasone and fluorometholone.
1 unchanged sentence
We are engaged in the development of formulations of our hydrogel administered via intracanalicular inserts to address large markets for diseases and conditions of the surface of the eye.
−Removed: Our initial development efforts are focused on the use of our extended-delivery hydrogel in combination with well-known and well-understood drugs (corticosteroids and cyclosporine) for the treatment of dry eye disease, allergic conjunctivitis and inflammation and pain following ophthalmic surgery.
−Removed: Dry Eye Disease Program
+Added: Our development efforts are focused on the use of our extended-delivery hydrogel in combination with well-known and well-understood drugs (corticosteroids and cyclosporine) for the treatment of dry eye disease, allergic conjunctivitis and inflammation and pain following ophthalmic surgery.
OTX-DED (dexamethasone intracanalicular insert)
4 unchanged sentences
However, safety limitations associated with the prolonged use of corticosteroids for dry eye disease have limited widespread adoption.
−Removed: We believe that OTX-DED has potential as a short-term treatment of the signs and symptoms of dry eye disease caused by inflammation.
−Removed: Our product candidate OTX-DED incorporates the FDA-approved corticosteroid dexamethasone as a preservative-free active pharmaceutical ingredient in a hydrogel, drug-eluting intracanalicular insert.
+Added: We believe that our product candidate OTX-DED has potential as a short-term treatment of the signs and symptoms of dry eye disease caused by inflammation.
+Added: OTX-DED incorporates the FDA-approved corticosteroid dexamethasone as a preservative-free active pharmaceutical ingredient in a hydrogel, drug-eluting intracanalicular insert.
OTX-DED incorporates the same active drug as DEXTENZA but includes a lower dose of the drug, is administered in the office setting as a smaller insert and is designed to release dexamethasone over a period of two to three weeks, compared with up to thirty days in the case of DEXTENZA.
9 unchanged sentences
The clinical trial achieved its pre-specified primary endpoint.
−Removed: Although the clinical trial was not powered to show statistical significance, the topline results demonstrated a statistically significant change of bulbar conjunctival hyperemia from baseline to day 15 compared to the vehicle hydrogel using a central reading photographic assessment in the modified ITT population.
+Added: Although the clinical trial was not powered to show statistical significance, the topline results
+Added: demonstrated a statistically significant change of bulbar conjunctival hyperemia from baseline to day 15 compared to the vehicle hydrogel using a central reading photographic assessment in the modified ITT population.
Change from baseline using the CCLRU Grading scale (0-4) was -0.51 for the OTX-DED 0.2 mg group (n=55), -0.43 for the OTX-DED 0.3 mg group (n=56), and -0.21 for the vehicle hydrogel insert group (n=55).
These differences were statistically significant compared with the vehicle hydrogel for both the OTX-DED 0.2 mg group (p=.004) and the OTX-DED 0.3 mg group (p=.028).
−Removed: Sensitivity analysis using different methods of imputation including last observation carry forward (LOCF), Markov Chain Monte Carlo (MCMC), and fully conditioned specifications (FCS) were consistent with the primary
+Added: Sensitivity analysis using different methods of imputation including last observation carry forward (LOCF), Markov Chain Monte Carlo (MCMC), and fully conditioned specifications (FCS) were consistent with the primary analysis.
Improvements from baseline were noted in the VAS dry eye symptoms for both OTX-DED 0.2 mg and OTX-DED 0.3 mg groups, but there was little separation between OTX-DED and the vehicle hydrogel insert.
5 unchanged sentences
All other non-ocular adverse events occurred in less than 1% of subjects.
−Removed: Regulatory Pathway
−Removed: Based on the data from the Phase 2 clinical trial, we intend to conduct a small trial in connection with our efforts to develop an appropriate placebo comparator that may be used in both the OTX-DED and OTX-CSI programs.
−Removed: Specifically, we intend to evaluate the performance of OTX-DED versus placebo inserts, namely fast-dissolving, biodegradable collagen plugs, and no inserts at all, to explain the placebo performance seen in the Phase 2 clinical trials evaluating both OTX-DED and OTX-CSI in which the vehicle hydrogel placebo insert or placebo comparator vehicle remained in the canaliculus longer than anticipated, performing more like an active comparator than a placebo.
−Removed: We currently expect to begin this trial in the first half of 2023.
−Removed: If we determine to advance the program, we believe we could advance the program to pivotal trials subject to a discussion with the FDA.
−Removed: We would then be required to successfully complete two well-controlled Phase 3 clinical trials conducted under an IND to obtain marketing approval from the FDA.
−Removed: If our development efforts are successful, we expect that we would submit an NDA under Section 505(b)(2) of the FDCA.
−Removed: See “—Government Regulation—Section 505(b)(2) NDAs” for additional information.
+Added: Ongoing Clinical Work
+Added: Based on the data from the Phase 2 clinical trial, we initiated a small trial in the second quarter of 2023 in connection with our efforts to develop an appropriate placebo comparator that may be used in both the OTX-DED and OTX-CSI programs.
+Added: This trial is evaluating the performance of OTX-DED versus placebo inserts, namely fast-dissolving, biodegradable collagen plugs, and no inserts at all, to explain the placebo performance seen in the Phase 2 clinical trials evaluating both OTX-DED and OTX-CSI in which the vehicle hydrogel placebo insert or placebo comparator vehicle remained in the canaliculus longer than anticipated, performing more like an active comparator than a placebo.
+Added: We anticipate we will complete enrollment for this trial in the first half of 2024, and to deliver topline data in the fourth quarter of 2024.
+Added: We plan to use the results of this trial to inform the next steps for both the OTX-DED and OTX-CSI programs.
+Added: If the data from the ongoing trial of evaluating OTX-DED versus potential comparators is favorable, we intend to evaluate our strategic alternatives for advancing the development of OTX-DED.
OTX-CSI (cyclosporine intracanalicular insert)
38 unchanged sentences
The most common non-ocular event was COVID-19 and was seen in 3% of subjects.
−Removed: Regulatory Pathway
−Removed: We are continuing formulation work to extend the durability of the OTX-CSI insert and select the most appropriate formulations to move forward.
−Removed: If we determine to advance the program, we believe we could advance the program to pivotal trials subject to discussions with the FDA.
−Removed: We would then be required to successfully complete two well-controlled pivotal clinical trials conducted under an IND to obtain marketing approval from the FDA.
−Removed: If our development efforts are successful, we expect that we would submit an NDA under Section 505(b)(2) of the FDCA.
−Removed: See “—Government Regulation—Section 505(b)(2) NDAs” for additional information.
−Removed: Additional Potential Areas for Growth
−Removed: We continue to leverage the potential of our hydrogel platform to explore areas for growth with a focus on formulating, developing and commercializing innovative therapies for diseases and conditions of the eye.
−Removed: Complement Inhibitor .
−Removed: In June 2021, we entered into an agreement with Mosaic Biosciences, Inc., or Mosaic, to identify new targets and discover novel therapeutic agents aimed at the treatment of dry AMD.
−Removed: Dry AMD can progress to an advanced condition known as geographic atrophy, or GA.
−Removed: Vision loss from GA is typically more gradual than it is from wet AMD.
−Removed: In its 2022 Retinal Pharmaceuticals Market Report, Market Scope estimated that there are 1.6 million people with GA in the United States and more than 13 million globally, both growing at an estimated compound annual growth rate of 3%.
−Removed: Our collaboration with Mosaic has yielded lead compounds that Mosaic has humanized and is now optimizing for our preclinical complement inhibitor program.
−Removed: We believe that product candidates with these compounds have the potential for targeted dosing of every three to four months.
−Removed: Companies actively pursuing treatments for GA through the inhibition of the complement system include Apellis Pharmaceuticals, Inc.
−Removed: and Iveric bio, Inc.
−Removed: Apellis’ Syfovre received marketing approval from the FDA in February of 2023.
−Removed: In February 2023, Iveric Bio, Inc.
−Removed: also announced that the FDA had accepted the company’s NDA for avacincaptad pegol for filing and established a PDUFA target action date in August 2023.
−Removed: We are aware that several other companies are actively developing product candidates for the treatment of GA, including Annexon Biosciences, Inc.
−Removed: Novartis Ionis (in collaboration with Roche/Genentech), AstraZeneca, The Janssen Pharmaceutical Companies of Johnson & Johnson (after acquisition from Hemera Biosciences), Alkeus Pharmaceuticals, Inc., Lineage Cell Therapeutics, Inc.
−Removed: (in collaboration with Roche/Genentech), and Regenerative Patch Technologies, LLC.
−Removed: Gene Delivery Program.
−Removed: We have a preclinical program using our hydrogel technology to control the release of vectors such as AAV to ocular tissues for the treatment of inherited and acquired ocular diseases, including dry or wet AMD.
−Removed: We believe that our hydrogel formulation technology may be uniquely suited to deliver a gene therapy safely, effectively and efficiently with a longer duration of effect.
−Removed: Companies actively pursuing gene therapy to address ocular diseases and conditions of the eye include Adverum Biotechnologies, GenSight, REGENXBIO, and Spark Therapeutics.
+Added: If the data from the ongoing trial of evaluating OTX-DED versus potential comparators is favorable, we intend to evaluate our strategic alternatives for advancing the development of OTX-CSI.
Commercial Portfolio
19 unchanged sentences
Over 25 of the trials have completed enrollment, and the remaining trials are actively enrolling and treated subjects are being followed.
+Added: To date, 19 of the trials have published study reports.
Post-Approval Studies
1 unchanged sentence
This clinical trial is a post-approval requirement of the FDA in accordance with the Pediatric Research Equity Act of 2003, in connection with the FDA’s prior approval of DEXTENZA for the treatment of inflammation and pain following ophthalmic surgery in adults.
−Removed: We intend to enroll approximately 60 subjects in this clinical trial.
−Removed: It is designed to evaluate the safety and biological activity of DEXTENZA compared to an active control, prednisolone acetate suspension eye drops, for the treatment of inflammation and pain following ocular surgery for pediatric cataract in children between zero and three years of age.
−Removed: The primary endpoint is the absence of pain at day eight post-treatment as measured by a FLACC (Face, Legs, Activity, Cry, Consolability) score of zero.
−Removed: Enrollment is ongoing.
−Removed: The FDA has agreed that this Phase 3 clinical trial evaluating DEXTENZA for the treatment of post-surgical ocular inflammation and pain in children following cataract surgery may also satisfy the post-approval requirement for a pediatric trial as it relates to indication ocular itching associated with allergic conjunctivitis.
+Added: We enrolled 65 subjects in this clinical trial.
+Added: It is designed to evaluate the safety of DEXTENZA compared to an active control, prednisolone acetate suspension eye drops, for the treatment of inflammation and pain following ocular surgery for pediatric cataract in children between zero and five years of age.
+Added: The FDA has agreed that this Phase 3 clinical trial evaluating DEXTENZA for the treatment of post-surgical ocular inflammation and pain in children following cataract surgery may also satisfy the post-approval requirement for a pediatric trial as it relates to the indication for ocular itching associated with allergic conjunctivitis.
+Added: All subjects have exited this trial and we are in the process of analyzing the final data.
+Added: We anticipate that we will submit the clinical study report and updated package insert to the FDA in the second quarter of 2024.
Foreign Approvals
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Given our prioritization of the clinical development of our sustained-release product candidates and our planned commercialization efforts for our initial intracanalicular insert product candidates in the United States, we will need to engage third parties to assist us in the approval process.
−Removed: We have entered into a license agreement and collaboration with AffaMed for the development and commercialization of DEXTENZA, along with OTX-TIC, in specified Asian markets.
+Added: We have entered into a license agreement and collaboration with AffaMed for the development and commercialization of DEXTENZA, along with PAXTRAVA in mainland China, Taiwan, Hong Kong, Macau, South Korea, and the countries of the Association of Southeast Asian Nations, or the AffaMed License Agreement .
In January 2022, AffaMed dosed its first subject in a study conducted in China evaluating the safety and efficacy of DEXTENZA for the treatment of ocular inflammation and pain post-cataract surgery.
