We are a leader in the field of gene therapy and seek to deliver to patients suffering from rare and other devastating diseases single treatments with potentially curative results.
−Removed: We are advancing a focused pipeline of innovative gene therapies, including product candidates for the treatment of hemophilia B, which effective May 6, 2021, we licensed to CSL Behring pursuant to the CSL Behring Agreement (as defined below), and Huntington’s disease.
−Removed: We believe our technology platform and manufacturing capabilities provide us distinct competitive advantages, including the potential to reduce development risk, cost, and time to market.
+Added: We are advancing a pipeline of innovative gene therapies, including our clinical candidate for the treatment of Huntington’s disease and amyotrophic lateral sclerosis (“ALS”) as well as preclinical product candidates, including candidates for the treatment of refractory temporal lobe epilepsy (“rTLE”) and Fabry disease.
+Added: In November 2022 and February 2023, our internally-developed HEMGENIX Ô , a gene therapy for the treatment of hemophilia B, was approved for commercialization by the United States Food and Drug Administration (“FDA”) and the European Medicines Agency (“EMA”), respectively.
+Added: In June 2020, we agreed to license HEMGENIX Ô to CSL Behring LLC (“CSL Behring”), which is now responsible for the commercialization of HEMGENIX Ô .
+Added: We are manufacturing HEMGENIX Ô for CSL Behring and are entitled to specific milestone payments and royalties on net sales.
+Added: We believe our validated technology platform and manufacturing capabilities provide us distinct competitive advantages, including the potential to reduce development risk, cost, and time to market.
We produce our Adeno-associated virus (“AAV”) -based gene therapies in our own facilities with a proprietary, commercial-scale, current good manufacturing practices (“cGMP”)-compliant, manufacturing process.
We believe our Lexington, Massachusetts-based facility is one of the world’s most versatile gene therapy manufacturing facilities.
−Removed: Acquisition of Corlieve Therapeutics
−Removed: On June 21, 2021, we entered into a share and purchase agreement (“SPA”) to acquire all outstanding ordinary shares of Corlieve Therapeutics SAS (“Corlieve”), a privately held French gene therapy company (together, the “Corlieve Transaction”).
−Removed: Upon the closing of the Corlieve Transaction on July 30, 2021 (“Acquisition Date”), we acquired 97.7% of the outstanding ordinary shares of Corlieve in return for EUR 44.9 million ($53.3 million as of the Acquisition Date).
−Removed: As contractually required in the SPA, we acquired the remaining outstanding ordinary shares on February 9, 2022 following the expiration of a minimum holding period (“Mandatorily Redeemable Shares”).
−Removed: We recorded a liability related to these Mandatorily Redeemable Shares for an amount of EUR 0.7 million ($0.9 million) as of the Acquisition Date.
−Removed: We financed the Corlieve Transaction from cash on hand.
−Removed: Following its formation in November 2019, Corlieve obtained exclusive licenses to certain patents from two French research institutions that continue to collaborate with Corlieve and us.
−Removed: Corlieve also obtained an exclusive license from Regenxbio Inc.
−Removed: (“Regenxbio”) for the use of AAV9 to deliver any sequence that affects the expression of the Glutamate inotropic receptor kainate type subunit 2 (“GRIK 2”) gene sequence in humans.
−Removed: Corlieve and Regenxbio simultaneously entered into a collaboration plan related to agreed joint preclinical research and development activities.
−Removed: At the Acquisition Date, Corlieve and its Swiss subsidiary, Corlieve Therapeutics AG, employed seven employees.
−Removed: Corlieve’s gene therapy program, AMT-260, employs micro ribonucleic acid (“miRNA”) silencing technology to target suppression of aberrantly expressed kainate receptors in the hippocampus of patients with temporal lobe epilepsy (“TLE”).
−Removed: TLE affects approximately 1.3 million people in the U.S.
−Removed: and Europe alone, of which approximately 0.8 million patients are unable to adequately control acute seizures with currently approved anti-epileptic therapies.
−Removed: Patients with refractory TLE experience increased morbidity, excess mortality, and poor quality of life.
−Removed: In addition to the payments to acquire 100% of the outstanding ordinary shares, Corlieve’s former and remaining shareholders are eligible to receive up to EUR 35.8 million (or $40.6 million as of December 31, 2021) upon the achievement of development milestones through Phase I/II and EUR 143.1 million (or $162.3 million as of December 31, 2021) upon the achievement of milestones associated with Phase III development and obtaining approval to commercialize AMT-260 in the United States of America and the European Union.
−Removed: We may elect to pay up to 25% of such milestone payments through the issuance of our ordinary shares.
−Removed: We recorded a EUR 20.2 million ($24.0 million) liability related to these contingent consideration payments as of the Acquisition Date.
−Removed: Total consideration of EUR 65.8 million ($78.1 million), which consisted of the cash paid upon the Acquisition Date, the payment for the Mandatorily Redeemable Shares and the contingent consideration payments, was allocated to identifiable intangible assets related to the in-process research and development of AMT-260 (“IPR&D Intangible Asset”).
−Removed: The IPR&D Intangible Asset’s fair value was determined at EUR 53.6 million ($63.6 million) as of the Acquisition Date.
−Removed: We also recognized a EUR 13.4 million ($15.9 million) deferred tax liability in relation to this IPR&D Intangible Asset.
−Removed: The total consideration in excess of the net assets acquired was EUR 23.9 million ($28.4 million) and was allocated to goodwill.
−Removed: CSL Behring commercialization and license agreement
−Removed: On June 24, 2020, (the “Signing Date”), uniQure biopharma B.V., a wholly-owned subsidiary of uniQure N.V., entered into a commercialization and license agreement (as amended, the “CSL Behring Agreement”) with CSL Behring LLC (“CSL Behring”) pursuant to which CSL Behring received exclusive global rights to etranacogene dezaparvovec, our investigational gene therapy for patients with hemophilia B (the “Product”).
−Removed: The transaction became fully effective on May 6, 2021, one day after the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976 (the “HSR Act”) expired on May 5, 2021.
−Removed: CSL Behring is responsible for the development and commercialization of the Product.
−Removed: We agreed to complete the validation of the current manufacturing process as well as to the development and validation of a next generation manufacturing process.
−Removed: We will be entitled to receive a development milestone payment if we complete these activities in accordance with an agreed development plan and timeline.
−Removed: CSL Behring is responsible for global regulatory submissions and commercialization requirements for the Product.
−Removed: Certain clinical development and regulatory activities performed by us are reimbursed by CSL Behring.
−Removed: On the Signing Date, we and CSL Behring also entered into a development and commercial supply agreement, pursuant to which, among other things, we will supply the Product to CSL Behring at an agreed-upon price commensurate with the stand-alone selling price (“SSP”).
−Removed: We will be responsible to supply the Product until such time that these capabilities may be transferred to CSL Behring or its designated contract manufacturing organization.
−Removed: Other than under the CSL Behring Agreement, neither we nor CSL Behring may perform any clinical trials, with the exception of trials required to extend the label or gain marketing authorization outside the United States or the European Union, for any gene therapy product, gene-editing product, or any other product comprising an AAV vector to conduct nucleotide transfer (including deoxyribonucleic acid (“DNA”) and ribonucleic acid (“RNA”)) for the treatment, prevention, or cure of hemophilia B for a period commencing on June 24, 2020 and continuing for a period of four years following the first commercial sale of the Product in the United States, and neither we nor CSL Behring may commercialize such a product for a period commencing as of June 24, 2020 and continuing for a period of seven years following the first commercial sale of the Product in the United States.
−Removed: This exclusivity commitment would not bind an acquirer of us that owns or controls such a product so long as certain precautions are followed to ensure that CSL Behring’s confidential information and our proprietary technology related to the Product are not used or accessed by personnel of such acquirer who are developing or commercializing such competing product.
−Removed: Unless earlier terminated as described below, the CSL Behring Agreement will continue on a country-by-country basis until expiration of the royalty term in a country.
−Removed: The royalty term expires in a country on the later of (a) 15 years after the first commercial sale of the Product in such country, (b) expiration of regulatory exclusivity for the Product in such country and (c) expiration of all valid claims of specific licensed patents covering the Product in such country.
−Removed: Either we or CSL Behring may terminate the CSL Behring Agreement for the other party’s material breach if such breach is not cured within a specified cure period.
−Removed: In addition, if CSL Behring fails to commercialize the Product in any of a group of major countries for an extended period of time following the first regulatory approval of the Product in any of such group of countries (other than due to certain specified reasons) and such failure has not been cured within a specified cure period, then we may terminate the CSL Behring Agreement.
−Removed: CSL Behring may also terminate the CSL Behring Agreement for convenience.
−Removed: The effectiveness of the transactions contemplated by the CSL Behring Agreement was contingent on completion of review under antitrust laws in the United States, Australia, and the United Kingdom, and certain provisions of the CSL Behring Agreement did not become effective until after we had received all such regulatory approvals and after the waiting period under the HSR Act expired on May 5, 2021.
−Removed: Following the closing of the CSL Behring Agreement, we recorded $462.4 million, including a $450.0 million upfront cash payment, as license revenue.
−Removed: Upon closing, we contractually owed to our licensors $15.5 million of the upfront payment received from CSL Behring.
−Removed: We are eligible to receive more than $0.3 billion in regulatory, development, and first commercial sale milestones, $1.3 billion in additional commercial milestones, and tiered double-digit royalties of up to a low-twenties percentage of net product sales arising from the collaboration.
−Removed: As of December 31, 2021, we accrued revenue of $55.0 million related to milestone payments we expect to receive under the CSL Behring Agreement following the submissions of a Biological License Application (“BLA”) to the U.S.
−Removed: Food and Drug Administration (“FDA”) and a Marketing Access Authorization (“MAA”) to the European Medicines Agency (“EMA”), which are expected to be submitted during the first half of 2022.
−Removed: Hemophilia B program – Etranacogene dezaparvovec (AMT-061)
−Removed: Etranacogene dezaparvovec is our lead gene therapy candidate and includes an AAV serotype 5 (“AAV-5”) vector incorporating the functional human Factor IX (“FIX”) Padua variant.
−Removed: We are currently conducting, on behalf of CSL Behring, a pivotal Phase III study in 54 patients with severe and moderately-severe hemophilia B (“HOPE-B Study”).
−Removed: We expect that a BLA is to be submitted to the FDA and MAA to the EMA in the first half of 2022.
−Removed: The FDA has agreed that etranacogene dezaparvovec will fall under the existing Breakthrough Therapy Designation and IND for AMT-060 (our first-generation hemophilia B gene therapy), and the EMA has also agreed that etranacogene dezaparvovec will fall under the PRIME designation.
−Removed: On December 9, 2021, we announced the achievement of the pre-specified primary endpoint of non-inferiority in annualized bleeding rate (“ABR”) 18-months following administration compared to baseline Factor IX (“FIX”) prophylactic therapy in the HOPE-B Study.
−Removed: ABR for all bleeds after stable FIX expression, assessed at 18 months, was 1.51 compared with the ABR of 4.19 for the lead-in period of at least six months, achieving the primary non-inferiority endpoint and a secondary superiority endpoint (p=0.0002) in the HOPE-B Study.
−Removed: ABR for investigator-adjudicated FIX-treated bleeds was 0.83 compared with lead-in ABR of 3.65 (p<0.0001).
−Removed: All participants continued to demonstrate durable, sustained increases in FIX activity at 18-months post-infusion with a mean FIX activity of 36.9 percent of normal, as measured by a one-stage activated partial thromboplastin time-based (“aPTT-based”) clotting assay, compared to a mean FIX activity of 39.0 percent of normal at 26-weeks of follow-up.
−Removed: Etranacogene dezaparvovec was generally well-tolerated with over 80% of adverse events considered mild.
+Added: CSL Behring collaboration
+Added: On June 24, 2020 (the “Signing Date”), uniQure biopharma B.V., a wholly owned subsidiary of uniQure N.V., entered into a commercialization and license agreement (the “CSL Behring Agreement”) with CSL Behring, pursuant to which CSL Behring received exclusive global rights to etranacogene dezaparvovec (the “Product”).
+Added: The transaction became fully effective in May 2021 (the “Closing”).
+Added: In March and April 2022, CSL Behring submitted marketing applications for the Product in the United States (“U.S.”) and European Union (“EU”).