−Removed: This prospective, single-arm, real-world trial is designed to assess the safety and efficacy of DEXTENZA for the treatment of ocular inflammation and pain following cataract surgery in approximately 120 patients at the Bo’ao Super Hospital.
−Removed: The trial’s primary efficacy endpoint is the absence of anterior chamber cells in the study eye at Day 14, and the key secondary endpoint is the absence of pain in the study eye at Day 8.
+Added: This prospective, single-arm, real-world trial is designed to assess the safety and efficacy of DEXTENZA for the treatment of ocular inflammation and pain following cataract surgery in approximately 120 subjects at the Bo’ao Super Hospital, or the Bo’ao Real World Study.
+Added: The Bo’ao Real World Study’s primary efficacy endpoint is the absence of anterior chamber cells in the study eye at Day 14, and the key secondary endpoint is the absence of pain in the study eye at Day 8.
+Added: In October 2023, AffaMed announced positive topline results from the Bo’ao Real World Study .
+Added: As announced by AffaMed, the trial met its primary endpoint, with DEXTENZA demonstrating a significant reduction of ocular inflammation as measured by the absence of anterior chamber cells (i.e.
+Added: score of "0") in the study eye on Day 14 after cataract surgery.
+Added: AffaMed also announced that the trial also met its secondary endpoint, demonstrating a significant reduction of ocular pain on Day 8, and that DEXTENZA was well-tolerated and had a favorable safety profile consistent with all prior trials.
+Added: In April 2023, AffaMed announced that China’s National Medical Products Administration, or NMPA, had approved AffaMed’s Clinical Trial Application to initiate a Phase 3 registrational study in China to investigate the efficacy and safety of DEXTENZA in subjects following ophthalmic surgery, or the Phase 3 Registrational Study.
+Added: In September 2023, AffaMed announced that the first subject had been treated in the Phase 3 Registrational Study.
+Added: In February 2024, AffaMed announced that the Singapore Health Sciences Authority has accepted AffaMed’s new drug application for DEXTENZA for the treatment of ocular inflammation and pain following ophthalmic surgery, and ocular itching associated with allergic conjunctivitis for evaluation.
In April 2022, AffaMed announced that DEXTENZA has been approved in Macau, China for the treatment of ocular inflammation and pain following ophthalmic surgery.
6 unchanged sentences
DEXTENZA (dexamethasone ophthalmic insert) for the Treatment of Ocular Itching Associated with Allergic Conjunctivitis
−Removed: In October 2021, the FDA approved our sNDA, for DEXTENZA to include the treatment of ocular itching associated with allergic conjunctivitis as an additional indication.
+Added: In October 2021, the FDA approved our supplemental New Drug Application, sNDA, for DEXTENZA to include the treatment of ocular itching associated with allergic conjunctivitis as an additional indication.
With the approval, DEXTENZA became the first, FDA-approved, physician-administered intracanalicular insert capable of delivering a preservative-free drug for the treatment of ocular itching associated with allergic conjunctivitis with a single administration for up to 30 days.
DEXTENZA for the treatment of ocular itching associated with allergic conjunctivitis also represents our first indication approved to be administered in a physician’s office during a routine, non-surgical appointment.
−Removed: Although dexamethasone is clinically effective in the treatment of late-phase inflammatory allergic reactions, the safety limitations associated with eye drop administration, including the potential to generate spikes in IOP due to the high levels of drug due to potential patient abuse to treat this symptomatic condition, have limited its widespread adoption.
+Added: Although dexamethasone is clinically effective in the treatment of late-phase inflammatory allergic reactions, the safety limitations associated with eye drop administration, including the potential to generate spikes in IOP due to the high levels of drug due to potential patient abuse to treat this symptomatic condition, have limited its widespread
These elevations in IOP can lead to drug-induced glaucoma, although the incidence is low.
−Removed: Further, use of oral
−Removed: antihistamine medications as well as anti-histamine eye drops for allergic conjunctivitis may dry out the eye and exacerbate the discomfort to some patients.
+Added: Further, use of oral antihistamine medications as well as anti-histamine eye drops for allergic conjunctivitis may dry out the eye and exacerbate the discomfort to some patients.
Based on our clinical trial results to date, we believe that using DEXTENZA for allergic conjunctivitis can create a low, tapered, consistent dose of dexamethasone, potentially minimizing or eliminating side effects associated with the eye drop formulation, while retaining the drug’s anti-inflammatory effects.
3 unchanged sentences
In the fourth quarter of 2022, we redeployed this small sales force to join the DEXTENZA sales force focused on the ophthalmic surgery market, specifically cataract surgery, in ambulatory surgery centers, or ASCs, and hospital outpatient departments, or HOPDs.
−Removed: We believe that cataract surgeries represent a larger, near-term market opportunity and a faster return-on-investment.
−Removed: Prevention of Wound Leaks Following Cataract Surgery
−Removed: ReSure Sealant
−Removed: ReSure Sealant is a topical liquid hydrogel that creates a temporary, adherent, soft and lubricious sealant to prevent post-surgical leakage from clear corneal incisions that are made during cataract surgery.
−Removed: The FDA granted marketing approval for ReSure Sealant in January 2014 and we commercially launched ReSure Sealant in the United States in February 2014.
−Removed: We have received only limited revenues from ReSure Sealant to date as the product is only used in a minority of cataract surgeries and, currently, there is no direct separate reimbursement for the product—meaning ReSure Sealant is only reimbursed as part of a bundled payment for the associated surgery.
−Removed: As of the fourth quarter of 2021, we suspended the production of ReSure Sealant in order to focus our manufacturing resources on the commercialization of DEXTENZA.
−Removed: Currently, ReSure Sealant is not commercially available in the United States.
+Added: We believe that cataract surgeries represent a larger, near-term market opportunity.
AffaMed License Agreement
−Removed: In October 2020, we entered into a license agreement and collaboration with AffaMed Therapeutics Limited, or AffaMed, for the development and commercialization of DEXTENZA and OTX-TIC in mainland China, Taiwan, Hong Kong, Macau, South Korea, and the countries of the Association of Southeast Asian Nations.
−Removed: Under the terms of the agreement, we received an upfront payment of $12 million and became eligible to receive development, regulatory and commercial milestone payments and clinical development support payments of up to $91 million in the aggregate, as well as royalties from future product sales.
+Added: Under the terms of the AffaMed License Agreement, we received an upfront payment of $12 million and became eligible to receive development, regulatory and commercial milestone payments and clinical development support payments of up to $91 million in the aggregate, as well as royalties from future product sales.
In the fourth quarter of 2021, we received a $1 million milestone payment upon the approval by the FDA of an sNDA for DEXTENZA to include the treatment of ocular itching associat ed with allergic conjunctivitis as an additional indication ;
−Removed: in the second quarter of 2022, we received a $2 million clinical support payment in connection with dosing the first subject in a Phase 2 clinical trial evaluating OTX-TIC for the treatment of open-angle glaucoma or ocular hypertension.
+Added: in the second quarter of 2022, we received a $2 million clinical support payment in connection with dosing the first subject in a Phase 2 clinical trial evaluating PAXTRAVA for the treatment of OAG or OHT;
+Added: and in the second quarter of 2023, we received a $1 million milestone payment upon the NMPA’s approval of AffaMed’s Phase 3 Registrational Study.
Royalties are tiered and will range from the low teens to low twenty percent range.
−Removed: In return, we agreed to grant AffaMed exclusive rights to develop and commercialize DEXTENZA for the treatment of post-surgical inflammation and pain following ophthalmic surgery and ocular itching in patients with allergic conjunctivitis, and OTX-TIC for the reduction of elevated IOP in patients with primary open-angle glaucoma or ocular hypertension in specified Asian markets.
−Removed: We retain the right to develop and commercialize DEXTENZA and OTX-TIC in all other global markets.
−Removed: In January 2022, AffaMed announced that it had dosed its first patient in a real-world setting study conducted in China evaluating the safety and efficacy of DEXTENZA ® (0.4mg dexamethasone ophthalmic insert) for the treatment of ocular inflammation and pain post-cataract surgery.
−Removed: This prospective, single-arm, real-world trial is designed to assess the safety and efficacy of DEXTENZA for the treatment of ocular inflammation and pain following cataract surgery in approximately 120 patients at the Bo’ao Super Hospital.
−Removed: The trial’s primary efficacy endpoint is the absence of anterior
−Removed: chamber cells in the study eye at Day 14, and the key secondary endpoint is the absence of pain in the study eye at Day 8.
−Removed: In April 2022, AffaMed announced that DEXTENZA has been approved in Macau, China for the treatment of ocular inflammation and pain following ophthalmic surgery.
−Removed: We do not expect that DEXTENZA sales in Macau will result in material revenues to us.
+Added: In return, we agreed to grant AffaMed exclusive rights to develop and commercialize DEXTENZA for the treatment of post-surgical inflammation and pain following ophthalmic surgery and ocular itching in patients with allergic conjunctivitis, and PAXTRAVA for the reduction of elevated IOP in patients with primary OAG or OHT in specified Asian markets.
+Added: We retain the right to develop and commercialize DEXTENZA and PAXTRAVA in all other global markets.
Sales, Marketing and Distribution
2 unchanged sentences
If we decide to commercialize our products outside of the United States, we expect to utilize a variety of types of collaboration, distribution and other marketing arrangements with one or more third parties to commercialize any product of ours that receives marketing approval.
−Removed: We sell DEXTENZA in the United States to a network of specialty distributors, who then resell DEXTENZA to ASCs and HOPDs.
+Added: We sell DEXTENZA in the United States primarily to a network of specialty distributors on a direct basis, who then resell DEXTENZA to ASCs, HOPDs, and physicians’ offices.
+Added: We also sell DEXTENZA on a direct basis to a small number of ASCs.
+Added: We intend to offer this distribution option more broadly to our end customers starting in the third quarter of 2024.
+Added: In addition to distribution agreements with specialty distributors and a small number of ASCs, we enter into arrangements with government payors that provide for government-mandated rebates and chargebacks with respect to the purchase of DEXTENZA.
We have built a highly targeted, key account sales force of KAMs, or key account managers, Regional Directors, and FRMs, or field reimbursement managers, that focus on the ASCs and their affiliates responsible for the largest volumes of cataract surgery in the United States, with an initial emphasis on the approximately two million cataract procedures performed annually under Medicare Part B.
−Removed: With the approval of DEXTENZA for the indication of ocular itching associated with allergic conjunctivitis, we launched a commercial effort in the first half of 2022 with four KAMs and two FRMs dedicated to selling DEXTENZA to the offices of ophthalmologists and optometrists, where the vast majority of prescriptions for allergies are written.
−Removed: As of the fourth quarter of 2022, we redeployed the office-focused personnel back to the ocular surgical market, calling on ASCs and HOPDs.
+Added: During 2022, we adjusted our discounting and rebate strategy to meet the demands of the market.
In the third quarter of 2022, we implemented an off-invoice discount program whereby providers receive the discounted price immediately upon purchase, rather than having to wait until the end of the quarter for a rebate payment.
+Added: We focus our sales efforts on sales to ASCs and strategic accounts that own and control multiple ASCs.
+Added: In the first quarter of 2023, we launched a Commercial Assurance Program to provide assistance with patients’ out-of-pocket costs, supporting the expansion of DEXTENZA for commercially insured patients not covered by government payors.
Manufacturing
11 unchanged sentences
This structure enables us to efficiently transfer research stage product concepts into manufacturing.
−Removed: We have designed our
−Removed: manufacturing facility and processes to provide flexibility for the manufacture of different product candidates.
+Added: We have designed our manufacturing facility and processes to provide flexibility for the manufacture of different product candidates.
We outsource sterilization services for our products.
4 unchanged sentences
We have issued patents and/or patent applications pending for all of our commercial products and product candidates, as well as trade secrets to protect proprietary manufacturing processes.
−Removed: As of March 1, 2023, patents and/or patent applications pending owned by us, are 95 pending applications:
−Removed: 5 pending provisional applications, 11 pending U.S.
−Removed: patent applications, 11 pending World Intellectual Property Organization applications and 68 foreign applications.
+Added: As of December 31, 2023, we owned or exclusively licensed in certain fields of use over 250 issued U.S.
+Added: patents, pending U.S.
+Added: patent applications, issued foreign patents and pending foreign patent applications.
Certain of our U.S.
−Removed: patents and applications, and foreign counterparts, are Company owned and other U.S.
−Removed: patents and applications, and foreign counterparts have been in-licensed from Incept.
+Added: patents and applications, and foreign counterparts, are owned by us and other U.S.
+Added: patents and applications, and their foreign counterparts have been in-licensed from Incept.
+Added: The existence of patent applications does not guarantee that a patent will issue, or that any patent that does issue will cover the product or product candidate.
+Added: Issued patents are subject to validity, enforceability and infringement challenges by third parties with uncertain chances of success.
+Added: The term of individual patents depends upon the legal term for patents in the countries in which they are granted.
+Added: In most countries, including the United States, the patent term is generally 20 years from the earliest claimed filing date of a non-provisional patent application in the applicable country.
+Added: In the United States, a patent’s term may, in certain cases, be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the United States Patent and Trademark Office in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over a commonly owned patent or a patent naming a common inventor and having an earlier expiration date.
+Added: The Drug Price Competition and Patent Term Restoration Act of 1984, or the Hatch-Waxman Act, permits a patent term extension of up to five years beyond the expiration date of a U.S.
+Added: patent for certain patents as partial compensation for the length of time the drug is under regulatory review while the patent is in force.
+Added: A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, only one patent applicable to each regulatory review period may be extended and only those claims covering the approved drug, a method for using it or a method for manufacturing it may be extended.
+Added: Similar provisions are available in the European Union and certain other foreign jurisdictions to extend the term of a patent that covers an approved drug.
+Added: In the future, if and when our product candidates receive approval by the FDA or foreign regulatory authorities, where applicable, we expect to apply for patent term extensions on certain issued patents covering those products, depending upon the length of the clinical trials for each drug and other factors.
+Added: The expiration dates referred to above are without regard to potential patent term extension or other market exclusivity that may be available to us.
+Added: We may rely, in some circumstances, on trade secrets to protect our technology.
+Added: However, trade secrets can be difficult to protect.
+Added: We seek to protect our proprietary technology and processes, in part, by confidentiality agreements with our employees, and certain consultants, scientific advisors and contractors.
+Added: We also seek to preserve the integrity and confidentiality of our data.
The following is a summary of patents and patent applications that cover our commercial products and potentially cover our product candidates:
−Removed: OTX-TKI (axitinib intravitreal implant) for Wet AMD, DME and RVO
−Removed: We own issued patents in the U.S.
−Removed: that cover this product candidate, with current expiration dates in 2041.
+Added: AXPAXLI (axitinib intravitreal implant) for Wet AMD, DME and RVO
+Added: We own issued patents in the United States and patents in certain foreign jurisdictions that cover this product candidate, with current expiration dates in 2041.
Additional U.S.
and foreign patent applications are pending.
−Removed: OTX-TIC (travoprost intracameral implant) for open-angle glaucoma or ocular hypertension
+Added: PAXTRAVA (travoprost intracameral implant) for OAG or OHT
We have licenses to pending U.S.
applications and certain foreign patent applications pending that potentially cover this product candidate that, if granted, are expected to expire in 2037.
−Removed: We own pending patent applications in the U.S., and certain foreign counterparts, with the potential to cover this product candidate that, if granted, are expected to expire in 2041.
−Removed: OTX-CSI (cyclosporine intracanalicular insert) for dry eye disease
−Removed: We have licenses to U.S.
−Removed: patents, and certain foreign counterparts, that cover this product candidate, with current expiration dates in 2030.
−Removed: We own issued patents and pending patent applications in the U.S.
−Removed: that cover this product candidate with current expiration dates in 2037 and in 2041, and corresponding foreign patent applications that, if granted, are expected to expire in 2041.
+Added: Certain foreign licensed patent applications have been issued and expire in 2037.
+Added: We own an issued patent in the United States and patents in certain foreign jurisdictions that cover this product candidate, with current expiration dates in 2041.
+Added: Additional owned U.S.
+Added: and foreign patent applications are pending.
OTX-DED (dexamethasone intracanalicular insert) for episodic dry eye disease
1 unchanged sentence
patents, and certain foreign counterparts, with current expiration dates in 2030.
−Removed: We own an issued patent that expires in 2037 that covers this product candidate and a pending patent application in the U.S., and certain foreign counterparts, with the potential to cover this product candidate that, if granted, are expected to expire in 2041.
+Added: We own an issued patent that expires in 2037 that covers this product candidate and a pending patent application in the United States, and certain foreign counterparts, with the potential to cover this product candidate that, if granted, are expected to expire in 2041.
+Added: OTX-CSI (cyclosporine intracanalicular insert) for dry eye disease
+Added: We have licenses to U.S.
+Added: patents, and certain foreign counterparts, that cover this product candidate, with current expiration dates in 2030.
+Added: We own issued patents and pending patent applications in the United States that cover this product candidate with current expiration dates in 2037 and in 2041, and corresponding foreign patent applications that, if granted, are expected to expire in 2041.
DEXTENZA (dexamethasone ophthalmic insert) 0.4 mg
7 unchanged sentences
We also own a U.S.
−Removed: patent that covers this product with a current expiration date in 2037 and a pending patent application in the U.S., and certain foreign counterparts, with the potential to cover this product candidate that, if granted, is expected to expire in 2041.
+Added: patent that covers this product with a current expiration date in 2037 and a pending patent application in the United States, and certain foreign counterparts, with the potential to cover this product candidate that, if granted, is expected to expire in 2041.
ReSure Sealant
3 unchanged sentences
patent is expected to expire in 2032 and relates to certain features of the ReSure Sealant package.
−Removed: The existence of patent applications does not guarantee that a patent will issue, or that any patent that does issue will cover the product or product candidate.
−Removed: Issued patents are subject to validity, enforceability and infringement challenges by third parties with uncertain chances of success.
−Removed: The term of individual patents depends upon the legal term for patents in the countries in which they are granted.
−Removed: In most countries, including the United States, the patent term is generally 20 years from the earliest claimed filing date of a non-provisional patent application in the applicable country.
−Removed: In the United States, a patent’s term may, in certain cases, be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the United States Patent and Trademark Office in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over a commonly owned patent or a patent naming a common inventor and having an earlier expiration date.
−Removed: The Drug Price Competition and Patent Term Restoration Act of 1984, or the Hatch-Waxman Act, permits a patent term extension of up to five years beyond the expiration date of a U.S.
−Removed: patent for certain patents as partial compensation for the length of time the drug is under regulatory review while the patent is in force.
−Removed: A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, only one patent applicable to each regulatory review period may be extended and only those claims covering the approved drug, a method for using it or a method for manufacturing it may be extended.
−Removed: Similar provisions are available in the European Union and certain other foreign jurisdictions to extend the term of a patent that covers an approved drug.
−Removed: In the future, if and when our product candidates receive approval by the FDA or foreign regulatory authorities, where applicable, we expect to apply for patent term extensions on issued patents covering those products, depending upon the length of the clinical trials for each drug and other factors.
−Removed: The expiration dates referred to above are without regard to potential patent term extension or other market exclusivity that may be available to us.
−Removed: We may rely, in some circumstances, on trade secrets to protect our technology.
−Removed: However, trade secrets can be difficult to protect.
−Removed: We seek to protect our proprietary technology and processes, in part, by confidentiality agreements with our employees, consultants, scientific advisors and contractors.
−Removed: We also seek to preserve the integrity and confidentiality of our data.
In January 2012, we entered into an amended and restated license agreement, which we refer to as either the Prior Agreement or Original License, with Incept under which we hold an exclusive, worldwide, perpetual, irrevocable license under specified patents and technology owned or controlled by Incept to make, have made, use, offer for sale, sell, sublicense, have sublicensed, offer for sublicense and import, products delivered to or around the human eye for diagnostic, therapeutic or prophylactic purposes relating to all human ophthalmic diseases or conditions.
9 unchanged sentences
We will solely own, without a license to Incept, all intellectual property rights conceived solely by one or more individuals from our company, or the Company Individuals, after the Effective Date, subject to exceptions specified therein.
−Removed: Subject to certain exceptions specified in the Second Amended Agreement, Incept will own and license to the us (i) all intellectual property rights included in the Original License, or the Original IP, in the Ophthalmic Field of Use and the Additional Field of Use, (ii) intellectual property rights in the field of drug delivery conceived solely by the Company Individuals on or before the Effective Date, or Incept IP, and (iii) intellectual property rights in the field of drug delivery conceived by one or more Company Individuals jointly with one or more individuals from Incept, including Dr.
+Added: Subject to certain exceptions specified in the Second Amended Agreement, Incept will own and license to the us (i) all intellectual property rights included in the Original License, or the Original IP, in the Ophthalmic Field of Use and the Additional Field of Use, (ii) intellectual property rights in the field of drug delivery conceived solely by the Company Individuals on or before the Effective Date, or Incept IP, and (iii) intellectual property rights in the field of
+Added: drug delivery conceived by one or more Company Individuals jointly with one or more individuals from Incept, including Dr.
Sawhney, or the Incept Individuals, after the Effective Date.
2 unchanged sentences
We and any of our sublicensees are obligated to pay Incept royalties as follows under the Second Amended Agreement:
−Removed: (i) consistent with the Prior Agreement, a royalty equal to a low single-digit percentage of net sales by the us or our affiliates of products, devices, materials, or components thereof, or Licensed Products, including or covered by Original IP, excluding the Shape-Changing IP, in the Ophthalmic Field of Use;
+Added: (i) consistent with the Prior Agreement, a royalty equal to a low single-digit percentage of net sales by us or our affiliates of products, devices, materials, or components thereof, or Licensed Products, including or covered by Original IP, excluding the Shape-Changing IP, in the Ophthalmic Field of Use;
(ii) a royalty equal to a mid-single-digit percentage of net sales by us or our affiliates of Licensed Products including or covered by Original IP, excluding the Shape-Changing IP, in the Additional Field of Use;
13 unchanged sentences
AffaMed License Agreement
−Removed: On October 29, 2020, we entered into a license agreement, or the License Agreement, with AffaMed for the development and commercialization of DEXTENZA regarding ocular inflammation and pain following cataract surgery and allergic conjunctivitis, or collectively, the DEXTENZA Field, and for OTX-TIC, or collectively with DEXTENZA, the AffaMed Licensed Products, regarding open-angle glaucoma and ocular hypertension, or collectively, the TIC Field and, with the DEXTENZA Field, each a Field, in each case in mainland China, Taiwan, Hong Kong, Macau, South Korea, and the countries of the Association of Southeast Asian Nations, or collectively, the Territories.
+Added: On October 29, 2020, we entered into the AffaMed License Agreement with AffaMed for the development and commercialization of DEXTENZA regarding ocular inflammation and pain following cataract surgery and allergic conjunctivitis, or collectively, the DEXTENZA Field, and for PAXTRAVA, or collectively with DEXTENZA, the AffaMed Licensed Products, regarding OAG and OHT, or collectively, the TIC Field and, with the DEXTENZA Field, each a Field, in each case in mainland China, Taiwan, Hong Kong, Macau, South Korea, and the countries of the Association of Southeast Asian Nations, or collectively, the Territories.
We retain development and commercialization rights for the AffaMed Licensed Products in the rest of the world.
−Removed: Under the License Agreement, we granted AffaMed (i) a non-exclusive, royalty-free, non-sublicensable license under certain of our intellectual property rights and know-how to use the AffaMed Licensed Products in connection with specified activities in accordance with a development plan agreed between the parties and (ii) an exclusive, royalty-bearing, sublicensable, non-transferable (subject to specified exceptions), license under certain of our intellectual property rights and know-how to commercialize the AffaMed Licensed Products in the applicable Field in the Territories.
−Removed: We have further agreed not to, and to cause its affiliates or agents not to, develop or commercialize in the Territories (i) the AffaMed Licensed Products outside of the applicable Fields and (ii) any other product containing the same active pharmaceutical ingredients as the AffaMed Licensed Products and administered into the anterior chamber of the eye, in each case without AffaMed’s prior written consent.