+Added: In March and April 2022, we received the $55.0 million owed to us by CSL Behring related to the submission of these marketing applications.
+Added: In November 2022, the FDA approved the marketing application for the U.S., and in February 2023 the EMA approved the marketing application for the EU.
+Added: We are eligible to receive a $100.0 million payment from CSL Behring following the first sale of the Product in the U.S.
+Added: We are also eligible to receive a $75.0 million payment from CSL Behring following the first sale of the Product in any of five major European countries, namely France, Germany, Italy, Spain, and the United Kingdom, provided the first sale occurs prior to July 2, 2023.
+Added: We recorded the $100.0 million milestone payment we are eligible to receive from CSL Behring associated with the first sale in the U.S.
+Added: as license revenue in the year ended December 31, 2022, as we expect this event to occur in 2023.
+Added: We did not record license revenue related to a $75.0 million payment in the year ended December 31, 2022, as the accomplishment of this milestone prior to July 2, 2023 is contingent on factors outside our control.
+Added: We are eligible to receive up to $1.3 billion in additional commercial milestones, and tiered double-digit royalties of up to a low-twenties percentage of net product sales arising from the Product.
Huntington’s disease program (AMT-130)
AMT-130 is our novel gene therapy candidate for the treatment of Huntington’s disease.
−Removed: AMT-130 utilizes our proprietary, gene-silencing miQURE platform and incorporates an AAV vector carrying a miRNA specifically designed to silence the huntingtin gene and the potentially highly toxic exon 1 protein fragment.
−Removed: We are currently conducting a Phase I/II clinical trial for AMT-130 in the U.S.
−Removed: and a Phase Ib/II study in the EU.
−Removed: Together, these studies are intended to establish safety, proof of concept, and the optimal dose of AMT-130 to take forward into Phase III development or into a confirmatory study should an accelerated registration pathway be feasible.
−Removed: AMT-130 has received Orphan Drug and Fast Track designations from the FDA and Orphan Medicinal Product Designation from the EMA.
−Removed: On April 5, 2021, we announced the completion of enrollment of the low-dose cohort of the U.S.
−Removed: Phase I/II study of AMT-130.
−Removed: The low- dose cohort includes 10 patients, of which six patients received treatment with AMT-130 and four patients received imitation (“Sham”) surgery.
−Removed: Phase I/II clinical trial is a randomized, controlled, double-blinded, dose-escalation study of AMT-130.
−Removed: On June 13, 2021, we announced the enrollment of the first two patients in the high-dose cohort of a U.S.
−Removed: Phase I/II study.
−Removed: The high-dose cohort is planned to include 16 patients, of which 10 patients will receive treatment with AMT-130 and six patients will receive Sham surgery.
−Removed: The initiation of patient enrollment in the high-dose cohort followed a meeting of the trial’s independent Data Safety Monitoring Board (“DSMB”) that reviewed safety data for the fully enrolled first cohort of 10 patients.
−Removed: On December 16, 2021, we announced initial 12-month observations on the first four patients enrolled in the low-dose cohort of the U.S.
−Removed: Phase I/II study.
−Removed: Two of the four enrolled patients received AMT-130, and two patients received Sham surgery as a control.
−Removed: AMT-130 was generally well tolerated in the treated patients, with no serious adverse events related to AMT-130.
−Removed: Neurofilament light chain (“NfL”), a biomarker of injury in the brain, increased as expected immediately following the surgical procedure and returned to baseline in the treated patients.
−Removed: NfL remained relatively constant in the two untreated control patients.
−Removed: Structural magnetic resonance imaging did not reveal any clinically meaningful safety findings in either treated or control patients at one year of follow-up.
−Removed: Measurements of total and mutant HTT protein in the cerebral spinal fluid of the four patients were highly variable and inconclusive.
−Removed: As of December 31, 2021, 19 patients have been enrolled in the clinical trial to date, including nine of 16 in the high-dose cohort.
−Removed: Also on December 16, 2021, we announced the initiation of patient screening in our 15 patient, open-label, Phase Ib/II study of AMT-130 in the EU, as well our plans to initiate a third cohort in the ongoing U.S.
−Removed: Phase I/II clinical trial.
−Removed: The third cohort, which will include up to 18 additional randomized patients receiving the higher dose, will explore the use of alternative stereotactic navigation systems to simplify placement of catheters for infusions of AMT-130.
−Removed: As of December 31, 2020, a $35.0 million term loan was outstanding in accordance with the Second Amended and Restated Loan and Security Agreement (the “2018 Amended Facility”) between us and Hercules Capital, Inc.
−Removed: (“Hercules”).
−Removed: On January 29, 2021, we and Hercules amended the 2018 Amended Facility (“2021 Amended Facility”).
−Removed: Pursuant to the 2021 Amended Facility, Hercules agreed to an additional Facility of $100.0 million (“Tranche B”) increasing the aggregate principal amount of the term loan facilities from $35.0 million to up to $135.0 million.
−Removed: On January 29, 2021, we drew down $35.0 million of the Tranche B.
−Removed: Advances under Tranche B bore interest at a rate equal to the greater of (i) 8.25% or (ii) 8.25% plus the prime rate, less 3.25% per annum.
−Removed: The principal balance of $70.0 million and all accrued but unpaid interest on advances under Tranche B was due on June 1, 2023.
−Removed: The back-end fee in respect of advances under the 2021 Amended Facility ranged from 1.65% to 6.85%, depending on the repayment date.
−Removed: In addition to Tranche B, the 2021 Amended Facility also extended the interest only payment period of the previously funded $35.0 million term loan (“Tranche A”) from January 1, 2022 to June l, 2023.
−Removed: On December 15, 2021, we and Hercules amended and restated the 2021 Amended Facility (“2021 Restated Facility”).
−Removed: Pursuant to the 2021 Restated Facility, Tranche A and Tranche B of the 2021 Amended Facility with a total outstanding balance of $70.0 million were consolidated into one tranche with a total commitment of $100.0 million.
−Removed: We drew down an additional $30.0 million, resulting in total principal outstanding as of December 31, 2021 of $100.0 million.
−Removed: The 2021 Restated Facility extended the loan’s maturity date from June 1, 2023 until December 1, 2025.
−Removed: The interest-only period is extended from January 1, 2023 to December 1, 2024, or December 1, 2025 if, prior to June 30, 2024, either (a) the BLA for AMT-061 is approved by the FDA or (b) AMT-130 is advanced into a pivotal trial.
−Removed: The interest rate is adjustable and is the greater of (i) 7.95% and (ii) 7.95% plus the prime rate less 3.25% per annum.
−Removed: Under the 2021 Restated Facility, we owe a back-end fee of 4.85% of the outstanding debt.
−Removed: We are required to repay the facility in equal monthly installments of principal and interest between the end of the interest-only period and the maturity date.
−Removed: We continue to owe a $2.5 million back-end fee related to the 2021 Amended Facility which is due on June 1, 2023.
−Removed: On March 1, 2021, we entered into a Sales Agreement with SVB Leerink LLC (“SVB Leerink”) with respect to an at-the-market (“ATM”) offering program, under which we may, from time to time in our sole discretion, offer and sell through SVB Leerink, acting as agent, our ordinary shares, up to an aggregate offering price of $200.0 million.
−Removed: We pay SVB Leerink a commission equal to 3% of the gross proceeds of the sales price of all ordinary shares sold through it as a sales agent under the Sales Agreement.
−Removed: In March and April of 2021, we issued 921,730 ordinary shares at a weighted average price of $33.52 per ordinary share, with net proceeds of $29.6 million, after deducting underwriting discounts and net of offering expenses.
−Removed: In February 2021, we commenced the expansion of our Amsterdam site to build additional laboratories to support the expansions of our research and development activities as well as the construction of a cleanroom capable of manufacturing cGMP materials at a 500-liter scale.
−Removed: The construction and validation of the cleanroom and the additional laboratories were completed in December 2021.
−Removed: In May 2021, we entered into a sublease agreement to let an additional approximately 1,080 square meters of office space at our Amsterdam site to accommodate the hiring of additional full-time employees.
−Removed: The lease expires in October 2028 and includes an option to break the lease on October 31, 2023.
−Removed: In December 2021, we entered into a new lease for an additional facility in Lexington, Massachusetts, United States of approximately 13,501 square feet of space.
−Removed: The lease is expected to commence in the second half of 2022, is set for seven years starting from the rent commencement date and is non-cancellable.
−Removed: The lease is renewable for one five-year term.
−Removed: In February 2022, we also entered into a new lease for an additional facility in Lexington, Massachusetts, United States of approximately 12,716 square feet.
−Removed: The lease is expected to commence in the second half of 2022 and is set for a non-cancellable period of seven years and four months.
−Removed: The lease is renewable for one five-year term.
−Removed: On May 17, 2021, Pierre Caloz was appointed as Chief Operating Officer.
−Removed: Caloz oversees all manufacturing operations, global CMC development and innovation, supply chain, and facilities.
−Removed: On June 15, 2021, Christian Klemt was appointed as Chief Financial Officer.
−Removed: Klemt was our Chief Accounting Officer from August 2017 to June 2021, and he will continue to serve as general manager of our Amsterdam site.
−Removed: Matthew Kapusta, who has been our Chief Executive Officer since December 2016 and had been our Chief Financial Officer from January 2015 to June 2021, will continue to serve as our Chief Executive Officer.
−Removed: In connection with his transition to Chief Financial Officer, Mr.
−Removed: Klemt will also serve as our Principal Financial Officer.
−Removed: On June 16, 2021, our shareholders voted to approve the reappointment of Mr.
−Removed: David Meek and Ms.
−Removed: Paula Soteropoulos as non-executive directors of the Board of Directors.
−Removed: Meek has been appointed chairman of the Board.
−Removed: Philip Astley-Sparke did not stand for reappointment and retired from the Board on June 16, 2021.
−Removed: On October 21, 2021, we held an Extraordinary General Meeting of our shareholders and Rachelle Jacques was appointed to the Board of Directors (the “Board”).
−Removed: Jacques will also serve as a member of the Audit Committee of the Board effective as of October 21, 2021.
−Removed: Intellectual Property
−Removed: On May 11, 2021, Pfizer, Inc.
−Removed: filed three petitions at the USPTO seeking Inter Partes Review of U.S.
−Removed: 9,982,248 (the “‘248 Patent”) and 10,465,180 (the “‘180 Patent” and together with the ‘248 Patent, the “Patents”).
−Removed: The petitions collectively seek to invalidate all claims of the Patents.
−Removed: In August 2021, we filed our responses asking the USPTO to deny institution of the IPR proceedings.
−Removed: On November 17, 2021, the PTAB issued decisions granting institution on all three IPR proceedings.
−Removed: Our response to the petition is currently due to be filed on March 3, 2022.
+Added: We are currently conducting a randomized, controlled and blinded Phase I/II clinical trial for AMT-130 in the U.S.
+Added: The lower-dose cohort of this trial includes 10 patients, of which six patients received treatment with AMT-130 and four patients received imitation surgery.
+Added: The higher-dose cohort includes 16 patients, of which 10 patients received treatment with AMT-130 and six patients received imitation surgery.
+Added: Patients receiving imitation surgery have the option to cross over after 12 months if they meet the inclusion criteria for the study.
+Added: We are also conducting an open-label Phase Ib/II study in the EU, which includes six patients in the lower-dose cohort and nine patients in the higher-dose cohort.
+Added: All 15 patients in the EU study will receive AMT-130.
+Added: On March 21, 2022, we announced that we completed the enrollment of all 26 patients in the first two cohorts of our Phase I/II clinical trial of AMT-130 in the U.S.
+Added: In July 2022, we began crossing over patients who received the imitation surgical procedure.
+Added: On June 23, 2022, we announced safety and biomarker data from the 10 patients enrolled in the low-dose cohort.
+Added: At 12 months of follow-up on the patients in the low-dose cohort:
+Added: ● AMT-130 was generally well-tolerated with no serious adverse events related to AMT-130 reported in the treated patients.
+Added: There were two serious adverse events unrelated to AMT-130, including a deep-vein thrombosis in the elbow of one patient that was resolved with anticoagulants and transient post-operative delirium in the second patient that was resolved through supportive care.
+Added: ● In the four treated patients with evaluable data, mean levels of mutant Huntingtin protein in the cerebral spinal fluid (“CSF mHTT”) declined at all timepoints compared to baseline, and decreased by 53.8% at 12 months of follow-up (range from 44% decrease to 71% decrease).