+Added: Under the AffaMed License Agreement, we granted AffaMed (i) a non-exclusive, royalty-free, non-sublicensable license under certain of our intellectual property rights and know-how to use the AffaMed Licensed Products in connection with specified activities in accordance with a development plan agreed between the parties and (ii) an exclusive, royalty-bearing, sublicensable, non-transferable (subject to specified exceptions), license under certain of our intellectual property rights and know-how to commercialize the AffaMed Licensed Products in the applicable Field in the Territories.
+Added: We have further agreed not to, and to cause its affiliates or agents not to, develop or commercialize in the Territories (i) the AffaMed Licensed Products outside of the applicable Fields and (ii) any other product containing
+Added: the same active pharmaceutical ingredients as the AffaMed Licensed Products and administered into the anterior chamber of the eye, in each case without AffaMed’s prior written consent.
AffaMed has agreed not to, and to cause its affiliates or agents not to, engage in the development, manufacture, or commercialization of any competing product in the Territories.
−Removed: Under the terms of the License Agreement, we received upfront payments totaling $12 million in the fourth quarter of 2020.
−Removed: We also became eligible to receive up to an additional $91 million in aggregate, inclusive of a low-seven-figure clinical support payment, upon the achievement of certain development and commercial milestones.
−Removed: In the fourth quarter of 2021, we received a $1 million milestone payment under the License Agreement from AffaMed;
−Removed: in the second quarter of 2022, we received a $2 million clinical support payment in connection with dosing the first subject in a Phase 2 clinical trial evaluating OTX-TIC for the treatment of open-angle glaucoma or ocular hypertension.
+Added: Under the terms of the AffaMed License Agreement, we received upfront payments and we also became eligible to receive additional payments upon the achievement of certain development and commercial milestones.
There can be no guarantee, however, that any of the remaining milestones will be achieved.
We are also entitled to receive tiered, escalating royalties on the net sales of the AffaMed Licensed Products ranging from a low-teen to low-twenties percentage.
−Removed: Royalties under the License Agreement are payable on an AffaMed Licensed Product-by-AffaMed Licensed Product and jurisdiction-by-jurisdiction basis and are subject to potential reductions in specified circumstances, subject to a specified floor.
−Removed: Pursuant to the terms of the License Agreement, we are generally responsible for expenses related to the development of the AffaMed Licensed Products in the applicable Fields in the Territories, provided that AffaMed (i) reimburse us a low-teen percentage of expenses incurred in connection with certain clinical trials conducted by us and designed to support marketing approval of the AffaMed Licensed Product by FDA or the European Medicines Agency, or the Global Studies;
+Added: Royalties under the AffaMed License Agreement are payable on an AffaMed Licensed Product-by-AffaMed Licensed Product and jurisdiction-by-jurisdiction basis and are subject to potential reductions in specified circumstances, subject to a specified floor.
+Added: Pursuant to the terms of the AffaMed License Agreement, we are generally responsible for expenses related to the development of the AffaMed Licensed Products in the applicable Fields in the Territories, provided that AffaMed (i) reimburse us a low-teen percentage of expenses incurred in connection with certain clinical trials conducted by us and designed to support marketing approval of the AffaMed Licensed Product by FDA or the European Medicines Agency, or the Global Studies;
(ii) is solely responsible for expenses incurred in connection with territory-specific clinical trials that it conducts in furtherance of the development plan agreed between the parties in the applicable Fields in the Territories, or the Local Studies;
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AffaMed is further obligated, at its sole cost and expense, to use commercially reasonable efforts to commercialize the AffaMed Licensed Products in the applicable Fields in the Territories.
−Removed: The License Agreement contemplates that the parties negotiate and enter into a future agreement requiring us to use commercially reasonable efforts to manufacture
−Removed: and supply finished drug products in sufficient quantity for clinical development and commercialization of the AffaMed Licensed Products in the applicable Fields in the Territories.
−Removed: In accordance with its terms, the License Agreement expires upon the expiration of the last royalty term for the last AffaMed Licensed Product in any applicable Field in the Territories.
−Removed: Either party may, subject to specified cure periods, terminate the License Agreement in the event of the other party’s uncured breach.
−Removed: Either party may also terminate the License Agreement under specified circumstances relating to the other party’s insolvency.
−Removed: During an established period following a change of control of us or our entry into a global licensing agreement that includes the Territories with a third party, we have the option to terminate the License Agreement, subject to a specified notice period and the repayment of any costs and expenses incurred by AffaMed in connection with the License Agreement, including upfront and milestone payments AffaMed has previously paid to us, at a prespecified premium.
−Removed: AffaMed has the right to terminate the License Agreement at any time following the completion of a Phase 3 clinical trial to evaluate OTX-TIC.
−Removed: Mosaic Biosciences Agreement
−Removed: In June 2021, we entered into an agreement with Mosaic to identify new targets and discover novel therapeutic agents aimed at the treatment of dry AMD.
−Removed: Our collaboration with Mosaic has yielded lead compounds that Mosaic has humanized and is now optimizing for our preclinical complement inhibitor program for the treatment of dry AMD.
−Removed: We own all intellectual property created under this agreement.
+Added: The AffaMed License Agreement contemplates that the parties negotiate and enter into a future agreement requiring us to use commercially reasonable efforts to manufacture and supply finished drug products in sufficient quantity for clinical development and commercialization of the AffaMed Licensed Products in the applicable Fields in the Territories.
+Added: In accordance with its terms, the AffaMed License Agreement expires upon the expiration of the last royalty term for the last AffaMed Licensed Product in any applicable Field in the Territories.
+Added: Either party may, subject to specified cure periods, terminate the AffaMed License Agreement in the event of the other party’s uncured breach.
+Added: Either party may also terminate the AffaMed License Agreement under specified circumstances relating to the other party’s insolvency.
+Added: During an established period following a change of control of us or our entry into a global licensing agreement that includes the Territories with a third party, we have the option to terminate the AffaMed License Agreement, subject to a specified notice period and the repayment of any costs and expenses incurred by AffaMed in connection with the AffaMed License Agreement, including upfront and milestone payments AffaMed has previously paid to us, at a prespecified premium.
+Added: AffaMed has the right to terminate the AffaMed License Agreement at any time following the completion of a Phase 3 clinical trial to evaluate PAXTRAVA.
The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products.
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Many of our potential competitors have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do.
−Removed: These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.
+Added: These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for,
+Added: our programs.
Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.
−Removed: The key competitive factors affecting the success of each of our product candidates, if approved for marketing, are likely to be efficacy, safety, method of administration, convenience, price, the level of generic competition and the availability of coverage and adequate reimbursement from government and other third-party payors.
+Added: The key competitive factors affecting the success of each of our product candidates, if approved for marketing, are likely to be efficacy, safety, method and frequency of administration, convenience, price, the level of generic competition and the availability of coverage and adequate reimbursement from government and other third-party payors.
Because the active pharmaceutical ingredients in our product candidates are available on a generic basis, or are soon to be available on a generic basis, competitors will be able to offer and sell products with the same active pharmaceutical ingredient as our products so long as these competitors do not infringe the patents that we license.
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As such, if a third party were able to design around the formulation and process patents that we license and create a different formulation using a different production process not covered by our licensed patents or patent applications, we would likely be unable to prevent that third party from manufacturing and marketing its product.
−Removed: Competitors of OTX-TKI
−Removed: Our intravitreal implant for the treatment of wet AMD will compete with anti-VEGF compounds administered in their current formulation and prescribed for the treatment of wet AMD as these agents can in some instances deliver one to two months or more of therapeutic effect.
−Removed: They include Lucentis, Eylea, Beovu, Vabysmo and off-label use of the cancer therapy Avastin.
−Removed: Multiple companies, although all in early stages of development, are exploring ways to deliver anti-VEGF products in a sustained-release fashion, including Regeneron which is pursuing a high-dose version of Eyelea;
−Removed: Clearside Biomedical, Inc., which is pursuing a TKI (axitinib) administered into the suprachoroidal space;
−Removed: Eyepoint Pharmaceuticals, Inc., which is pursuing a sustained-release bioerodible device containing a TKI (vorolanib) using its Durasert technology;
+Added: Competitors of AXPAXLI
+Added: Our intravitreal implant for the treatment of wet AMD will compete with anti-VEGF compounds administered in their current formulation and prescribed for the treatment of wet AMD as these agents can in some instances deliver three to four months or more of therapeutic effect.
+Added: They include Lucentis, Eylea and Eylea HD, Beovu, Vabysmo and off-label use of the cancer therapy Avastin.
+Added: Multiple companies, although all in early stages of development, are exploring ways to deliver anti-VEGF products in a sustained-release fashion, including Regeneron which received approval for its 8mg version of Eylea in August 2023;
+Added: Clearside Biomedical, which is pursuing a TKI (axitinib) administered into the suprachoroidal space;
+Added: Eyepoint Pharmaceuticals, which is pursuing a sustained-release bioerodible device containing a TKI (vorolanib) using its Durasert technology;
Aerie Pharmaceuticals, which is pursuing development of a four to six month TKI implant (axitinib) using its Print® manufacturing technology;
−Removed: and Kodiak Sciences Inc., which is pursuing sustained release therapies based on its anti-VEGF biopolymer conjugate technology.
+Added: and Kodiak Sciences, which is pursuing sustained release therapies based on its anti-VEGF biopolymer conjugate technology.
In October 2021, Genentech received approval for Susvimo which utilizes the company’s port delivery system for delivery of ranibizumab but has recently launched a voluntary recall of the product due to manufacturing issues.
−Removed: In addition, there are several companies pursuing gene therapy to treat retinal diseases including Adverum Biotechnologies, Inc.
−Removed: and REGENXBIO Inc.
−Removed: There also are a number of companies with products in development targeting the inhibition of the complement system to address retinal diseases, specifically geographic atrophy including Apellis Pharmaceuticals, IVERIC bio, Inc., Annexion Biosciences, Novartis (Gyroscope Therapeutics), Genentech/Ionis and Janssen Pharmaceuticals, among others.
−Removed: Apellis recently received approval of SYFOVRE as the first approved treatment for geographic atrophy.
−Removed: Competitors of OTX-TIC
−Removed: Allergan PLC, now owned by AbbVie, Inc., received approval in March 2020 of DURYSTA, a biodegradable bimatoprost intracameral implant consisting of a PGA and a biodegradable polymer matrix for the reduction of IOP in patients with open-angle glaucoma or ocular hypertension.
+Added: In addition, there are several companies pursuing gene therapy to treat retinal diseases including Adverum Biotechnologies, and REGENXBIO.
+Added: There also are a number of companies with products in development targeting the inhibition of the complement system to address retinal diseases, specifically geographic atrophy, or GA, including Apellis Pharmaceuticals, IVERIC bio, now owned by Astellas Pharma, Annexion Biosciences, Novartis (Gyroscope Therapeutics), Genentech/Ionis and Janssen Pharmaceuticals, among others.
+Added: Apellis received approval of SYFOVRE as the first approved treatment for GA in February 2023, and IVERIC bio’s Izervay was approved for the treatment of GA in August 2023.
+Added: Competitors of PAXTRAVA
+Added: Allergan, now owned by AbbVie, received approval in March 2020 of DURYSTA, a biodegradable bimatoprost intracameral implant consisting of a PGA and a biodegradable polymer matrix for the reduction of IOP in patients with OAG or OHT.
Allergan purchased ForSight VISION5 who was conducting a Phase 2 clinical trial with the Helios insert, a sustained-release ocular insert placed below the eyelid that delivers bimatoprost for the treatment of glaucoma.
−Removed: In February 2023, Glaukos, Inc.
−Removed: submitted an NDA for its iDose technology to deliver travoprost for the treatment of glaucoma.
+Added: In December 2023, Glaukos received approval for iDose, a prostaglandin analog indicated for the reduction of IOP in patients with OHT or OAG.
In addition, several other companies have announced their intention to develop products for treatment of glaucoma using sustained-release therapy, although each of these is at an early stage of development.
Mati Therapeutics has conducted a Phase 2 clinical trial with an intracanalicular insert for the treatment of glaucoma.
−Removed: Competitors of OTX-CSI and OTX-DED
+Added: Competitors of OTX-DED and OTX-CSI
A number of therapies are currently available for the treatment of dry eye disease in the United States.
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Restasis and Cequa, both calcineurin inhibitor immunosuppressants, and Xiidra, a LFA-1 antagonist, address chronic inflammation associated with dry eye disease.
−Removed: Kala Pharmaceuticals received approval in 2020 and launched EYSUVIS, (loteprednol etabonate ophthalmic suspension) 0.25% for the short term (up to two weeks) treatment of the signs and symptoms of dry eye disease.
+Added: Kala Pharmaceuticals
+Added: received approval in 2020 and launched EYSUVIS, (loteprednol etabonate ophthalmic suspension) 0.25% for the short term (up to two weeks) treatment of the signs and symptoms of dry eye disease.
EYSUVIS was sold to Alcon in July 2022.
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Eyepoint launched DEXYCU commercially in the first quarter of 2019.
+Added: DEXYCU lost separate government reimbursement as of January 1, 2023 and is no longer actively marketed.
OMIDRIA, purchased by Rayner Surgical Group Limited, is a prescription medication used during cataract surgery.
According to the OMIDRIA website, this product helps the black part in the center of your eye (pupil) stay open (dilated) during cataract surgery and decreases eye pain after surgery.
−Removed: Competitors of ReSure Sealant
−Removed: ReSure Sealant is the first and only surgical sealant approved for ophthalmic use in the United States.
−Removed: Outside the United States, Beaver Visitec is commercializing its product OcuSeal, which is designed to provide a protective hydrogel film barrier to stabilize ocular wounds.
−Removed: This product has received a CE Mark in Europe but is not approved for
−Removed: use in the United States.
−Removed: Sutures are the primary alternative device for closing ophthalmic wounds.
−Removed: Most commonly, however, a technique called stromal hydration, which involves the localized injection of a balanced salt solution at the wound edges, is often used to facilitate the sealing of a wound.
Government Regulation
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● approval by an independent institutional review board, or IRB, representing each clinical site before each clinical trial may be initiated;
−Removed: ● performance of adequate and well-controlled human clinical trials in accordance with Good Clinical Practices, or GCP, to establish the safety and efficacy of the proposed drug product for each indication;
−Removed: ● preparation and submission to the FDA of a new drug application, or NDA, for a drug candidate product and a biological licensing application, or BLA, for a biological product requesting marketing for one or more proposed indications;
+Added: ● performance of adequate and well-controlled human clinical trials in accordance with GCPs, to establish the safety and efficacy of the proposed drug product for each indication;
+Added: ● preparation and submission to the FDA of a new drug application, or NDA, demonstrating the safety and efficacy for the drug candidate product or, with respect to biologics, a biological licensing application, or
+Added: BLA, demonstrating the safety, purity and potency of the proposed biological product for one or more proposed indications;
● review by an FDA advisory committee, where appropriate or if applicable;
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The FDA requires a 30-day waiting period after the filing of each IND before clinical trials may begin.
−Removed: This waiting period is designed to allow the FDA to review the IND to determine whether human research subjects will be exposed to unreasonable health risks.
+Added: This waiting period is designed to allow the FDA to review the IND to assure the safety and rights of patients and to help assure that the quality of the investigation will be adequate to permit an evaluation of the drug’s effectiveness and safety
+Added: and of the biological product’s safety, purity and potency .
At any time during this 30-day period, or thereafter, the FDA may raise concerns or questions about the conduct of the trials as outlined in the IND and impose a clinical hold or partial clinical hold.
In this case, the IND sponsor and the FDA must resolve any outstanding concerns before clinical trials can begin.
−Removed: For our intracanalicular insert product candidates, we have typically conducted our initial and earlier-stage clinical trials outside the United States.
−Removed: We generally plan to conduct our later stage and pivotal clinical trials of our intracanalicular insert product candidates in the United States.
−Removed: A sponsor may choose, but is not required, to conduct a foreign clinical trial under an IND.
−Removed: When a foreign clinical trial is conducted under an IND, all FDA IND requirements must be met unless waived.
−Removed: When a foreign clinical trial is not conducted under an IND, the sponsor must ensure that the trial complies with certain regulatory requirements of the FDA in order to use the trial as support for an IND or application for marketing approval.
−Removed: Specifically, the FDA requires such trials to be conducted in accordance with GCP, including review and approval by an independent ethics committee and informed consent from subjects.
−Removed: The GCP requirements encompass both ethical and data integrity standards for clinical trials.
−Removed: The FDA’s regulations are intended to help ensure the protection of human subjects enrolled in non-IND foreign clinical trials, as well as the quality and integrity of the resulting data.
−Removed: They further help ensure that non-IND foreign trials are conducted in a manner comparable to that required for IND trials.
In addition to the foregoing IND requirements, an IRB representing each institution participating in the clinical trial must review and approve the plan for any clinical trial before it commences at that institution, and the IRB must conduct continuing review and reapprove the study at least annually.
−Removed: The IRB must review and approve, among other
−Removed: things, the study protocol and informed consent information to be provided to study subjects.
+Added: The IRB must review and approve, among other things, the study protocol and informed consent information to be provided to study subjects.
An IRB must operate in compliance with FDA regulations.
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Suspension or termination of development during any phase of clinical trials can occur if it is determined that the participants or patients are being exposed to an unacceptable health risk.
−Removed: Other reasons for suspension or termination may be made by us based on evolving business objectives and/or competitive climate.
Reporting Clinical Trial Results
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The NIH’s Final Rule on registration and reporting requirements for clinical trials became effective in 2017.
−Removed: Although the FDA has historically not enforced these reporting requirements due to the Department of Health and Human Services (HHS) long delay in issuing final implementing regulations, the FDA has issued several Notices of Noncompliance to manufacturers since April 2021.
Expanded Access to an Investigational Drug for Treatment Use
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There is no obligation for a sponsor to make its investigational products available for expanded access;
−Removed: however, as required by amendments to the FDCA included in the 21st Century Cures Act, or the Cures Act, passed in 2016, if a sponsor has a policy regarding how it responds to expanded access requests with respect to product candidates in development to treat serious diseases or conditions, it must make that policy publicly available.
+Added: however, as required by amendments to the FDCA included in the 21st Century Cures Act, or the Cures Act, passed in 2016, if a sponsor has a policy regarding how it responds to expanded access requests with respect to product candidates in
+Added: development to treat serious diseases or conditions, it must make that policy publicly available.
Sponsors are required to make such policies publicly available upon the earlier of initiation of a Phase 2 or Phase 3 study for a covered investigational product;
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The drug or biologic is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to statistically evaluate the efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product, and to provide adequate information for the labeling of the product.
+Added: In some cases, the FDA may approve an NDA or BLA for a product candidate but require the sponsor to conduct additional clinical trials to further assess the product candidate’s safety and effectiveness after approval.
+Added: Such post-approval trials, typically referred to as Phase 4 clinical trials, may be conducted after initial marketing approval.
+Added: These trials are used to gain additional experience from the treatment of a larger number of patients in the intended treatment group.
+Added: In certain instances, the FDA may mandate the performance of Phase 4 clinical trials, such as to verify clinical benefit in the case of products approved under accelerated approval regulations.
+Added: Failure to exhibit due diligence with regard to conducting mandatory Phase 4 clinical trials could result in withdrawal of FDA approval for products.
A clinical trial may combine the elements of more than one phase, and the FDA often requires more than one Phase 3 trial to support marketing approval of a product candidate.
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In addition to these requirements, the legislation directs the FDA to issue new guidance on diversity action plans.
−Removed: In some cases, the FDA may approve an NDA or BLA for a product candidate but require the sponsor to conduct additional clinical trials to further assess the product candidate’s safety and effectiveness after approval.
−Removed: Such post-approval trials, typically referred to as Phase 4 clinical trials, may be conducted after initial marketing approval.
−Removed: These trials are used to gain additional experience from the treatment of a larger number of patients in the intended treatment group.
−Removed: In certain instances, the FDA may mandate the performance of Phase 4 clinical trials, such as to verify clinical
−Removed: benefit in the case of products approved under accelerated approval regulations.
−Removed: Failure to exhibit due diligence with regard to conducting mandatory Phase 4 clinical trials could result in withdrawal of FDA approval for products.
−Removed: In response to the COVID-19 pandemic, FDA issued guidance on March 18, 2020, and has updated it periodically since that time to address the conduct of clinical trials during the pandemic.
−Removed: The guidance sets out a number of considerations for sponsors of clinical trials impacted by the pandemic, including the requirement to include in the clinical study report (or as a separate document) contingency measures implemented to manage the study, and any disruption of the study as a result of COVID-19;
−Removed: a list of all study participants affected by COVID-19-related study disruptions by a unique subject identifier and by investigational site, and a description of how the individual’s participation was altered;
−Removed: and analyses and corresponding discussions that address the impact of implemented contingency measures (e.g., participant discontinuation from investigational product and/or study, alternative procedures used to collect critical safety and/or efficacy data) on the safety and efficacy results reported for the study, among other things.
−Removed: On January 30, 2023, the Biden Administration announced that it will end the public health emergency declarations related to COVID-19 on May 11, 2023.
−Removed: On January 31, 2023, the FDA indicated that it would soon issue a Federal Register notice describing how the termination of the public health emergency will impact the agency’s COVID-19 related guidance’s, including the clinical trial guidance and updates thereto.
−Removed: At this point, it is unclear how, if at all, these developments will impact our efforts to develop and commercialize our product candidates.
+Added: In June 2023, the FDA issued draft guidance with updated recommendations for GCPs aimed at modernizing the design and conduct of clinical trials.
+Added: The updates are intended to help pave the way for more efficient clinical trials to facilitate the development of medical products.
+Added: The draft guidance is adopted from the International Council for Harmonisation’s recently updated E6(R3) draft guideline that was developed to enable the incorporation of rapidly developing technological and methodological innovations into the clinical trial enterprise.
+Added: In addition, the FDA issued draft guidance outlining recommendations for the implementation of decentralized clinical trials.
+Added: Clinical Trials Outside the United States in Support of FDA Approval
+Added: We generally plan to conduct our later stage and pivotal clinical trials of our product candidates in the United States.
+Added: Nonetheless, in connection with our clinical development program, we may have trial sites outside the United States.
+Added: When a foreign clinical trial is conducted under an IND, all IND requirements must be met unless waived.
+Added: When a foreign clinical trial is not conducted under an IND, the sponsor must ensure that the trial complies with certain regulatory requirements of the FDA in order to use the trial as support for an IND or application for marketing approval.
+Added: Specifically, the trials must be conducted in accordance with GCP, including undergoing review and receiving approval by an independent ethics committee, or IEC, and seeking and receiving informed consent from subjects.
+Added: GCP requirements encompass both ethical and data integrity standards for clinical studies.
+Added: The FDA’s regulations are intended to help ensure the protection of human subjects enrolled in non-IND foreign clinical trials, as well as the quality and integrity of the resulting data.
+Added: They further help ensure that non-IND foreign trials are conducted in a manner comparable to that required for IND trials.
+Added: The acceptance by the FDA of trial data from clinical trials conducted outside the United States in support of US approval may be subject to certain conditions or may not be accepted at all.
+Added: In cases where data from foreign clinical trials are intended to serve as the sole basis for marketing approval in the United States, the FDA will generally not approve the application on the basis of foreign data alone unless (i) the data are applicable to the U.S.
+Added: population and U.S.
+Added: medical practice;
+Added: (ii) the trials were performed by clinical investigators of recognized competence and pursuant to GCP regulations;
+Added: and (iii) the data may be considered valid without the need for an on-site inspection by the FDA, or if the FDA considers such inspection to be necessary, the FDA is able to validate the data through an on-site inspection or other appropriate means.
+Added: In addition, even where the foreign trial data are not intended to serve as the sole basis for approval, the FDA will not accept the data as support for an application for marketing approval unless the trial is well-designed and well-conducted in accordance with GCP requirements and the FDA is able to validate the data from the trial through an onsite inspection if deemed necessary.
+Added: Many foreign regulatory authorities have similar approval requirements.