+Added: In the three control patients with evaluable data, mean levels of CSF mHTT showed an increase compared to baseline at one, three, six and nine months of follow-up, and decreased by 16.8% compared at 12 months of follow-up (range 35% increase to 47% decrease).
+Added: ● In the six treated patients, measurements of neurofilament light chain in the cerebral spinal fluid (“CSF NfL”), a biomarker of neuronal damage, initially increased as expected following the AMT-130 surgical procedure and declined thereafter, nearing baseline at 12 months of follow-up.
+Added: At 12 months, mean CSF NfL showed an 8% increase compared to baseline (range 46% increase to 14% decrease).
+Added: Two of the six treated patients were at or below baseline at 12 months of follow-up, with an additional patient below baseline at 15 and 18 months of follow-up.
+Added: In the four control patients, mean CSF NfL remained stable or slightly declined over 12 months (range 1% increase to 35% decrease).
+Added: Also on June 23, 2022, we announced that 10 patients in our Phase Ib/II study in the EU had been treated with AMT-130.
+Added: In August 2022, we announced a voluntary postponement of AMT-130 higher-dose procedures due to suspected unexpected severe adverse reactions (“SUSARs”) reported in three of the 14 patients that were treated with the higher dose of AMT-130.
+Added: In October 2022, after completing a comprehensive safety investigation, the Data Safety Monitoring Board (“DSMB”) recommended resuming treatment at the higher dose of AMT-130 for the remaining five European patients and any patients in the U.S.
+Added: trial eligible to cross over from the control arm to the treatment.
+Added: All three patients have experienced full resolution of the reported SUSARs.
+Added: Preclinical programs
+Added: In May 2022, we presented certain preclinical findings on our gene therapy candidates for refractory temporal lobe epilepsy, Fabry disease, Parkinson’s disease, Amyotrophic lateral sclerosis, and Alzheimer’s disease at the American Society of Gene and Cell Therapy Hybrid Congress.
+Added: In July and August 2022, respectively, we initiated Investigational New Drug-enabling (“IND-enabling”), Good Laboratory Practice (“GLP”) toxicology studies in non-human primates for our gene therapy candidates in rTLE and Fabry disease.
+Added: In November 2022, we hosted a virtual investor event focused on the target candidate for the treatment of temporal lobe epilepsy (“AMT-260”).
+Added: The presentation highlighted preclinical data on AMT-260 and our initial plans for clinical development, as well as our miQURE™ and linQURE™ technology platforms that utilize micro ribonucleic acids (“miRNAs”) to reduce the expression of abhorrent genes.
+Added: We also highlighted our progress in developing a commercial-scale AAV manufacturing platform.
+Added: Termination of Bristol-Myers Squibb Agreement
+Added: We entered into a collaboration and license agreement with Bristol-Myers Squibb (“BMS”) in May 2015 (“BMS CLA”).
+Added: BMS had initially designated four Collaboration Targets in 2015.
+Added: The initial four-year research term under the collaboration terminated on May 21, 2019.
+Added: On December 1, 2020, we and BMS amended the BMS CLA (the “Amended BMS CLA”).
+Added: The Amended BMS CLA did not extend the initial research term, and BMS did not replace any of the active Collaboration Targets.
+Added: On November 21, 2022, we received written notice that BMS was terminating the BMS CLA as amended (“Termination Notice”), effective on February 21, 2023 (“Termination Date”).
+Added: As a result of the termination of the BMS CLA, the contractually defined payment set for in the Amended BMS CLA that would have required us to make a payment to BMS in the event of a change of control transaction is of no further force or effect.
+Added: The Investor Agreement dated April 2015 between the Company and BMS remains in force according to its terms, but various provisions of the Investor Agreement have been terminated.
+Added: Amyotrophic Lateral Sclerosis (AMT-162)
+Added: On January 31, 2023, we announced that we have entered into a global licensing agreement for a one-time, intrathecally administered gene therapy for ALS with Apic Bio.
+Added: With this agreement, we have added to our pipeline of gene therapies to treat neurological disorders.
+Added: We made an initial cash payment of $10.0 million.
+Added: In addition, we will pay Apic Bio up to $43.0 million in milestones upon achievement of regulatory approvals in the U.S.
+Added: and Europe and pre-specified annual net sales, and a tiered royalty on net sales ranging from the mid-single digits to low double digits.
Our Mission and Strategy
2 unchanged sentences
Our strategy to achieve this mission is to:
−Removed: In collaboration with our partner, achieve regulatory approvals and the commercial launch of etranacogene dezaparvovec (AMT-061).
−Removed: Etranacogene dezaparvovec is a one-time administered gene therapy that combines the potential advantages of AAV5 with an enhanced Padua-FIX transgene, and may provide clinical and tolerability benefits to nearly all patients with hemophilia B.
−Removed: In June 2020, we entered into a commercialization and license agreement with CSL Behring pursuant to which CSL Behring received exclusive global rights to etranacogene dezaparvovec.
−Removed: We are responsible for the manufacturing of etranacogene dezaparvovec and CSL Behring is responsible for the development and commercialization of the Product.
−Removed: In September 2021, we completed the last patient’s 78-week follow-up visit in the HOPE-B Phase III pivotal study, which enrolled a total of 54 patients.
Advance the development of AMT-130, a potential one-time gene-therapy approach for the treatment of Huntington’s disease.
AMT-130 is the first AAV-based gene therapy to enter clinical development for Huntington’s disease.
−Removed: It consists of an AAV5 vector carrying an artificial micro-RNA specifically tailored to silence the huntingtin gene and leverages our proprietary miQURE™ silencing technology.
−Removed: The therapeutic goal of AMT-130 is to inhibit the production of the mutant protein (mHTT).
−Removed: Patient enrollment is ongoing in two clinical trials of AMT-130 being conducted in the U.S.
−Removed: Build a pipeline of gene therapy programs focused on rare, liver-directed and central-nervous system (“CNS”) diseases.
−Removed: Beyond our lead clinical program in Huntington’s disease and our late-stage program in hemophilia B now partnered with CSL Behring, we have a pipeline of additional AAV-based gene therapy programs in various stages of preclinical development focused on larger market opportunities and built on validated targets and technologies.
−Removed: We are leveraging novel vectors, promoters, and manufacturing capabilities, to develop gene therapies that have the potential to be best or first in class and are primarily focused on rare, monogenic liver-directed, and CNS disorders as well as cardiovascular and muscle diseases.
+Added: It consists of an AAV5 vector carrying an artificial miRNA specifically tailored to silence the huntingtin gene and leverages our proprietary miQURE™ silencing technology.
+Added: The therapeutic goal of AMT-130 is to inhibit the production of the mutant HTT protein.
+Added: In June 2022, we announced initial data from patients in the lower-dose cohort of the U.S.
+Added: Phase I/II study.
+Added: Patient enrollment is ongoing in the U.S.
+Added: Phase I/II study as well as an EU Phase Ib/II study.
+Added: Support the commercialization and global expansion of HEMGENIX Ô .
+Added: HEMGENIX Ô is an FDA and EMA approved one-time administered gene therapy for the treatment of patients with severe and moderately severe hemophilia B.
+Added: In 2020 we licensed the commercial rights to HEMGENIX Ô to CSL Behring .
+Added: We will be supplying CSL Behring with HEMGENIX Ô for a number of years.
+Added: We are eligible to receive up to $1.3 billion in additional commercial milestones, and tiered double-digit royalties of up to a low-twenties percentage of net product sales arising from HEMGENIX Ô .
+Added: Advance our pipeline of other preclinical and clinical-stage gene therapy candidates into first-in-human trials.
+Added: We expect to advance additional one-time administered gene therapy product candidates into clinical studies, including AMT-260 for the treatment of rTLE, AMT-162 for the treatment of superoxide dismutase 1 (“SOD1”)-ALS, and AMT-191 for the treatment of Fabry disease.
+Added: AMT-260 and AMT-162 utilize an AAV9 vector to deliver customized miRNAs to suppress the expression of the glutamate inotropic receptor kainate type subunit 2 (“GRIK2”) and SOD1 genes, respectively.
+Added: AMT-191 is an AAV5 gene therapy incorporating the α-galactosidase A (“GLA”) transgene.
+Added: Initiate additional gene therapy programs leveraging validated technologies and focused on central-nervous system (“CNS”) and other debilitating disorders.
+Added: We are leveraging proven enabling technologies, including AAV vectors, promoters, and manufacturing capabilities, to develop gene therapies that have the potential to be best or first-in-class.
+Added: Many of our gene therapy product candidates incorporate AAV5 or AAV9 vectors, which are currently being utilized in commercially available, approved gene therapies, as well as extensively studied in the clinical setting.
+Added: We believe AAV5 may potentially offer a favorable immunogenicity profile and the ability to confer therapeutic effect in patients with pre-existing antibodies.
+Added: We have also developed substantial know-how around optimizing delivery of gene therapies to the central nervous system and the liver, which can be leveraged across multiple product candidates.
Maintain our leadership position in commercial-scale AAV manufacturing.
−Removed: We have established cGMP, commercial-scale manufacturing capabilities for AAV-based gene therapies in our state-of-the-art Lexington, Massachusetts facility and begun construction of a second cGMP manufacturing facility in our Amsterdam, the Netherlands facility that will complement our work in Lexington.
−Removed: We seek to establish larger scale and highly cost-effective capabilities to address more prevalent disorders, and we believe the modularity of our platform provides us with distinct advantages, including the potential for reduced development risk and faster times to market.
−Removed: Leverage the favorable immunogenicity profile of AAV5-based gene therapies to develop multiple products.
−Removed: We have developed extensive experience with our AAV5-based gene therapies, including in five clinical trials in multiple liver-directed and CNS diseases.
−Removed: During these clinical trials, no patient treated with AAV5-based gene therapies experienced a confirmed immune response to the AAV5 capsid or complications associated with T-cell activation.
−Removed: Additionally, the AAV5 capsid has demonstrated a low avidity to pre-existing neutralizing antibodies (“Nab”), which may enable all, or nearly all patients to be eligible for treatment with AAV5-based gene therapies.
−Removed: We are now in the process of developing Smart AAV capsids that combine the advantages of AAV5 with antibody-directed delivery to move cargo across the blood brain barrier and to improve transduction of cells in the CNS.
+Added: We have established cGMP, commercial-scale manufacturing capabilities for AAV-based gene therapies in our commercially-licensed Lexington, Massachusetts facility and completed construction of a second cGMP manufacturing facility in Amsterdam, the Netherlands that complements our work in Lexington.
+Added: We believe our manufacturing platform enables us to rapidly produce new products for clinical investigation, minimize time between clinical phases and complete scale-up as product candidates advance into late-stage development and commercialization.
Invest in next-generation technologies with the goal of enhancing safety, improving efficacy, and expanding the applicability of gene therapy to patients.
−Removed: We are developing proprietary technologies that have the potential to augment the safety and efficacy of our product candidates and broaden the applicability of our gene therapies to a wider range of diseases and patients.
−Removed: These technologies include (i) miQURE, our one-time administered gene silencing platform, (ii) goQURE for simultaneous silencing of a disease gene and replacement with a healthy gene, (iii) AbQURE, using the power of AAV5 to deliver therapeutic antibodies systemically from the liver or into the CNS from cells in the brain, (iv) QUREDose for dosing through neutralizing antibodies and re-dosing technology;
−Removed: along with other tailored vectors, promoters, and novel transgenes.
−Removed: These technologies are developed both in-house by our experienced research team in Amsterdam, the Netherlands, as well as via collaborations with third parties.
+Added: We are developing technologies that have the potential to augment the safety and efficacy of our product candidates and broaden the applicability of our gene therapies to a wider range of diseases and patients.
+Added: These technologies include next-generation delivery approaches, such as smart AAV capsids potentially capable of improved CNS transduction and crossing the blood-brain barrier, as well as novel cargo technologies such as miQURE, our one-time administered gene silencing platform.
+Added: We are expanding our cargo platforms to include additional technologies, such as linkQURE to combine multiple miRNAs to suppress different genes, goQURE for simultaneous silencing of a disease gene and replacement with a healthy gene, and abQURE for the delivery of therapeutic antibodies.
+Added: We are also developing novel administration approaches, such as QUREDose, to enable dosing through neutralizing antibodies and re-dosing.