+Added: In addition, such foreign trials are subject to the applicable local laws of the foreign jurisdictions where the trials are conducted.
Interactions with FDA During the Clinical Development Program
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In addition, sponsors are given opportunities to meet with the FDA at certain points in the clinical development program.
−Removed: Specifically, sponsors may meet with the FDA prior to the submission of an IND (pre-IND meeting), at the end of Phase 2 clinical trial (EOP2 meeting) and before an NDA or BLA is submitted (pre-NDA or pre-BLA meeting).
+Added: Specifically, sponsors may meet with the FDA prior to the submission of an IND (pre-IND meeting), at the
+Added: end of Phase 2 clinical trial (EOP2 meeting) and before an NDA or BLA is submitted (pre-NDA or pre-BLA meeting).
Meetings at other times may also be requested.
−Removed: There are four types of meetings that occur between sponsors and the FDA.
+Added: There are five types of meetings that occur between sponsors and the FDA.
Type A meetings are those that are necessary for an otherwise stalled product development program to proceed or to address an important safety issue.
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A Type C meeting is any meeting other than a Type A or Type B meeting regarding the development and review of a product, including for example meetings to facilitate early consultations on the use of a biomarker as a new surrogate endpoint that has never been previously used as the primary basis for product approval in the proposed context of use.
−Removed: Finally, a Type D meeting is focused on a narrow set of issues, which should be limited to no more than two focused topics, and should not require input from more than three disciplines or Divisions.
+Added: A Type D meeting is focused on a narrow set of issues, which should be limited to no more than two focused topics and should not require input from more than three disciplines or Divisions.
+Added: Finally, INTERACT meetings are intended for novel products and development programs that present unique challenges in the early development of an investigational product.
These meetings provide an opportunity for the sponsor to share information about the data gathered to date with the FDA and for the FDA to provide advice on the next phase of development.
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The FDA has indicated that its responses, as conveyed in meeting minutes and advice letters, only constitute mere recommendations and/or advice made to a sponsor and, as such, sponsors are not bound by such recommendations and/or advice.
−Removed: Nonetheless, from a practical perspective, a sponsor’s failure to follow the FDA’s recommendations for design of a clinical program may put the program at significant risk of failure.
+Added: From a practical perspective, a sponsor’s failure to follow the FDA’s recommendations for design of a clinical program may put the program at significant risk of failure.
+Added: Special Protocol Assessment Agreements
+Added: A Special Protocol Assessment, or SPA, agreement is an agreement between a sponsor and the FDA on the design and size of studies and clinical trials that can be used for approval of a drug or biological product.
+Added: The FDA’s guidance on such agreements states that an agreement may not be changed by the sponsor or the agency unless through a written agreement of the two entities or if FDA determines there is a substantial scientific issue essential to determining the safety or effectiveness of the drug or the safety, potency or purity of the biologic product.
+Added: The protocols that are eligible for SPA agreements are:
+Added: animal carcinogenicity protocols, final product stability protocols and clinical protocols for Phase 3 trials where the data will form the primary basis for an efficacy claim.
+Added: The FDA may meet with sponsors, provided certain conditions are met, for the purpose of reaching an SPA agreement on the design and size of clinical trials intended to form the primary basis of an efficacy claim in a marketing application.
+Added: If a sponsor makes a reasonable written request to meet with the FDA for the purpose of reaching agreement on the design and size of a clinical trial, then the FDA will meet with the sponsor.
+Added: If an agreement is reached, the FDA will reduce the agreement to writing and make it part of the administrative record.
+Added: An agreement may not be changed by the sponsor or FDA after the trial begins, except with the written agreement of the sponsor and FDA, or if the director of the FDA reviewing division determines that “a substantial scientific issue essential to determining the safety or effectiveness of the investigational product was identified after the testing began.
+Added: If a sponsor and the FDA meet regarding the design and size of a clinical trial and the parties cannot agree that the trial design is adequate to meet the goals of the sponsor, the FDA will clearly state the reasons for the disagreement in a letter to the sponsor.
Manufacturing and Other Regulatory Requirements
Concurrently with clinical trials, sponsors usually complete additional animal safety studies, develop additional information about the chemistry and physical characteristics of the product candidate and finalize a process for manufacturing commercial quantities of the product candidate in accordance with cGMP requirements.
−Removed: manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other criteria, the sponsor must develop methods for testing the identity, strength, quality, and purity of the finished product.
+Added: The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other criteria, the sponsor must develop methods for testing the identity, strength, quality, and purity of the finished product.
Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.
Specifically, the FDA’s regulations require that pharmaceutical products be manufactured in specific approved facilities and in accordance with cGMPs.
−Removed: The cGMP regulations include requirements relating to organization of personnel, buildings and facilities, equipment, control of components and product containers and closures, production and process controls, packaging and labeling controls, holding and distribution, laboratory controls, records and reports and returned or salvaged products.
+Added: The cGMP regulations include requirements relating to organization of personnel, buildings and facilities, equipment, control of components and product containers and closures, production and process controls, packaging and labeling controls, holding and distribution, laboratory controls, records and reports
+Added: and returned or salvaged products.
Manufacturers and other entities involved in the manufacture and distribution of approved pharmaceuticals are required to register their establishments with the FDA and some state agencies, and they are subject to periodic unannounced inspections by the FDA for compliance with cGMPs and other requirements.
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The FDA also maintains a list of diseases that are exempt from PREA requirements due to low prevalence of disease in the pediatric population.
+Added: In May 2023, the FDA issued new draft guidance that further describes the pediatric study requirements under PREA.
Section 505(b)(2) NDAs
14 unchanged sentences
To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of a drug product and the safety, potency and purity of the biological product to the satisfaction of the FDA.
−Removed: The fee required for the submission and review of an application under the Prescription Drug User Fee Act, or PDUFA, is substantial (for example, for FY2023 this application fee is approximately $3.25 million), and the sponsor of an approved application is also subject to an annual program fee, currently more than $394,000 per eligible prescription product.
+Added: The fee required for the submission and review of an application under the Prescription Drug User Fee Act, or PDUFA, is substantial (for example, for FY2024 this application fee is approximately $4.0 million), and the sponsor of an approved application is also subject to an annual program fee, which for FY2024 is currently set at $416,734 per eligible prescription product.
These fees are typically adjusted annually, and exemptions and waivers may be available under certain circumstances, such as where a waiver is necessary to protect the public health, where the fee would present a significant barrier to innovation, or where the sponsor is a small business submitting its first human therapeutic application for review.
10 unchanged sentences
The FDA reviews the application to determine, among other things, whether the proposed product is safe and effective for its intended use, whether it has an acceptable purity profile and whether the product is being manufactured in accordance with cGMP.
−Removed: Under the goals and policies agreed to by the FDA under PDUFA, the FDA has ten months from the filing date in which to complete its initial review of a standard application that is a new molecular entity, and six months from
−Removed: the filing date for an application with “priority review.” The review process may be extended by the FDA for three additional months to consider new information or in the case of a clarification provided by the sponsor to address an outstanding deficiency identified by the FDA following the original submission.
+Added: Under the goals and policies agreed to by the FDA under PDUFA, the FDA has ten months from the filing date in which to complete its initial review of a standard application that is a new molecular entity, and six months from the filing date for an application with “priority review.” The review process may be extended by the FDA for three additional months to consider new information or in the case of a clarification provided by the sponsor to address an outstanding deficiency identified by the FDA following the original submission.
Despite these review goals, it is not uncommon for FDA review of an application to extend beyond the PDUFA target action date.
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This approach was subsequently endorsed by Congress in 1998 with legislation providing, in pertinent part, that “If FDA determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness, FDA may consider such data and evidence to constitute substantial evidence.” This modification to the law recognized the potential for FDA to find that one adequate and well controlled clinical investigation with confirmatory evidence, including supportive data outside of a controlled trial, is sufficient to establish effectiveness.
−Removed: In December 2019, FDA issued draft guidance further
−Removed: explaining the studies that are needed to establish substantial evidence of effectiveness.
−Removed: It has not yet finalized that guidance.
+Added: In December 2019, FDA issued draft guidance further explaining the studies that are needed to establish substantial evidence of effectiveness.
+Added: The FDA has not yet finalized that guidance.
After evaluating the application and all related information, including the advisory committee recommendations, if any, and inspection reports of manufacturing facilities and clinical trial sites, the FDA will issue either a CRL or an approval letter.
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and whether risk management tools are necessary to manage specific risks.
−Removed: In connection with this assessment, the FDA review team will assemble all individual reviews and other documents into an “action package,” which becomes the record for FDA review.
+Added: connection with this assessment, the FDA review team will assemble all individual reviews and other documents into an “action package,” which becomes the record for FDA review.
The review team then issues a recommendation, and a senior FDA official makes a decision.
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The FDA has limited experience with accelerated approvals based on intermediate clinical endpoints, but has indicated that such endpoints generally may support accelerated approval where the therapeutic effect measured by the endpoint is not itself a clinical benefit and basis for traditional approval, if there is a basis for concluding that the therapeutic effect is reasonably likely to predict the ultimate clinical benefit of a drug.
−Removed: The accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended period of time is required to measure the intended clinical benefit of a drug, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly.
+Added: The accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended period of time is required to measure the intended clinical benefit of a drug, even if the effect on the surrogate
+Added: or intermediate clinical endpoint occurs rapidly.
The accelerated approval pathway is usually contingent on a sponsor’s agreement to conduct, in a diligent manner, additional post-approval confirmatory studies to verify and describe the drug’s clinical benefit.
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Further, FDORA requires the FDA to publish on its website “the rationale for why a post-approval study is not appropriate or necessary” whenever it decides not to require such a study upon granting accelerated approval.
+Added: In March 2023, the FDA issued draft guidance that outlines its current thinking and approach to accelerated approval.
+Added: The guidance provides that although single-arm trials have been commonly used to support accelerated approval, a randomized controlled trial is the preferred approach as it provides a more robust efficacy and safety assessment and allows for direct comparisons to an available therapy.
+Added: While this guidance is currently only in draft form and will ultimately not be legally binding even when finalized, sponsors typically observe FDA’s guidance closely to ensure that their investigational products qualify for accelerated approval.
Post-Approval Regulation
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imposition of post-market studies or clinical trials to assess new safety risks;
−Removed: or imposition of distribution or other restrictions under a REMS program.
+Added: imposition of distribution or other restrictions under a REMS program.
Other potential consequences include, among other things:
12 unchanged sentences
Previously, such communications were permitted under FDA guidance but the new legislation explicitly provides protection to sponsors who convey certain information about products and product candidates in development to payors, including unapproved uses of approved products.
+Added: In addition, in October 2023, the FDA published draft guidance outlining the agency’s non-binding policies governing the distribution of scientific information on unapproved uses to healthcare providers.
+Added: This draft guidance calls for such communications to be truthful, non-misleading, factual, and unbiased and include all information necessary for healthcare providers to interpret the strengths and weaknesses and validity and utility of the information about the unapproved use.
In addition, the distribution of prescription pharmaceutical products is subject to a variety of federal and state laws, the most recent of which is still in the process of being phased into the U.S.
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If the ANDA sponsor has provided a Paragraph IV certification to the FDA, the sponsor must also send notice of the Paragraph IV certification to the NDA owner and patent holders once the ANDA has been accepted for filing by the FDA.
−Removed: The NDA owner and patent holders
−Removed: may then initiate a patent infringement lawsuit in response to the notice of the Paragraph IV certification.
−Removed: The filing of a patent infringement lawsuit within 45 days after the receipt of a Paragraph IV certification automatically prevents the FDA from approving the ANDA or 505(b)(2) NDA until the earliest of 30 months after the receipt of the Paragraph IV notice, expiration of the patent and a decision in the infringement case that is favorable to the ANDA or 505(b)(2) NDA sponsor.
+Added: The NDA owner and patent holders may then initiate a patent infringement lawsuit in response to the notice of the Paragraph IV certification.
+Added: The filing of a patent infringement lawsuit within 45 days after the receipt of a Paragraph IV certification automatically prevents the
+Added: FDA from approving the ANDA or 505(b)(2) NDA until the earliest of 30 months after the receipt of the Paragraph IV notice, expiration of the patent and a decision in the infringement case that is favorable to the ANDA or 505(b)(2) NDA sponsor.