+Added: These various technologies are developed both in-house by our experienced research team in Amsterdam, the Netherlands, as well as via collaborations with third parties.
Continue to expand our intellectual property portfolio.
−Removed: We have established what we believe is a leading intellectual property portfolio covering various aspects of our technology and programs, including (i) elements of our gene therapy constructs, such as AAV vectors, promoters and transgenes (ii) innovative delivery technologies, such as re-administration of AAV gene therapy;
+Added: We have established what we believe is a leading intellectual property portfolio covering various aspects of our technology and programs, including (i) elements of our gene therapy constructs, such as AAV vectors, promoters and transgenes;
+Added: (ii) innovative delivery technologies, such as re-administration of AAV gene therapy;
and (iii) proprietary manufacturing processes covering key components of our upstream and downstream capabilities.
3 unchanged sentences
Liver-directed diseases
−Removed: Hemophilia B (etranacogene dezaparvovec)
+Added: Hemophilia B (HEMGENIX™ or etranacogene dezaparvovec)
Hemophilia B Disease and Market Background
−Removed: Hemophilia B is a serious and rare inherited disease in males characterized by insufficient blood clotting.
−Removed: The condition can lead to repeated and sometimes life-threatening episodes of external and internal bleeding following accidental trauma or medical interventions.
−Removed: Severe hemophilia is characterized by recurrent episodes of spontaneous joint bleeds that cause long-term damage to the joints resulting in disabling arthropathy.
−Removed: Bleeds may be fatal if they occur in the brain.
−Removed: The deficient blood clotting results from the lack of functional human Factor IX (“hFIX”).
−Removed: Treatment of hemophilia B today consists of prophylactic or on-demand protein replacement therapy, in which one to three times weekly intravenous administrations of plasma-derived or recombinant hFIX are required to prevent bleeding and once daily infusions in case bleeding occurs.
−Removed: Hemophilia B occurs in approximately 1 out of 30,000 live male births.
+Added: Hemophilia B is a rare, lifelong bleeding disorder caused by a single gene defect, resulting in insufficient production of factor IX, a protein primarily produced by the liver that helps blood clots form.
+Added: Treatments for moderate to severe hemophilia B include prophylactic infusions of factor IX replacement therapy to temporarily replace or supplement low levels of blood-clotting factor and, while these therapies are effective, those with hemophilia B must adhere to strict, lifelong infusion schedules.
+Added: They may also still experience spontaneous bleeding episodes as well as limited mobility, joint damage or severe pain as a result of the disease.
+Added: For appropriate patients, HEMGENIX™ allows people living with hemophilia B to produce their own factor IX, which can lower the risk of bleeding.
CSL Behring collaboration
−Removed: On June 24, 2020, we entered into the CSL Behring Agreement pursuant to which CSL Behring received exclusive global rights to etranacogene dezaparvovec.
+Added: On June 24, 2020, we entered into the CSL Behring Agreement pursuant to which CSL Behring received exclusive global rights to HEMGENIX™.
The transaction became fully effective on May 6, 2021, one day after the waiting period under the HSR Act expired on May 5, 2021.
−Removed: CSL Behring is responsible for the development and commercialization of the Product.
−Removed: We agreed to complete the validation of the current manufacturing process as well as to the development and, if requested by CSL Behring, the validation of a next generation manufacturing process.
−Removed: We will be entitled to receive a development milestone payment if we complete these activities in accordance with an agreed development plan and timeline.
−Removed: CSL Behring is responsible for global regulatory submissions and commercialization requirements for the Product.
−Removed: Certain clinical development and regulatory activities performed by us are reimbursed by CSL Behring.
−Removed: On the Signing Date, we and CSL Behring also entered into a development and commercial supply agreement, pursuant to which, among other things, we will supply the Product to CSL Behring at an agreed-upon price commensurate with the SSP.
−Removed: We will be responsible to supply the Product until such time that these capabilities may be transferred to CSL Behring or its designated contract manufacturing organization.
−Removed: Development of etranacogene dezaparvovec for Hemophilia B
−Removed: We believe we have substantially completed the development of etranacogene dezaparvovec, a gene therapy for patients with hemophilia B that is designed to restore FIX activity, an essential protein for blood clotting.
−Removed: Etranacogene dezaparvovec includes an AAV5 vector incorporating the FIX-Padua variant (“FIX-Padua”).
−Removed: Etranacogene dezaparvovec is intended to be delivered by intravenous (“IV”)-infusion, without immunosuppressant therapy, through the peripheral vein in a single treatment session for approximately 30 minutes.
−Removed: Our goal for etranacogene dezaparvovec was to develop a gene therapy with the following profile:
−Removed: - long-term safety, including a favorable immunogenicity profile;
−Removed: - predictable, sustained and potentially curative increases in FIX activity;
−Removed: - significant reductions in both bleeding rates and the need for FIX replacement therapy;
−Removed: - broad patient eligibility, including the potential to treat all or nearly all patients with hemophilia B.
−Removed: AAV5-based gene therapies have been used in a multitude of clinical trials, including five clinical trials conducted by us in patients with hemophilia B and other disorders.
−Removed: No patient treated in clinical trials with our AAV5-based gene therapies has experienced any confirmed, cytotoxic T-cell-mediated immune response to the capsid.
−Removed: An independent clinical trial has demonstrated that AAV5 has the lowest prevalence of pre-existing neutralizing antibodies compared to other AAV vectors.
−Removed: Data from our clinical, preclinical, and nonclinical studies suggest that all, or nearly all patients may be eligible for treatment with etranacogene dezaparvovec.
−Removed: In June 2018, we initiated our Phase III HOPE-B pivotal trial of etranacogene dezaparvovec.
−Removed: The trial is a multinational, multi-center, open-label, single-arm study to evaluate the safety and efficacy of etranacogene dezaparvovec.
−Removed: In March 2020, we completed dosing of the 54 patients in the HOPE-B trial.
−Removed: The targeted number of patients to be dosed per the clinical trial protocol was 50.
−Removed: The adult hemophilia B patients, who were classified as severe or moderately severe, were enrolled in a six-month observational period prior to dosing during which time they continued to use their current standard of care to establish a baseline control.
−Removed: After the six-month lead-in period, patients received a single IV-administration of etranacogene dezaparvovec.
−Removed: Patients enrolled in the HOPE-B trial were tested for the presence of pre-existing neutralizing antibodies to AAV5 but not excluded from the trial based on their titers.
−Removed: Following a pre-BLA submission meeting with the FDA on June 4, 2021 the primary endpoint was set as a non-inferiority analysis in ABR 18-months following administration compared to baseline FIX prophylactic therapy in the pivotal Phase III HOPE-B gene therapy trial (approximately 52-weeks after steady-state is achieved).
−Removed: In September 2021, we completed the last patient’s 18-months follow-up visit which enrolled a total of 54 patients.
−Removed: On December 9, 2021, we announced the achievement of the pre-specified primary endpoint of non-inferiority in ABR 18-months following administration compared to baseline FIX prophylactic therapy in the HOPE-B Study.
−Removed: ABR for all bleeds after stable FIX expression, assessed at 18 months, was 1.51 compared with the ABR of 4.19 for the lead-in period of at least six months, achieving the primary non-inferiority endpoint and a secondary superiority endpoint (p=0.0002) in the HOPE-B Study.
−Removed: ABR for investigator-adjudicated FIX-treated bleeds was 0.83 compared with lead-in ABR of 3.65 (p<0.0001).
−Removed: All participants continued to demonstrate durable, sustained increases in FIX activity at 18-months post-infusion with a mean FIX activity of 36.9 percent of normal, as measured by a one-stage aPTT-based clotting assay, compared to a mean FIX activity of 39.0 percent of normal at 26-weeks of follow-up.
−Removed: Etranacogene dezaparvovec was generally well-tolerated with over 80% of adverse events considered mild.
−Removed: We expect that a BLA is to be submitted to the FDA and a MAA to the EMA in the first half of 2022.
−Removed: In September 2018, we completed the dosing of a Phase IIb dose-confirmation study of etranacogene dezaparvovec.
−Removed: The Phase IIb study is an open-label, single-dose, single-arm, multi-center trial being conducted in the United States.
−Removed: The objective of the study was to evaluate the safety and tolerability of etranacogene dezaparvovec and confirm the dose based on FIX activity at six weeks after administration.
−Removed: Three patients with severe hemophilia were enrolled in this study and received a single intravenous infusion of 2x10 13 genome copies per kilogram (“gc/kg”).
−Removed: Patients were evaluated for the presence of pre-existing neutralizing antibodies to AAV5 but were not excluded from the trial on this basis.
−Removed: We have followed the patients for more than two years to assess FIX activity, bleeding rates and usage of FIX replacement therapy, and will monitor the three patients for a total of five years to evaluate the safety of etranacogene dezaparvovec.
−Removed: In December 2018, the study’s Data Monitoring Committee evaluated initial data from the Phase IIb study and confirmed the dose of 2x10 13 gc/kg for the Phase III pivotal trial.
−Removed: In February, May, July, and December 2019, and in December 2020, we presented updated data from the Phase IIb dose-confirmation study of etranacogene dezaparvovec.
−Removed: The most recent data that we announced in December 2020 from the Phase IIb study of etranacogene dezaparvovec showed that all three patients experienced increasing and sustained FIX levels after a one-time administration of etranacogene dezaparvovec.
−Removed: Mean FIX activity was 44.2% of normal two years after administration, exceeding threshold FIX levels generally considered sufficient to significantly reduce the risk of bleeding events.
−Removed: The first patient achieved FIX activity of 44.7% of normal, the second patient was 51.6% of normal and the third patient was 36.3% of normal.
−Removed: The second and third patients had previously screen-failed and were excluded from another gene therapy study due to pre-existing neutralizing antibodies to a different AAV vector.
−Removed: At two years after dosing, two of the three participants remain free from bleeds and use of FIX replacement therapy.
−Removed: A single bleed has been reported in one participant, who has used a total of two FIX infusions (excluding surgery).
−Removed: All patients have remained free of prophylaxis in the two years since receiving etranacogene dezaparvovec.
−Removed: The FDA has agreed that etranacogene dezaparvovec will fall under the existing Breakthrough Therapy Designation and IND for AMT-060 (our first-generation hemophilia B gene therapy), and the EMA has also agreed that etranacogene dezaparvovec will fall under the PRIME designation.
+Added: Unless earlier terminated as described below, the CSL Behring Agreement will continue on a country-by-country basis until expiration of the royalty term in a country.
+Added: The royalty term expires in a country on the later of (a) 15 years after the first commercial sale of the Product in such country, (b) expiration of regulatory exclusivity for the Product in such country and (c) expiration of all valid claims of specific licensed patents covering the Product in such country.
+Added: Either we or CSL Behring may terminate the CSL Behring Agreement for the other party’s material breach if such breach is not cured within a specified cure period.
+Added: In addition, if CSL Behring fails to commercialize the Product in any of a group of major countries for an extended period of time following the first regulatory approval of the Product in any of such group of countries (other than due to certain specified reasons) and such failure has not been cured within a specified cure period, then we may terminate the CSL Behring Agreement.
+Added: CSL Behring may also terminate the CSL Behring Agreement for convenience.
+Added: In March and April 2022, we received the total $55.0 million owed to us by CSL Behring related to CSL Behring’s submissions of marketing applications for HEMGENIX™ in the EU in March 2022 and the U.S.
+Added: in April 2022.
+Added: In November 2022 the FDA approved the marketing application for the U.S.
+Added: and in February 2023 the EMA approved the marketing application for the EU.
+Added: We are eligible to receive a $100.0 million payment from CSL Behring following the first sale of the Product in the U.S.
+Added: We are also eligible to receive a $75.0 million payment from CSL Behring following the first sale of the Product in any of five major European countries, namely France, Germany, Italy, Spain, and the United Kingdom, provided the first sale occurs prior to July 2, 2023.
+Added: We recorded the $100.0 million payment associated with the first sale in the U.S.
+Added: as license revenue in the year ended December 31, 2022 as we expect this event to occur in 2023.
+Added: We did not record license revenue related to a $75.0 million payment in the year ended December 31, 2022, as the accomplishment of this milestone prior to July 2, 2023 is contingent on factors outside our control.
+Added: We and CSL Behring also entered into a development and commercial supply agreement, pursuant to which, among other things, we will supply the Product to CSL Behring.
+Added: We are contractually obligated to supply the Product until such time that these capabilities are transferred to CSL Behring or its designated contract manufacturing organization.
+Added: On September 6, 2022, CSL Behring notified us of its intent to transfer manufacturing technology in the coming years related to HEMGENIX™ to a third-party contract manufacturer designated by CSL Behring.
+Added: CSL Behring also informed us of its intent to retain us as a source for manufacturing after the completion of the technology transfer.
+Added: Development of HEMGENIX™ (etranacogene dezaparvovec) for Hemophilia B
+Added: HEMGENIX™ is approved for adults 18 years or older with hemophilia B who currently use factor IX prophylaxis therapy or have current or historical life-threatening hemorrhage or have repeated, serious spontaneous bleeding episodes.
+Added: HEMGENIX™ includes an AAV5 vector incorporating the FIX-Padua variant (“FIX-Padua”).
+Added: The product is intended to be delivered by intravenous (“IV”)-infusion, without immunosuppressant therapy, through the peripheral vein in a single treatment session for approximately 30 minutes.
+Added: The approvals were based in part on data from our Phase III HOPE-B pivotal trial to evaluate the safety and efficacy of HEMGENIX™.
+Added: In the open-label, single arm, HOPE-B study, 54 adult male hemophilia B patients with severe or moderately severe hemophilia B, with or without pre-existing AAV5 neutralizing antibodies, were infused with a single dose of HEMGENIX™.
+Added: HEMGENIX™ produced mean factor IX activity of 39.0 IU/dL at six months and 36.9 IU/dL at 18 months post infusion, which was sustained at 36.7 IU/dL in the long-term follow-up data at two years.
+Added: In addition, 94 percent (51 out of 54) of patients treated with HEMGENIX™ discontinued use of prophylaxis and remained free of previous continuous routine prophylaxis therapy.
+Added: The data demonstrate the annualized bleeding rate (“ABR”) for all bleeds was reduced by 64% during months 7-24 of the study (mean ABR 1.51 vs.
+Added: 4.18 during the lead-in period;
+Added: p=0.0002), sustaining the same bleed reduction that satisfied the study's primary endpoint.
+Added: The FDA-approved prescribing information for HEMGENIX™ shows that ABR for all bleeds was reduced by 54% during months 7-18 of the study.
+Added: Treatment with HEMGENIX™ also reduced mean unadjusted annualized factor IX consumption by 96% from the lead-in period (257,339 IU/year/participant) to months 19–24 (9751 IU/year/participant;
+Added: Of the 557 treatment-emergent adverse events reported 24-months post-infusion, 424 (76%) were mild, 115 (21%) were moderate and 18 (3%) were severe.
+Added: A total of 38 participants (70.4%) experienced 93 treatment-related adverse events, with only one occurring during months 18-24.
+Added: There were no serious adverse effects related to treatment and the most common side effects (incidence ≥5%) were liver enzyme elevations, headache, elevated levels of a certain blood enzyme, flu-like symptoms, infusion-related reactions, fatigue, nausea and feeling unwell.
Intellectual Property for etranacogene dezaparvovec
3 unchanged sentences
Patent Number 9,249,405, (the “‘405 Patent”).
−Removed: The ‘405 Patent was subject to Inter Partes Review (“IPR”) proceedings at the Patent Trials and Appeal Board (“PTAB”) of the USPTO.
+Added: The ‘405 Patent was subject to Inter Partes Review (“IPR”) proceedings at the Patent Trials and Appeal Board (“PTAB”) of the United States Patent & Trademark Office (“USPTO”).
Ultimately, the challenged claims of the ‘405 Patent were withdrawn but the unchanged claims remain in force.
8 unchanged sentences
patents, on February 20, 2018, the Canadian Intellectual Property Office granted Patent Number 2,737,094, which covers FIX-Padua nucleic acids for use in gene therapy and FIX-Padua polypeptides for use in FIX replacement therapy.
−Removed: In Europe, European Patent 2337849 directed to a FIX polypeptide protein was withdrawn during opposition proceedings with the European Patent Office (“EPO”).
−Removed: In addition, EP 3252157, a refused divisional European patent application was withdrawn.
−Removed: We are still pursuing a European divisional patent application that was filed on May 14, 2019.
+Added: On October 14, 2022, Pfizer filed a Statement of Claim at the Federal Court in Canada to impeach our Canadian Patent CA 2,737,094.
+Added: We are currently defending this case.
+Added: On December 28, 2022, the European Patent Office granted Patent Number EP 3581650, which covers FIX-Padua nucleic acids and its uses in gene therapy.
+Added: That same day, Pfizer filed a Claim at the UK High Court, Patent Court seeking revocation of the UK part of EP 3581650.
+Added: We are currently defending this case.
Both in the U.S.
3 unchanged sentences
9,982,248 (the “‘248 Patent”) and 10,465,180 (the “‘180 Patent” and together with the ‘248 Patent, the “Patents”).
−Removed: The petitions collectively seek to invalidate all claims of the Patents.
−Removed: In August 2021, we filed our responses asking the USPTO to deny institution of the IPR proceedings.
−Removed: On November 17, 2021, the PTAB issued decisions granting institution on all three IPR proceedings.
−Removed: Our response to the petition is currently due to be filed on March 3, 2022.
+Added: On November 15, 2022, the PTAB issued three Final Written Decisions (“FWD”) finding the claims of the challenged patents invalid.
+Added: On January 17, 2023, Notices of Appeal were filed at the Court of Appeal of the Federal Circuit (“CAFC”) contesting these FWDs.
Fabry disease program (AMT-191)
15 unchanged sentences
Fabry disease occurs in all racial and ethnic populations and affects males and females.
−Removed: It is estimated that type 1 classic Fabry disease affects approximately one in 40,000 males.
+Added: It is estimated that type 1 classic Fabry disease affects approximately one in 40,000 males and approximately one in 20,000 females.
The type 2 later-onset phenotype is more frequent, and in some populations may occur as frequently as about 1 in 1,500 to 4,000 males.
Our Development of AMT-191 for Fabry Disease
−Removed: In September 2020, we selected a lead gene therapy candidate (AMT-191) for the treatment of Fabry disease to advance into Investigational New Drug-enabling studies (“IND-enabling studies”).
+Added: In September 2020, we selected a lead gene therapy candidate (AMT-191) for the treatment of Fabry disease.
The lead candidate is a one-time administered AAV5 gene therapy incorporating the GLA transgene.
−Removed: In preclinical studies comparing multiple product candidates, including constructs incorporating a modified alpha-N-acetylgalactosaminidase transgene (modNAGA), AMT-191 demonstrated the most robust and sustained increases in GLA activity.
+Added: In preclinical studies comparing multiple product candidates, including constructs incorporating a modified alpha-N-acetylgalactosaminidase transgene (“modNAGA”), AMT-191 demonstrated the most robust and sustained increases in GLA activity and subsequent functional improvement.
In October 2021, we presented preclinical data for AMT-191 at the European Society of Gene and Cell Therapy (“ESGCT”), confirming efficiency and cross correction in a Fabry mouse model, with increased gamma-linolenic acid in the liver, kidney, heart, and brain and normalized lysoglobotriaosylceramide-3 levels in main target organs.
+Added: In August 2022, we initiated IND-enabling, GLP toxicology studies in non-human primates for our lead candidate.
Central Nervous System diseases
19 unchanged sentences
(3) safe, on-target and durable knockdown of HTT and exon 1 HTT.
−Removed: In January 2019, our IND application for AMT-130 was cleared by the FDA.
−Removed: In February 2019, we presented new preclinical data at the 14 th Annual CHDI Huntington’s disease Therapeutics Conference that illustrate the therapeutic potential of AMT-130 in restoring function of damaged brain cells in Huntington’s disease.
−Removed: In that study, AMT-130 was generally well-tolerated and resulted in a sustained reduction of mutant huntingtin protein.
−Removed: On April 5, 2021, we announced the completion of enrollment of the low-dose cohort of the U.S.
−Removed: Phase I/II study of AMT-130.
−Removed: The low-dose cohort includes 10 patients, of which six patients received treatment with AMT-130 and four patients received Sham surgery.
−Removed: Phase I/II clinical trial is a randomized, controlled, double-blinded, dose-escalation study of AMT-130.
−Removed: On June 13, 2021, we announced the enrollment of the first two patients in the high-dose cohort of a U.S.
−Removed: Phase I/II study.
−Removed: The high-dose cohort is planned to include 16 patients, of which 10 patients will receive treatment with AMT-130 and six patients will receive Sham surgery.
−Removed: The initiation of patient enrollment in the high-dose cohort followed a meeting of the trial’s independent DSMB that reviewed safety data for the fully enrolled first cohort of 10 patients.
−Removed: On December 16, 2021, we announced initial 12-month observations on the first four patients enrolled in the low-dose cohort of the U.S.
−Removed: Phase I/II study.
−Removed: Two of the four enrolled patients received AMT-130, and two patients received Sham surgery as a control.
−Removed: AMT-130 was generally well tolerated in the treated patients, with no serious adverse events related to AMT-130.
−Removed: NfL, a biomarker of injury in the brain, increased as expected immediately following the surgical procedure and returned to baseline in the treated patients.
−Removed: NfL remained relatively constant in the two untreated control patients.
−Removed: Structural magnetic resonance imaging did not reveal any clinically meaningful safety findings in either treated or control patients at one year of follow-up.
−Removed: Measurements of total and mutant HTT protein in the cerebral spinal fluid of the four patients were highly variable and inconclusive.
−Removed: As of December 31, 2021, 19 patients have been enrolled in the clinical trial to date, including nine of 16 in the high-dose cohort.
−Removed: Also on December 16, 2021, we announced the initiation of patient screening in our 15 patient, open-label, Phase Ib/II study of AMT-130 in the EU, as well our plans to initiate a third cohort in the ongoing U.S.
−Removed: Phase I/II clinical trial.
−Removed: The third cohort, which will include up to 18 additional randomized patients receiving the higher dose, will explore the use of alternative stereotactic navigation systems to simplify placement of catheters for infusions of AMT-130.
+Added: On March 21, 2022, we announced that we completed the enrollment of all 26 patients in the first two cohorts of our randomized, double-blinded, Phase I/II clinical trial of AMT-130 taking place in the U.S.
+Added: In the study, patients are randomized to either treatment with AMT-130 or to an imitation surgical procedure.
+Added: The treated patients have received a single administration of AMT-130 using MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into the striatum (caudate and putamen).
+Added: The trial consists of a blinded 12-month period followed by unblinded long-term follow-up for five years.
+Added: The lower-dose cohort includes 10 patients, of which six patients received treatment with AMT-130 and four patients received imitation surgery between June 19, 2020 and April 5, 2021.
+Added: The higher-dose cohort includes 16 patients, of which 10 patients received treatment with AMT-130 and six patients received imitation surgery between June 13, 2021 and March 21, 2022.
+Added: In July 2022, we initiated dosing in patients crossing over from the imitation surgical procedure arm to treatment.
+Added: A third cohort, which will include up to 18 additional randomized patients receiving the higher dose, is intended to explore the use of alternative stereotactic navigation systems to simplify placement of catheters for infusions of AMT-130.
+Added: On June 23, 2022, we announced safety and biomarker data from the 10 patients enrolled in the lower-dose cohort.
+Added: At 12 months of follow-up on the patients in the lower-dose cohort:
+Added: ● AMT-130 was generally well-tolerated with no serious adverse events related to AMT-130 reported in the treated patients.
+Added: There were two serious adverse events unrelated to AMT-130, including a deep-vein thrombosis in the elbow of one patient that was resolved with anticoagulants and transient post-operative delirium in the second patient that was resolved through supportive care.
+Added: ● In the four treated patients with evaluable data, mean levels of CSF mHTT declined at all timepoints compared to baseline and decreased by 53.8% at 12 months of follow-up (range 44% decrease to 71% decrease).
+Added: In the three control patients with evaluable data, mean levels of CSF mHTT showed an increase compared to baseline at one, three, six and nine months of follow-up, and decreased by 16.8% compared at 12 months of follow-up (range 35% increase to 47% decrease).
+Added: ● In the six treated patients, measurements of CSF NfL, a biomarker of neuronal damage, initially increased as expected following the AMT-130 surgical procedure and declined thereafter, nearing baseline at 12 months of follow-up.