Regulatory Exclusivity Governing Biologics
2 unchanged sentences
The BPCIA amended the PHSA to create an abbreviated approval pathway for biological products that are biosimilar to or interchangeable with an FDA-licensed reference biological product.
−Removed: To date, the FDA has approved a number of biosimilars and the first interchangeable biosimilar product was approved on July 30, 2021 and a second product previously approved as a biosimilar was designated as interchangeable in October 2021.
−Removed: The FDA has also issued numerous guidance documents outlining its approach to reviewing and licensing biosimilars and interchangeable biosimilars under the PHSA, including a draft guidance issued in November 2020 that seeks to provide additional clarity to manufacturers of interchangeable biosimilars.
+Added: Since enactment of this statute, the FDA has approved a number of biosimilars and interchangeable biosimilar products.
Under the BPCIA, a manufacturer may submit an application for a product that is “biosimilar to” a previously approved biological product, which the statute refers to as a “reference product.” In order for the FDA to approve a biosimilar product, it must find that there are no clinically meaningful differences between the reference product and the proposed biosimilar product in terms of safety, purity and potency.
12 unchanged sentences
For drug products, the six-month exclusivity may be attached to the term of any existing patent or regulatory exclusivity, including the orphan exclusivity and regulatory exclusivities available under the Hatch-Waxman Act.
−Removed: For biologic products, the six month period may be attached to any existing
−Removed: regulatory exclusivities but not to any patent terms.
+Added: For biologic products, the six-month period may be attached to any existing regulatory exclusivities but not to any patent terms.
The conditions for pediatric exclusivity include the FDA’s determination that information relating to the use of a new product in the pediatric population may produce health benefits in that population, the FDA making a written request for pediatric clinical trials, and the sponsor agreeing to perform, and reporting on, the requested clinical trials within the statutory timeframe.
1 unchanged sentence
The data do not need to show the product to be effective in the pediatric population studied;
−Removed: rather, if the clinical trial is deemed to fairly respond to the FDA’s request, the additional protection is granted.
+Added: rather, if the clinical trial is
+Added: deemed to fairly respond to the FDA’s request, the additional protection is granted.
If reports of requested pediatric studies are submitted to and accepted by the FDA within the statutory time limits, whatever statutory or regulatory periods of exclusivity or patents that cover the product are extended by six months.
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however, some Class I devices require premarket clearance by the FDA through the 510(k) premarket notification process.
−Removed: Class II devices are moderate-risk devices and are subject to the FDA’s general controls, and any other special controls, such as performance standards, post-market surveillance, and FDA guidelines, deemed necessary by the FDA
−Removed: to provide reasonable assurance of the devices’ safety and effectiveness.
+Added: Class II devices are moderate-risk devices and are subject to the FDA’s general controls, and any other special controls, such as performance standards, post-market surveillance, and FDA guidelines, deemed necessary by the FDA to provide reasonable assurance of the devices’ safety and effectiveness.
Premarket review and clearance by the FDA for Class II devices are accomplished through the 510(k) premarket notification procedure, although some Class II devices are exempt from the 510(k) requirements.
24 unchanged sentences
The FDA requires every manufacturer to make the determination regarding the need for a new 510(k) submission in the first instance, but the FDA may review any manufacturer’s decision.
−Removed: If the FDA disagrees with the manufacturer’s determination and requires new 510(k) clearances or PMA application approvals for modifications to previously cleared
−Removed: products for which the manufacturer concluded that new clearances or approvals are unnecessary, the manufacturer may be required to cease marketing or distribution of the products or to recall the modified product until it obtains clearance or approval, and the manufacturer may be subject to significant regulatory fines or penalties.
+Added: If the FDA disagrees with the manufacturer’s determination and requires new 510(k) clearances or PMA application approvals for modifications to previously cleared products for which the manufacturer concluded that new clearances or approvals are unnecessary, the manufacturer may be required to cease marketing or distribution of the products or to recall the modified product until it obtains clearance or approval, and the manufacturer may be subject to significant regulatory fines or penalties.
In addition, the FDA is currently evaluating the 510(k) process and may make substantial changes to industry requirements.
32 unchanged sentences
An IDE application must be supported by appropriate data, such as animal and laboratory testing results, showing that it is safe to test the device in humans and that the testing protocol is scientifically sound.
−Removed: An IDE application is
−Removed: considered approved 30 days after it has been received by the FDA, unless the FDA otherwise informs the sponsor prior to 30 calendar days from the date of receipt, that the IDE is approved, approved with conditions, or disapproved.
+Added: An IDE application is considered approved 30 days after it has been received by the FDA, unless the FDA otherwise informs the sponsor prior to 30 calendar days from the date of receipt, that the IDE is approved, approved with conditions, or disapproved.
The FDA typically grants IDE approval for a specified number of subjects to be enrolled at specified study centers.
The clinical trial must be conducted in accordance with applicable regulations, including but not limited to the FDA’s IDE regulations and GCP.
−Removed: The investigators must obtain subject informed consent, rigorously follow the investigational plan and study protocol, control the disposition of investigational devices, and comply with all reporting and record keeping requirements.
+Added: The investigators must obtain subject informed consent, rigorously follow the investigational plan
+Added: and study protocol, control the disposition of investigational devices, and comply with all reporting and record keeping requirements.
A clinical trial may be suspended or terminated by the FDA, the IRB or the sponsor at any time for various reasons, including a belief that the risks to the study participants outweigh the benefits of participation in the trial.
47 unchanged sentences
HIPAA also imposes certain obligations on the business associates of covered entities that obtain protected health information in providing services to or on behalf of covered entities.
−Removed: HIPAA may apply to us in certain
−Removed: circumstances and may also apply to our business partners in ways that may impact our relationships with them.
+Added: HIPAA may apply to us in certain circumstances and may also apply to our business partners in ways that may impact our relationships with them.
Our clinical trials are regulated by the Common Rule, which also includes specific privacy-related provisions.
1 unchanged sentence
In addition to possible federal civil and criminal penalties for HIPAA violations, state attorneys general are authorized to file civil actions for damages or injunctions in federal courts to enforce HIPAA and seek attorney’s fees and costs associated with pursuing federal civil actions.
−Removed: In addition, state attorneys general (along with private plaintiffs) have brought civil actions seeking injunctions and damages resulting from alleged violations of HIPAA’s privacy and security rules.
+Added: In addition, state attorneys general
+Added: (along with private plaintiffs) have brought civil actions seeking injunctions and damages resulting from alleged violations of HIPAA’s privacy and security rules.
State attorneys general also have authority to enforce state privacy and security laws.
6 unchanged sentences
The provisions in the CPRA may apply to some of our business activities.
−Removed: In addition, other states, including Virginia, Colorado, Utah, and Connecticut, already have passed state privacy laws.
−Removed: Virginia’s privacy law also went into effect on January 1, 2023, and the laws in the other three states will go into effect later in the year.
+Added: In addition to California, at least eleven other states have passed comprehensive privacy laws similar to the CCPA and CPRA.
+Added: These laws are either in effect or will go into effect sometime before the end of 2026.
+Added: Like the CCPA and CPRA, these laws create obligations related to the processing of personal information, as well as special obligations for the processing of “sensitive” data (which includes health data in some cases).
+Added: Some of the provisions of these laws may apply to our business activities.
+Added: There are also states that are strongly considering or have already passed comprehensive privacy laws during the 2023 legislative sessions that will go into effect in 2024 and beyond, including New Hampshire and New Jersey.
Other states will be considering these laws in the future, and Congress has also been debating passing a federal privacy law.
+Added: There are also states that are specifically regulating health information that may affect our business.
+Added: For example, Washington state passed a health privacy law in 2023 that will regulate the collection and sharing of health information, and the law also has a private right of action, which further increases the relevant compliance risk.
+Added: Connecticut and Nevada have also passed similar laws regulating consumer health data and additional states (including Vermont) are considering such legislation for 2024.
These laws may impact our business activities, including our identification of research subjects, relationships with business partners and ultimately the marketing and distribution of our products.
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The approval process ultimately varies between countries and jurisdictions and can involve additional product testing and additional administrative review periods.
−Removed: The time required to obtain approval in other countries and jurisdictions might differ from and be longer than that required to obtain FDA approval.
+Added: The time required to obtain approval in other
+Added: countries and jurisdictions might differ from and be longer than that required to obtain FDA approval.
Regulatory approval in one country or jurisdiction does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others.
+Added: Non-clinical Studies
+Added: Non-clinical studies are performed to demonstrate the health or environmental safety of new chemical or biological substances.
+Added: Non-clinical (pharmaco-toxicological) studies must be conducted in compliance with the principles of good laboratory practice (GLP) as set forth in EU Directive 2004/10/EC (unless otherwise justified for certain particular medicinal products – e.g., radio-pharmaceutical precursors for radio-labeling purposes).
+Added: In particular, non-clinical studies, both in vitro and in vivo , must be planned, performed, monitored, recorded, reported and archived in accordance with the GLP principles, which define a set of rules and criteria for a quality system for the organizational process and the conditions for non-clinical studies.
+Added: These GLP standards reflect the Organization for Economic Co-operation and Development requirements.
Clinical Trial Approval
9 unchanged sentences
However, overall related timelines will be defined by the Clinical Trials Regulation.
−Removed: The new regulation did not change the preexisting requirement that a sponsor must obtain prior approval from the competent national authority of the EU Member State in which the clinical trial is to be conducted.
−Removed: If the clinical trial is conducted in different EU Member States, the competent authorities in each of these EU Member States must provide their approval for the conduct of the clinical trial.
−Removed: Furthermore, the sponsor may only start a clinical trial at a specific clinical site after the applicable ethics committee has issued a favorable opinion.
−Removed: Parties conducting certain clinical trials must, as in the United States, post clinical trial information in the European Union at the EudraCT website:
−Removed: https://eudract.ema.europa.eu.
+Added: The Clinical Trials Regulation, or CTR, foresees a three-year transition period.
+Added: The extent to which ongoing and new clinical trials will be governed by the Clinical Trials Regulation varies.
+Added: Clinical trials for which an application was submitted (i) prior to January 31, 2022 under the Clinical Trials Directive, or (ii) between January 31, 2022 and January 31, 2023 and for which the sponsor has opted for the application of the Clinical Trials Directive remain governed by said Directive until January 31, 2025.
+Added: After this date, all clinical trials (including those which are ongoing) will become subject to the provisions of the CTR.
+Added: Parties conducting certain clinical trials must, as in the United States, post clinical trial information in the European Union at the EU Clinical Trials Register.
Marketing Authorization
11 unchanged sentences
Under this procedure, a sponsor submits an application based on identical dossiers and related materials, including a draft summary of product characteristics, and draft labeling and package leaflet, to the reference member state and concerned member states.
−Removed: The reference member state prepares a draft assessment report and drafts of the related
−Removed: materials within 210 days after receipt of a valid application.
+Added: The reference member state prepares a draft assessment report and drafts of the related materials within 210 days after receipt of a valid application.
Within 90 days of receiving the reference member state’s assessment report and related materials, each concerned member state must decide whether to approve the assessment report and related materials.
15 unchanged sentences
Once subsequently definitively renewed, the marketing authorization shall be valid for an unlimited period.
−Removed: Any authorization which is not followed by the actual placing of the medicinal product on the European Union market (in case of centralized procedure) or on the market of the authorizing European Union Member State within three years after authorization ceases to be valid (the so-called sunset clause).
+Added: Any authorization which is not followed by the actual placing of the medicinal product on the
+Added: European Union market (in case of centralized procedure) or on the market of the authorizing European Union Member State within three years after authorization ceases to be valid (the so-called sunset clause).
Regulatory Requirements after a Marketing Authorization has been Obtained
4 unchanged sentences
● The manufacturing of authorized medicinal products, for which a separate manufacturer’s license is mandatory, must also be conducted in strict compliance with the applicable European Union laws, regulations and guidance, including Directive 2001/83/EC, Directive 2003/94/EC, Regulation (EC) No 726/2004 and the European Commission Guidelines for Good Manufacturing Practice.