+Added: At 12 months, mean CSF NfL showed an 8% increase compared to baseline (range 46% increase to 14% decrease).
+Added: Two of the six treated patients were at or below baseline at 12 months of follow-up, with an additional patient below baseline at 15 and 18 months of follow-up.
+Added: In the four control patients, mean CSF NfL remained stable or slightly declined over 12 months (range 1% increase to 35% decrease).
+Added: On June 23, 2022, we announced that in our open-label, Phase Ib/II study in the EU all six patients in the lower-dose cohort and five out of the nine patients in the higher-dose cohort had been treated with AMT-130.
+Added: In August 2022, we announced a voluntary postponement of AMT-130 higher-dose procedures due to SUSARs reported in three of the 14 patients that were treated with the higher dose of AMT-130.
+Added: Two patients experienced localized inflammatory responses and related symptoms shortly after the procedure, while the third patient experienced severe headaches and other related symptoms.
+Added: In October 2022, after completing a comprehensive safety investigation, the DSMB recommended resuming treatment at the higher dose of AMT-130 for the remaining five European patients and any patients in the U.S.
+Added: trial who are eligible to cross over from the control arm to the treatment.
+Added: All three patients have experienced full resolution of the reported SUSARs.
+Added: We have added additional risk mitigation procedures including closer patient monitoring during the first two weeks after the administration of AMT-130 and a seven-day, post-surgical in-person visit.
+Added: The DSMB recommended that the use of immunosuppression remain at the discretion of the treating physician.
Temporal Lobe Epilepsy Program (AMT-260)
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TLE affects approximately 1.3 million people in the U.S.
−Removed: and Europe alone, of which approximately 0.8 million patients are unable to adequately control acute seizures with currently approved anti-epileptic therapies.
+Added: and EU alone, of which approximately 0.8 million patients are unable to adequately control acute seizures with currently approved anti-epileptic therapies.
Patients with refractory TLE experience increased morbidity, excess mortality, and poor quality of life.
Our Development of AMT-260 for Temporal Lobe Epilepsy
−Removed: AMT-260 is being developed based on exclusive licenses to certain patents obtained in 2020 from two French research institutions that continue to collaborate with us.
+Added: In July 2021, we acquired Corlieve Therapeutics (“Corlieve”) and its lead program, now known as AMT-260, to treat temporal lobe epilepsy.
+Added: AMT-260 is being developed based on exclusive licenses to certain patents Corlieve obtained in 2020 from two French research institutions that continue to collaborate with us.
AMT-260 is a gene therapy using an AAV9 vector.
−Removed: The use of AAV9 to deliver any sequence that affects the expression of the GRIK 2 gene sequence in humans has been exclusively licensed from Regenxbio.
+Added: The use of AAV9 to deliver any sequence that affects the expression of the GRIK2 gene in humans has been exclusively licensed from Regenxbio Inc (“Regenxbio”).
Regenxbio provides contractually agreed research and development services up to the transfer of manufacturing activities to a designated contract manufacturer.
−Removed: AMT-260, employs miRNA silencing technology to target suppression of aberrantly expressed kainate receptors in the hippocampus of patients with TLE.
+Added: AMT-260, employs miRNA silencing technology to target suppression of aberrantly expressed GluK2 containing kainate receptors in the hippocampus of patients with rTLE.
In October 2021, we presented preclinical data for AMT-260 at the ESGCT.
AMT-260 reduces the expression of GluK2 in cortical neurons, reduces epileptiform activity and hyperlocomotion in a preclinical model of epilepsy and blocks epileptiform discharges in organotypic slices from patients with TLE .
+Added: In July 2022, we initiated IND-enabling, GLP toxicology studies in non-human primates for our gene therapy candidate in rTLE.
Parkinson’s Disease (AMT-210)
−Removed: AMT-210 is our preclinical product candidate for the treatment of Parkinson’s disease, targeting alpha-synuclein as a potential treatment for Parkinson’s disease.
−Removed: Parkinson’s disease is a progressive neurodegenerative disorder that leads to motor deterioration and debilitating non-motor symptoms.
−Removed: It is the second most common neurodegenerative disorder after Alzheimer’s disease, and no disease-modifying therapies are available.
−Removed: Parkinson’s disease is believed to be caused through the presence of toxic alpha-synuclein aggregates, affecting dopaminergic circuits.
−Removed: AMT-210 is a one-time, brain-targeting AAV gene therapy incorporating uniQure’s miQURE gene silencing technology.
−Removed: It is designed to halt misfolded alpha-synuclein and subsequent fibril formation in familial and sporadic Parkinson’s disease patients.
+Added: AMT-210 is our preclinical product candidate for the treatment of α-synucleinopathies, a group of neurodegenerative diseases characterized by anormal accumulation of insoluble α-synuclein in neurons and glial cells, including Parkinson’s disease, dementia with Lewy bodies and multiple systems atrophy.
+Added: Although varying in prevalence, symptom patterns, and severity among disorders, all α-synucleinopathies have in common the loss of neurons that affects longevity and quality of life.
+Added: AMT-210 is a one-time, brain-target AAV gene therapy incorporating uniQure’s miQURE gene silencing technology.
+Added: It is designed to reduce the amount of misfolded alpha-synuclein protein and subsequent fibril formation in patients with familial and sporadic disease.
Alzheimer’s Disease (AMT-240)
AMT-240 is our preclinical product candidate for the treatment autosomal dominant Alzheimer’s disease.
−Removed: Alzheimer’s disease is the most prevalent neurodegenerative disease, causing dementia and subsequent gradual loss of ability to function with disease progression.
−Removed: Apolipoprotein E (APOE) is believed to potentially be an important factor in the pathogenesis of Alzheimer’s disease.
+Added: Alzheimer’s disease causes loss of memory and dementia and is the most common neurodegenerative disease.
+Added: Human genetic studies suggest that the Apolipoprotein E (APOE) gene is an important factor in the pathogenesis of Alzheimer’s disease.
APOE consists of 3 major isoforms that are structurally and functionally different.
−Removed: The APOE4 isoform is believed to potentially be the largest risk factor to develop Alzheimer’s.
−Removed: In contrast to the toxic properties of APOE4, clinical case studies indicate a potentially protective role of other APOE variants.
−Removed: AMT-240 is a one-time gene therapy using uniQure's miQURE gene-silencing technology to silence the toxic APOE variant, in combination with overexpressing a protective APOE variant as treatment for autosomal dominant Alzheimer’s disease patients.
−Removed: Amyotrophic Lateral Sclerosis (AMT-160)
−Removed: AMT-161 is our preclinical product candidate utilizing our miQURE gene silencing technology to target toxic C9ORF72 as a potential treatment for amyotrophic lateral sclerosis (ALS).
+Added: The APOE4 isoform is associated with earlier onset of Alzheimer’s disease while APOE2 and variants of APOE3 are protective.
+Added: AMT-240 is a one-time gene therapy using uniQure's miQURE gene-silencing technology to silence the toxic APOE4 variant while expressing a protective APOE variant.
+Added: It is initially targeted as a treatment for autosomal dominant Alzheimer’s disease patients but may be effective for a broader population of patients.
+Added: Amyotrophic Lateral Sclerosis Caused by Mutations in C9ORF72 (AMT-161)
+Added: AMT-161 is our preclinical product candidate that uses our miQURE gene silencing technology to target a toxic allele of C9ORF72 as a potential treatment for ALS.
ALS is caused by degeneration of upper and lower motor neurons, resulting in muscle weakness and atrophy.
−Removed: This rapid progressive loss of motor neurons typically starts at mid-life and median survival from disease manifestation is no more than two to four years.
−Removed: The most prevalent genetic defect causing ALS is a G4C2 hexanucleotide repeat expansion in the C9ORF72 gene, which acquires toxic properties resulting in degeneration starting in motor neurons in the spinal cord.
−Removed: AMT-161 is designed to be a one-time, intrathecally-administered AAV gene therapy using the miQURE silencing technology to target repeat-expanded C9ORF72 to lower toxic RNA aggregates and prevent dipeptide protein formation.
−Removed: Spinocerebellar Ataxia, Type 3 (AMT-150)
−Removed: After conducting a comprehensive review of our product candidates, we decided in December 2021 to deprioritize the preclinical development of AMT-150, shifting resources and focus to our other research programs.
−Removed: BMS Partnered Research Programs
−Removed: We and Bristol-Myers Squibb (“BMS”) entered into a collaboration and license agreement in May 2015 (“BMS CLA”).
−Removed: The BMS CLA p rovides BMS with exclusive access to our gene therapy technology platform for four targets primarily in cardiovascular diseases.
+Added: This rapid progressive loss of motor neurons typically starts at mid-life and progresses over the course of 2-8 years, leading to loss of movement and death.
+Added: About 20% of ALS has a genetic cause.
+Added: The most common genetic mutation that causes ALS is a G4C2 hexanucleotide repeat expansion in the C9ORF72 gene.
+Added: The hexanucleotide expansion causes the formation of ribonucleic acid (“RNA”) aggregates and the production of toxic dipeptides that ultimately lead to neuronal death.
+Added: AMT-161 is a one-time, intrathecally-administered AAV gene therapy that targets the repeat-expanded C9ORF72 allele to lower toxic RNA aggregates and prevent dipeptide protein formation.
+Added: Amyotrophic Lateral Sclerosis caused by mutations in SOD1(AMT-162)
+Added: On January 31, 2023, we announced that we entered into a global licensing agreement with Apic Bio for a novel, one-time, intrathecally administered gene therapy for ALS caused by mutations in superoxide dismutase 1 (“SOD1”), a rapidly progressing, rare motor neuron disease that leads to loss of everyday functions and is uniformly fatal (previously known as APB-102).
+Added: With this agreement, we have added AMT-162 to our pipeline of gene therapies to treat neurological disorders.
+Added: The FDA has cleared the investigational new drug application for APB-102 and has granted Orphan Drug and Fast Track designation.
+Added: Mutations in the SOD1 gene of ALS account for approximately one-fifth of all inherited forms of this fatal disease.
+Added: APB-102 is comprised of a recombinant AAVrh10 vector that expresses a miRNA designed to knock down the expression of SOD1 with the goal of slowing down or potentially reversing the progression of ALS in patients with SOD1 mutations.
+Added: We plan to initiate a Phase I/II trial of AMT-162 in the second half of 2023.
New Technology Development
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We are focused on innovative technologies across each of the key components of an AAV-based gene therapy, including:
−Removed: (i) the capsid, or the outer viral protein shell that encloses the target DNA;
−Removed: (ii) the promoter, or the DNA sequence that drives the expression of the transgene;
−Removed: and (iii) the transgene, or therapeutic gene.
+Added: (i) the capsid, or the outer viral protein shell that encloses the target deoxyribonucleic acid (“DNA”);
+Added: (ii) the cargo, including the transgene or therapeutic gene, and promoters, or the DNA sequence that drives the expression of the transgene;
+Added: and (iii) administration techniques.
We dedicate significant effort to designing and screening novel AAV capsids with the potential for (i) higher biological potency;
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and (iii) enhanced safety.
−Removed: We believe we have significant expertise in vector engineering and have created promising genetically engineered capsids using a “rational design” approach.
−Removed: We are focusing our efforts on rationally engineering the AAV capsids to target them to specific cells and/or tissues.
−Removed: These engineered viruses contain antibody fragments or peptides that target them to specific tissues or cells and to diminish potential off target effects.
−Removed: We work extensively on designing synthetic promoters with the potential of enabling higher levels of protein expression in specific tissue types.
+Added: We believe we have significant expertise in vector engineering and have created promising genetically engineered capsids using both rational and directed evolution approaches.
+Added: We also work on designing synthetic promoters that enable high levels of tissue or disease specific gene expression.
A “promoter” is an essential component of a gene therapy construct that controls expression of a therapeutic protein.
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The ability to reliably produce at a high quality and at commercial scale is a critical success factor in AAV gene therapy.
−Removed: We produce our gene therapies at our state-of-the-art, Lexington, Massachusetts-based manufacturing facility using a proprietary baculovirus expression vector system.
+Added: With the exception of AMT-260 we produce our gene therapies either at our Amsterdam, the Netherlands or our commercially-licensed, Lexington, Massachusetts-based manufacturing facility using a proprietary baculovirus expression vector system.