−Removed: These requirements include compliance with European Union cGMP standards when manufacturing medicinal products and active pharmaceutical
−Removed: ingredients, including the manufacture of active pharmaceutical ingredients outside of the European Union with the intention to import the active pharmaceutical ingredients into the European Union.
+Added: These requirements include compliance with European Union cGMP standards when manufacturing medicinal products and active pharmaceutical ingredients, including the manufacture of active pharmaceutical ingredients outside of the European Union with the intention to import the active pharmaceutical ingredients into the European Union.
● The marketing and promotion of authorized drugs, including industry-sponsored continuing medical education and advertising directed toward the prescribers of drugs and/or the general public, are strictly regulated in the European Union notably under Directive 2001/83EC, as amended, and European Union Member State laws.
12 unchanged sentences
The rules and requirements for obtaining a SPC are similar to those in the United States.
−Removed: An SPC may extend the term of a patent for up to five years after its originally scheduled expiration date and can provide up to a maximum of fifteen years of marketing exclusivity for a drug.
+Added: An SPC may extend the term of a patent for up to five years after its originally scheduled expiration date and can provide up to a maximum of fifteen years of marketing exclusivity
In certain circumstances, these periods may be extended for six additional months if pediatric exclusivity is obtained.
48 unchanged sentences
Brexit and the Regulatory Framework in the United Kingdom
−Removed: The United Kingdom’s withdrawal from the European Union took place on January 31, 2020.
−Removed: The European Union and the U.K.
−Removed: reached an agreement on their new partnership in the Trade and Cooperation Agreement, or the Trade and Cooperation Agreement, which was applied provisionally beginning on January 1, 2021 and which entered into force on May 1, 2021.
−Removed: The Trade and Cooperation Agreement focuses primarily on free trade by ensuring no tariffs or quotas on trade in goods, including healthcare products such as medicinal products.
−Removed: Thereafter, the European Union and the U.K.
−Removed: will form two separate markets governed by two distinct regulatory and legal regimes.
−Removed: As such, the Trade and Cooperation Agreement seeks to minimize barriers to trade in goods while accepting that border checks will become inevitable as a consequence that the U.K.
−Removed: is no longer part of the single market.
−Removed: As of January 1, 2021, the Medicines
−Removed: and Healthcare products Regulatory Agency, or the MHRA, became responsible for supervising medicines and medical devices in Great Britain, comprising England, Scotland and Wales under domestic law whereas Northern Ireland continues to be subject to European Union rules under the Northern Ireland Protocol.
−Removed: The MHRA will rely on the Human Medicines Regulations 2012 (SI 2012/1916) (as amended), or the HMR, as the basis for regulating medicines.
−Removed: The HMR has incorporated into the domestic law the body of European Union law instruments governing medicinal products that pre-existed prior to the U.K.’s withdrawal from the European Union.
−Removed: The MHRA may rely on a decision taken by the European Commission on the approval of a new marketing authorization via the centralized procedure until December 31, 2023.
−Removed: Furthermore, while the Data Protection Act of 2018 in the United Kingdom that “implements” and complements the European Union’s General Data Protection Regulation, or GDPR, has achieved Royal Assent on May 23, 2018 and is now effective in the United Kingdom, it is still unclear whether transfer of data from the European Economic Area, or EEA, to the United Kingdom will remain lawful under GDPR.
−Removed: The Trade and Cooperation Agreement provides for a transitional period during which the United Kingdom will be treated like an European Union member state in relation to processing and transfers of personal data for four months from January 1, 2021.
−Removed: This may be extended by two further months.
−Removed: After such period, the United Kingdom will be a “third country” under the GDPR unless the European Commission adopts an adequacy decision in respect of transfers of personal data to the United Kingdom.
−Removed: The United Kingdom has already determined that it considers all of the European Union 27 and EEA member states to be adequate for the purposes of data protection, ensuring that data flows from the United Kingdom to the European Union/EEA remain unaffected.
+Added: The UK’s withdrawal from the EU took place on January 31, 2020.
+Added: The EU and the UK reached an agreement on their new partnership in the Trade and Cooperation Agreement, which we refer to as the Agreement and which was applied provisionally beginning on January 1, 2021 and which entered into force on May 1, 2021.
+Added: The Agreement focuses primarily on free trade by ensuring no tariffs or quotas on trade in goods, including healthcare products such as medicinal products.
+Added: Thereafter, the EU and the UK will form two separate markets governed by two distinct regulatory and legal regimes.
+Added: As such, the Agreement seeks to minimize barriers to trade in goods while accepting that border checks will become inevitable as a consequence that the UK is no longer part of the single market.
+Added: As of January 1, 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) became responsible for supervising medicines and medical devices in Great Britain, comprising England, Scotland and Wales.
+Added: Under the 2023 “Windsor Framework” and related laws, the MHRA became responsible for approving all medicinal products destined for the UK market (i.e., Great Britian and Northern Ireland), effective January 1, 2025.
+Added: A single UK-wide marketing authorization will be granted by the MHRA for all medicinal products to be sold in the UK, enabling products to be sold in a single pack and under a single authorization throughout the UK.
+Added: The Human Medicines Regulations 2012 (SI 2012/1916) (as amended) (HMR) is the primary legal instrument for the regulation of medicines in the UK.
+Added: The HMR has incorporated into the domestic law the body of EU law instruments governing medicinal products that pre-existed prior to the UK’s withdrawal from the EU.
+Added: EU laws which have been transposed into UK law through secondary legislation continue to be applicable as “retained EU law.” However, new legislation such as the (EU) Clinical Trials Regulation will not be applicable in Great Britain.
+Added: Since a significant proportion of the regulatory framework for pharmaceutical products in the UK covering the quality, safety, and efficacy of pharmaceutical products, clinical trials, marketing authorizations, commercial sales, and distribution of pharmaceutical products is derived from EU directives and regulations, Brexit may have a material impact upon the regulatory regime with respect to the development, manufacture, importation, approval, and commercialization of our product candidates in the UK.
+Added: For example, the UK is no longer covered by the centralized procedures for obtaining EU-wide marketing authorizations from the EMA, and a separate marketing authorization will be required to market our product candidates in the UK.
+Added: A new international recognition framework has been in place since January 1, 2024, whereby the MHRA will have regard to decisions on the approval of marketing authorizations made by the EMA and certain other regulators when determining an application for a new Great Britian marketing authorization.
General Data Protection Regulation
7 unchanged sentences
In July 2020, the Court of Justice of the European Union, or the CJEU, invalidated the European Union-U.S.
−Removed: Privacy Shield framework, one of the mechanisms used to legitimize the transfer of personal data from the EEA to the United States.
+Added: Privacy Shield framework, one of the mechanisms used to legitimize the
+Added: transfer of personal data from the EEA to the United States.
The CJEU decision also drew into question the long-term viability of an alternative means of data transfer, the standard contractual clauses, for transfers of personal data from the EEA to the United States.
−Removed: Following the withdrawal of the U.K.
−Removed: from the European Union, the U.K.
−Removed: Data Protection Act 2018 applies to the processing of personal data that takes place in the U.K.
−Removed: and includes parallel obligations to those set forth by GDPR.
+Added: Following the withdrawal of the UK from the European Union, the UK Data Protection Act 2018 applies to the processing of personal data that takes place in the UK and includes parallel obligations to those set forth by GDPR.
Additionally, in October 2022, President Biden signed an executive order to implement the EU-U.S.
1 unchanged sentence
Privacy Shield.
−Removed: The EC initiated the process to adopt an adequacy decision for the EU-U.S.
−Removed: Data Privacy Framework in December 2022.
−Removed: It is unclear if and when the framework will be finalized and whether it will be challenged in court.
−Removed: The uncertainty around this issue may further impact our business operations in the EU.
+Added: The EU initiated the process to adopt an adequacy decision for the EU-U.S.
+Added: Data Privacy Framework in December 2022 and the European Commission adopted the adequacy decision on July 10, 2023.
+Added: The adequacy decision will permit U.S.
+Added: companies who self-certify to the EU-U.S.
+Added: Data Privacy Framework to rely on it as a valid data transfer mechanism for data transfers from the EU to the U.S.
+Added: However, some privacy advocacy groups have already suggested that they will be challenging the EU-U.S.
+Added: Data Privacy Framework.
+Added: If these challenges are successful, they may not only impact the EU-U.S.
+Added: Data Privacy Framework, but also further limit the viability of the standard contractual clauses and other data transfer mechanisms.
Pharmaceutical Coverage, Pricing and Reimbursement
20 unchanged sentences
However, the pass-through status for J1096 ended on December 31, 2022.
−Removed: In November 2022, as part of the annual CMS rule-making cycle, the CY 2023 OPPS rule was finalized and provided that DEXTENZA would qualify under the criteria established for non-opioid pain management drugs as a surgical supply provision.
+Added: In November 2022, as part of the annual CMS rule-making cycle, the CY 2023 OPPS rule was finalized and provided that DEXTENZA would qualify under the criteria established for non-opioid pain
+Added: management drugs as a surgical supply provision.
This provision allows for continued separate payment of DEXTENZA in the ASC setting for 2023 but does not require separate payment for DEXTENZA in the HOPD setting.
3 unchanged sentences
In 2023, the Medicare Physician Fee Schedule, or MPFS, for the insertion of DEXTENZA into the canaliculus was $32.53 in the ASCs and $38.29 in the physician’s office for unilateral insertion.
−Removed: In November 2022, the CY 2023 MPFS rule was finalized resulting in a marginal increase in physician payments over 2022 to $32.53 in the ASCs and $38.29 in the physician’s office for unilateral insertion.
+Added: In November 2023, the CY 2024 MPFS rule was finalized resulting in a marginal decrease in physician payments compared to 2023 to $31.43 in the ASCs and $37.33 in the physician’s office for unilateral insertion, due to a decrease in the conversion factor which CMS uses to translate the relative value units, or RVUs, of medical services into fee schedule payment amounts.
+Added: The RVU for code 68841 was unchanged.
In the European Union, pricing and reimbursement schemes vary widely from country to country.
Some countries provide that drug products may be marketed only after a reimbursement price has been agreed.
−Removed: Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular product candidate to
−Removed: currently available therapies.
+Added: Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular product candidate to currently available therapies.
For example, the European Union provides options for its member states to restrict the range of drug products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.
68 unchanged sentences
More recently, on August 16, 2022, the IRA was signed into law by President Biden.
−Removed: The new legislation has implications for Medicare Part D, which is a program available to individuals who are entitled to Medicare Part A or enrolled in Medicare Part B to give them the option of paying a monthly premium for outpatient prescription drug coverage.
+Added: The new legislation has implications for Medicare Part D, which is a program available to individuals who are entitled to Medicare Part A or
+Added: enrolled in Medicare Part B to give them the option of paying a monthly premium for outpatient prescription drug coverage.
Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap;
7 unchanged sentences
The legislation also requires manufacturers to pay rebates for drugs in Medicare Part D whose price increases exceed inflation.
−Removed: The new law also caps
−Removed: Medicare out-of-pocket drug costs at an estimated $4,000 a year in 2024 and, thereafter beginning in 2025, at $2,000 a year.
+Added: The new law also caps Medicare out-of-pocket drug costs at an estimated $4,000 a year in 2024 and, thereafter beginning in 2025, at $2,000 a year.
At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
12 unchanged sentences
We are committed to inclusion and diversity and believe that these are important elements of our culture that enables us to attract and retain a high quality workforce.
−Removed: As of December 31, 2022, our workforce was composed of approximately 47% female and 53% male, and approximately 18% of the workforce was non-white.
The development, attraction and retention of employees is a critical success factor for us for the execution of our business strategy and succession planning.
−Removed: To support the advancement of our employees, we offer training and development programs encouraging advancement from within and continue to fill our team with strong and experienced management talent.
+Added: To support the advancement of our employees, we offer training and development programs encouraging advancement from within and continue to fill our team with strong and experienced
+Added: management talent.
We leverage both formal and informal programs to identify, foster, and retain top talent at both the corporate and operating unit level.
15 unchanged sentences
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.