We believe our integrated manufacturing capabilities provide us several potential advantages, including:
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Controlling cGMP manufacturing allows us to rapidly adapt our production schedule to meet the needs of our business.
−Removed: By controlling our manufacturing, we do not rely on contract manufacturers, nor do we require costly and time-consuming technology transfers to third parties.
+Added: With the exception of AMT-260 and AMT-161 programs, we do not rely on contract manufacturers, nor do we require costly and time-consuming technology transfers to third parties.
Our facility is designed to commercially supply multiple products and are flexibly designed to accommodate expansion and scale up as our needs change.
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We believe our manufacturing platform enables us to rapidly produce new products for clinical investigation, minimize time between clinical phases and complete scale-up as product candidates advance into late-stage development and commercialization.
−Removed: For example, in transitioning our hemophilia B program from AMT-060 to AMT-061, we were able to rapidly demonstrate manufacturing comparability and produce clinical material for our ongoing Phase III pivotal study.
−Removed: (4) High Purity.
−Removed: The baculovirus system eliminates the risk of introducing mammalian cell derived impurities.
(4) Scalability.
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Intellectual Property
−Removed: We strive to protect the proprietary technologies that we believe are important to our business, including seeking and maintaining patent protection in the United States, Europe, and other countries for novel components of gene therapies, the chemistries, and processes for manufacturing these gene therapies, the use of these components in gene therapies, our technology platform, and other inventions and related technology.
+Added: We strive to protect the proprietary technologies that we believe are important to our business, including seeking and maintaining patent protection in the U.S., Europe, and other countries for novel components of gene therapies, the chemistries, and processes for manufacturing these gene therapies, the use of these components in gene therapies, our technology platform, and other inventions and related technology.
We also rely on trade secrets, security measures and careful monitoring of our proprietary information to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.
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Because most patent applications throughout the world are confidential for 18 months after the earliest claimed priority date, and since the publication of discoveries in the scientific and patent literature often lags actual discoveries, we cannot be certain that we were the first to invent or file applications for the inventions covered by our pending patent applications.
−Removed: Moreover, we may have to participate in post-grant proceedings in the patent offices of the United States or foreign jurisdictions, such as oppositions, reexaminations, or interferences, in which the patentability or priority of our inventions are challenged.
+Added: Moreover, we may have to participate in post-grant proceedings in the patent offices of the U.S.
+Added: or foreign jurisdictions, such as oppositions, reexaminations, or interferences, in which the patentability or priority of our inventions are challenged.
Such proceedings could result in substantial cost, even if the eventual outcome is favorable to us.
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In addition, we have filed manufacturing patent applications with claims directed to alternative compositions-of-matter and manufacturing processes to seek better protection from competitors.
−Removed: We file the initial patent applications for our commercially important technologies in both Europe and the United States.
+Added: We file the initial patent applications for our commercially important technologies in both Europe and the U.S..
For the same technologies, we typically file international patent applications under the PCT within a year.
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These patents relate to a variety of technologies including our product candidates that are in development and our manufacturing and technology platform.
−Removed: Our Patent Portfolio Related to Certain Development Programs
+Added: Our Patent Portfolio Related to Certain Programs
Hemophilia B (AMT-061)
−Removed: We own a patent family, including patents and patent applications, directed to the use of the Padua mutation in hFIX for gene therapy in etranacogene dezaparvovec.
+Added: We own a patent family, including patents and patent applications, directed to the use of the Padua mutation in human Factor IX (“hFIX”) for gene therapy in etranacogene dezaparvovec.
Huntington’s disease (AMT-130)
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In 2018, we entered into an amendment of the license agreement with CSHL that expanded the license to include the diagnosis, treatment, or prevention of all CNS diseases in the Field, including but not limited to Huntington’s disease.
−Removed: In addition, under the amended license agreement CSHL granted to us an exclusive license for a three-year term to develop and commercialize therapeutic products for the additional disease classifications in the Field of liver diseases, neuromuscular diseases, and cardiovascular diseases.
−Removed: If we meet certain diligence milestones during the initial three-year development term, we may include exclusively additional disease classifications within the additional Fields on similar terms and conditions as the CNS diseases.
−Removed: Under this license agreement, annual fees, development milestone payments and future single-digit royalties on net sales of a licensed product are payable to CSHL.
+Added: Under the amended license agreement CSHL granted to us an exclusive license to develop and commercialize therapeutic products for the additional disease classifications in the Field of liver diseases, neuromuscular diseases, and cardiovascular diseases and we have subsequently added such products to our pipeline.
+Added: Under this license agreement, as amended, annual fees, development milestone payments and future single-digit royalties on net sales of a licensed product are payable to CSHL.
Protein Sciences
In 2016, we revised our existing license contract with Protein Sciences Corporation for the use of its expresSF + insect cell line and associated technology for human therapeutic and prophylactic uses (except influenza) to provide us with a royalty free, perpetual right and license to the licensed technology in the field of AAV-based gene therapy.
−Removed: National Institutes of Health—AAV production
−Removed: In 2007, we entered into a non-exclusive license agreement with the NIH, which we amended in 2009 and 2013.
−Removed: The patents under this license cover technology to produce AAV vectors in insect cells.
−Removed: We may only grant sublicenses under this agreement with the NIH’s consent, which may not be unreasonably withheld.
−Removed: The standard 20-year term for the underlying patents will expire in 2022.
−Removed: Payment obligations to the NIH under this license agreement include a low single-digit percentage royalty on the net sales of licensed products by us or on our behalf;
−Removed: development and regulatory milestone payments;
−Removed: and an annual maintenance fee creditable against royalties.
−Removed: We do not have to pay royalties or milestone fees under this agreement if we must pay royalties or milestone fees under our 2011 agreement with the NIH, described below, for the same product.
−Removed: Under the license agreement, we have agreed to meet benchmarks in our development efforts, including as to development events, clinical trials, and marketing approval, within specified timeframes.
−Removed: The NIH may terminate this agreement in specified circumstances relating to our insolvency or bankruptcy.
−Removed: We may terminate this agreement for any reason, in any territory, subject to a specified notice period.
−Removed: National Institutes of Health—AAV5
−Removed: In 2011, we entered into another license agreement with the NIH, superseding the 2007 agreement.
−Removed: This agreement was amended in 2016.
−Removed: Under this agreement, the NIH granted us an exclusive, worldwide license to patents relating to AAV5 for use in therapeutic products to be delivered to the brain or liver for treatment of human diseases originating in the brain or liver but excluding arthritis-related diseases, and a non-exclusive, worldwide license to patents relating to AAV5 for all other diseases.
−Removed: We refer to the products licensed under this agreement as AAV5 products.
−Removed: We may grant sublicenses under this agreement only with the NIH’s consent, which may not be unreasonably withheld.
−Removed: The last patent under this license expired in July 2021.
−Removed: Payment obligations to the NIH under this license agreement include royalties equal to a low single-digit percentage of net sales of AAV5 products;
−Removed: development and regulatory milestone payments;
−Removed: and an annual maintenance fee creditable against royalties.
−Removed: If an AAV5 product is also covered by our 2007 agreement with the NIH, our obligation to pay royalties on net sales and our obligation to pay milestone fees only apply under this 2011 agreement and not the 2007 agreement.
−Removed: We have agreed to meet benchmarks in our development efforts, including as to development events, clinical trials, and marketing approval, within specified timeframes.
Technology Used for Specific Development Programs
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Pursuant to the Padua Assignment, we acquired from Dr.
−Removed: Simioni all right, title and interest in a patent family covering the variant of the FIX gene, carrying an R338L mutation (FIX-Padua;
+Added: Simioni all rights, title and interest in a patent family covering the variant of the FIX gene, carrying an R338L mutation (FIX-Padua;
Under the Padua Assignment, we have also licensed certain know-how included in the Padua IP.
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Jude on an apportionment of certain amounts we receive from CSL Behring as sublicensing revenue that is equivalent to a low-single digit percentage of such amounts.
−Removed: We have also agreed to pay St.
−Removed: Jude a one-time milestone of $5.0 million upon the BLA and MAA approval, and an annual maintenance fee creditable against royalties and milestones in the same year.
The agreement will remain in effect until no further payment is due relating to any licensed product under this agreement or either we or St.
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Temporal Lobe Epilepsy
−Removed: In June 2020, Corlieve entered into an agreement, subsequently amended in June 2021, with Regenxbio for an exclusive (in the field of using AAV9 to expression of the GRIK 2 gene in humans (the “Field”)), sublicensable, royalty-bearing, worldwide license under Regenxbio’s interest in EU patent application 19185533.7 (the “Foreground Patents”) and related patents, as well as patents covering inventions developed during the collaboration and certain patents and know-how relating to AAV9 (the “Background Technology”).
+Added: In June 2020, Corlieve entered into an agreement, subsequently amended in June 2021, with Regenxbio for an exclusive (in the field of using AAV9 to expression of the GRIK2 gene in humans (the “Field”)), sublicensable, royalty-bearing, worldwide license under Regenxbio’s interest in EU patent application 19185533.7 (the “Foreground Patents”) and related patents, as well as patents covering inventions developed during the collaboration and certain patents and know-how relating to AAV9.
The license also includes non-exclusive rights to exploit the licensed Foreground Patents and certain related patents know-how developed in collaboration pursuant to the license agreement outside the Field.
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We also seek to preserve the integrity and confidentiality of our data, trade secrets and know-how by maintaining physical security of our premises and physical and electronic security of our information technology systems.
−Removed: We have a number of material registered trademarks, including “uniQure”, that we have registered in various jurisdictions including the United States and the European Union.
+Added: We have a number of material registered trademarks, including “uniQure”, that we have registered in various jurisdictions including the U.S.
We may seek trademark protection for other product candidates and technologies as and when appropriate.
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We face worldwide competition from larger pharmaceutical companies, specialty pharmaceutical companies and biotechnology firms, universities and other research institutions and government agencies that are developing and commercializing pharmaceutical products.
−Removed: Our key competitors focused on developing therapies in various indications, include among others, Pfizer, Freeline Therapeutics, Intellia Therapeutics, Sangamo Biosciences, Voyager Therapeutics, Passage Bio, Roche, PTC Therapeutics, Prilenia Therapeutics, Triplet Therapeutics, CombiGene, AvroBio, Caritas Therapeutics, and 4D Molecular Therapeutics.
+Added: Our key competitors focused on developing therapies in various indications, include among others, Pfizer, Freeline Therapeutics, Intellia Therapeutics, Sangamo Biosciences, Voyager Therapeutics, Passage Bio, Roche, PTC Therapeutics, Prilenia Therapeutics, CombiGene, Caritas Therapeutics, Alnylam, Wave Life Sciences, Bayer AG, Amicus Therapeutics and 4D Molecular Therapeutics.
We also compete with existing standards of care, therapies, and symptomatic treatments, as well as any new therapies that may become available in the future for the indications we are targeting.
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Government Regulation and Reimbursement
−Removed: Government authorities in the United States, European Union and other countries extensively regulate, among other things, the approval, research, development, preclinical and clinical testing, manufacture (including any manufacturing changes), packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, reimbursement, and import and export of pharmaceutical products, biological products, and medical devices.
+Added: Government authorities in the U.S., EU and other countries extensively regulate, among other things, the approval, research, development, nonclinical and clinical testing, manufacture (including any manufacturing changes), packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, reimbursement, and import and export of pharmaceutical products, biological products, and medical devices.
We believe that all our product candidates will be regulated as biological products, or biologics, and in particular, as gene therapies, and will be subject to such requirements and regulations under U.S.
and foreign laws.
−Removed: For other countries outside of the United States and the European Union, marketing approval and pricing and reimbursement requirements vary from country to country.
−Removed: If we fail to comply with applicable regulatory requirements, we may be subject to, among other things, fines, refusal to approve pending applications, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions, and criminal prosecution.
+Added: For other countries outside of the U.S.
+Added: and the EU, marketing approval and pricing and reimbursement requirements vary from country to country.
+Added: If we fail to comply with applicable regulatory requirements, we may be subject to, among other things, civil penalties, refusal to approve pending applications, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions, and criminal prosecution.
Regulation in the United States
−Removed: In the United States, the FDA regulates biologics under the Public Health Service Act (“PHSA”) and the Federal Food, Drug, and Cosmetic Act (“FDCA”) and regulations and guidance implementing these laws.
+Added: In the U.S., the FDA regulates biologics under the Public Health Service Act (“PHSA”) and the Federal Food, Drug, and Cosmetic Act (“FDCA”) and regulations and guidance implementing these laws.
These laws and regulatory guidance are continually evolving.
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Congress passed the Coronavirus Aid, Relief, and Economic Security Act, or CARES Act, which includes various provisions regarding FDA drug shortage reporting requirements, as well as provisions regarding supply chain security, such as risk management plan requirements, and the promotion of supply chain redundancy and domestic manufacturing.
−Removed: The FDA has also issued a number of guidance documents concerning how sponsors and investigators may address COVID-19 challenges, including challenges specific to gene therapies.
+Added: Executive actions have also been issued to encourage domestic manufacturing and the Consolidated Appropriations Act, 2023, was passed at the end of 2022, which included a number of updates to the FDCA.
+Added: FDA has issued a number of guidance documents concerning how sponsors and investigators may address COVID-19 challenges, including challenges specific to gene therapies.
These guidance documents are continually evolving.
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All our current product candidates are subject to regulation by the FDA as biologics.
−Removed: An applicant seeking approval to market and distribute a new biologic in the United States must typically undertake the following:
−Removed: ● completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s current Good Laboratory Practice regulations;
+Added: An applicant seeking approval to market and distribute a new biologic in the U.S.
+Added: must typically undertake the following:
+Added: ● completion of nonclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s current Good Laboratory Practice regulations;
● submission to the FDA of an IND application which allows human clinical trials to begin unless the FDA objects within 30 days;
−Removed: the sponsor of an IND or its legal representative must be based in the United States
−Removed: ● approval by an independent institutional review board (“IRB”) and Institutional Biosafety Committee (“IBC”) before each clinical trial may be initiated;
−Removed: ● performance of adequate and well-controlled human clinical trials in accordance with the FDA’s cGCP to establish substantial evidence of the safety and efficacy proposed biological product for each indication;
−Removed: ● preparation and submission to the FDA of a BLA;
−Removed: ● satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with cGMP requirements and to assure that the facilities, methods, and controls are adequate to preserve the product’s identity, strength, quality, and purity, as well as selected clinical trial sites and investigators to determine cGCP compliance;
+Added: the sponsor of an IND or its legal representative must be based in the U.S.;
+Added: ● approval by an independent institutional review board (“IRB”) and, for some studies, Institutional Biosafety Committee (“IBC”) before each clinical trial may be initiated;
+Added: ● performance of adequate and well-controlled human clinical trials in accordance with the FDA’s cGCP to establish substantial evidence of the safety and efficacy for the proposed biological product for each indication;
+Added: ● preparation and submission to the FDA of a Biologics License Application (“BLA”);
+Added: ● satisfactory completion of one or more FDA inspections or remote regulatory assessments of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with cGMP requirements and to assure that the facilities, methods, and controls are adequate to preserve the product’s identity, strength, quality, and purity, as well as selected clinical trial sites and investigators to determine cGCP compliance;
● approval of the BLA by the FDA, in consultation with an FDA advisory committee, if deemed appropriate by the FDA;
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Human Clinical Studies in the United States under an IND
−Removed: Before initiating clinical studies in the United States or under an IND, investigational product sponsors must first complete pre-clinical studies.
−Removed: Preclinical studies include laboratory evaluation of chemistry, pharmacology, toxicity, and product formulation, as well as animal studies to assess potential safety and efficacy.
−Removed: Such studies must generally be conducted in accordance with the FDA’s Good Laboratory Practices (“GLPs”).
+Added: Before initiating clinical studies in the U.S.
+Added: or under an IND, investigational product sponsors must first complete nonclinical studies.
+Added: Nonclinical studies include laboratory evaluation of chemistry, pharmacology, toxicity, and product formulation, as well as animal studies to assess potential safety and efficacy.
+Added: Such studies must generally be conducted in accordance with the FDA’s GLPs.
Clinical trials involve the administration of the investigational biologic to human subjects under the supervision of qualified investigators in accordance with current GCP requirements, which includes requirements for informed consent, study conduct, and IRB review and approval.
+Added: Special clinical trial ethical considerations also must be taken into account if a study involves children.
A protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of an IND.
−Removed: INDs include preclinical study reports, together with manufacturing information, analytical data, any available clinical data, or literature, and proposed clinical study protocols among other things.
−Removed: A clinical trial may not proceed in the United States unless and until an IND becomes effective, which is 30 days after its receipt by the FDA.
+Added: Sponsors must also provide FDA with diversity action plans.
+Added: INDs include nonclinical study reports, together with manufacturing information, analytical data, any available clinical data, or literature, and proposed clinical study protocols among other things.
+Added: A clinical trial may not proceed in the U.S.
+Added: unless and until an IND becomes effective, which is 30 days after its receipt by the FDA.
The FDA may raise concerns or questions related to one or more components of an IND and place the IND on clinical hold if during its review the FDA determines that study subjects would be exposed to significant risk of illness or injury.
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The protocol and informed consent documents, as well as other subject communications must also be approved by an IRB that continues to oversee that trial.
−Removed: In the case of gene therapy studies, an IBC at the local level must also review and maintain oversight over the particular study, in addition to the IRB.
+Added: In the case of gene therapy studies, an IBC at the local level may also review and maintain oversight over the particular study, in addition to the IRB.
The FDA, an IRB, and IBC, or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk or that research requirements are not being met.
+Added: Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor that regularly reviews accumulated data and advises the study sponsor regarding the continuing safety of the trial.
+Added: This group may also review interim data to assess the continuing validity and scientific merit of the clinical trial.
+Added: This group receives special access to unblinded data during the clinical trial and may advise the sponsor to halt, pause, or otherwise modify the clinical trial.
Information about certain clinical trials, including results, must be submitted within specific timeframes for listing on the ClinicalTrials.gov website.
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Under some limited circumstances, however, the FDA may approve a BLA based upon a single Phase 3 clinical study plus confirmatory evidence or a single large multicenter trial without confirmatory evidence.
−Removed: In addition, under the Pediatric Research Equity Act, or PREA, a BLA or BLA supplement for a new active ingredient, indication, dosage form, dosage regimen, or route of administration, must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.
+Added: Recent legislation further established a new program that may be used to facilitate future marketing applications and development programs following a first product approval.
+Added: Specifically, the Consolidated Appropriations Act, 2023 established a program whereby a platform technology that is incorporated within or utilized by an approved drug or biologic product may be designated as a platform technology, provided that certain conditions are met, in which case development and approval of subsequent products using such technology may be expedited.
+Added: In addition, under the Pediatric Research Equity Act (the “PREA”), a BLA or BLA supplement for a new active ingredient, indication, dosage form, dosage regimen, or route of administration, must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.
The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.
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The manufacture of investigational drugs and biologics for the conduct of human clinical trials is subject to cGMP requirements.
−Removed: Investigational drugs and biologics and active ingredients and therapeutic substances imported into the United States are also subject to regulation by the FDA.
−Removed: Further, the export of investigational products outside of the United States is subject to regulatory requirements of the receiving country as well as U.S.
+Added: Investigational drugs and biologics and active ingredients and therapeutic substances imported into the U.S.
+Added: are also subject to regulation by the FDA.
+Added: Further, the export of investigational products outside of the U.S.
+Added: is subject to regulatory requirements of the receiving country as well as U.S.
export requirements under the FDCA.
−Removed: Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the product candidate as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.
+Added: Concurrent with clinical trials, companies usually complete additional nonclinical animal studies and must also develop additional information about the chemistry and physical characteristics of the product candidate as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.
The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, manufacturers must develop methods for testing the identity, strength, quality, potency, and purity of the final product.
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The FDA has also issued guidance documents specific to gene therapies during the COVID-19 public health emergency, including one on manufacturing considerations and the conduct of risk assessments.
−Removed: FDA has further issued guidance focused on the development of gene therapies for the treatment of rare neurodegenerative diseases, rare diseases, and hemophilia, as such products may face special challenges.
+Added: FDA has further issued guidance focused on the development of gene therapies for the treatment of neurodegenerative diseases, rare diseases, and hemophilia, as such products may face special challenges.
Certain gene therapy studies are also subject to the National Institutes of Health’s Guidelines for Research Involving Recombinant DNA Molecules, (“NIH Guidelines”).
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Recently, the information that must be submitted to the FDA regarding manufactured products was expanded through the Coronavirus Aid, Relief, and Economic Security, or CARES, Act to include the volume of drugs produced during the prior year.
−Removed: Establishments may be subject to periodic unannounced inspections by government authorities to ensure compliance with cGMPs and other laws.
+Added: Establishments may be subject to periodic unannounced inspections and remote regulatory assessments by government authorities to ensure compliance with cGMPs and other laws.
Discovery of non-compliance may result in the FDA placing restrictions on a product, manufacturer, or holder of an approved BLA, and may extend to requiring withdrawal of the product from the market, among other consequences.
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A biologic candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase 4 or post-approval clinical trials to confirm the effect on the clinical endpoint.
−Removed: Failure to conduct required post-approval studies, or confirm a clinical benefit during post-marketing studies, will allow the FDA to withdraw the drug or biologic from the market on an expedited basis.
+Added: By the date of approval of an accelerated approval product, FDA must specify the conditions for the required post approval studies, including enrollment targets, the study protocol, milestones, and target completion dates.
+Added: FDA may also require that the confirmatory Phase 4 studies be commenced prior to FDA granting a product accelerated approval.
+Added: Reports on the progress of the required Phase 4 confirmatory studies must be submitted to FDA every 180 days after approval.
+Added: Failure to conduct required post-approval studies, or confirm a clinical benefit during post-marketing studies, will allow the FDA to withdraw the drug or biologic from the market on an expedited basis using a statutorily defined streamlined process.
+Added: Failure to conduct the required Phase 4 confirmatory studies or to conduct such studies with due diligence, as well as failure to submit the required update reports can subject a sponsor to penalties..
All promotional materials for drug or biologic candidates approved under accelerated regulations are subject to prior review by the FDA.
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Accordingly, the FDA may be more conservative in granting accelerated approval or, if granted, may be more apt to withdrawal approval if clinical benefit is not confirmed.
+Added: FDA may also require that the confirmatory Phase 4 study be commenced prior to FDA granting a product accelerated approval.
Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.
Submission of a BLA
−Removed: The results of the preclinical and clinical studies, together with detailed information relating to the product’s chemistry, manufacture, controls, and proposed labeling, among other things, are submitted to the FDA as part of a BLA requesting a license to market the product for one or more indications.
+Added: The results of the nonclinical and clinical studies, together with detailed information relating to the product’s chemistry, manufacture, controls, and proposed labeling, among other things, are submitted to the FDA as part of a BLA requesting a license to market the product for one or more indications.
The submission of a BLA is subject to an application user fee, though products with orphan designation are exempt from the BLA filing fee.
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The PDUFA action date is only a goal, thus, the FDA does not always meet its PDUFA dates.
−Removed: Additionally, this review period may change as the PDUFA statute must be reauthorized by Congress by September 2022.
The FDA may also refer certain applications to an advisory committee.
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The FDA reviews applications to determine, among other things, whether a product candidate meets the agency’s approval standards and whether the manufacturing methods and controls are adequate to assure and preserve the product’s identity, strength, quality, potency, and purity.
−Removed: Before approving a marketing application, the FDA typically will inspect the facility or facilities where the product is manufactured, referred to as a Pre-Approval Inspection.
+Added: Before approving a marketing application, the FDA typically will inspect or conduct remote regulatory assessments of the facility or facilities where the product is manufactured.
The FDA will not approve an application unless it determines that the manufacturing processes and facilities, including contract manufacturers and subcontractors, are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.
−Removed: Additionally, before approving a marketing application the FDA will inspect one or more clinical trial sites to assure compliance with GCPs.
−Removed: After evaluating the marketing application and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter or a complete response letter.
+Added: Additionally, before approving a marketing application the FDA will inspect or conduct remote regulatory assessments one or more clinical trial sites to assure compliance with good clinical practices (“GCPs”).
+Added: After evaluating the marketing application and all related information, including the advisory committee recommendation, if any, and inspection and remote regulatory inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter or a complete response letter.
An approval letter authorizes commercial marketing of the biological product with specific prescribing information for specific indications.
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require that contraindications, warnings, or precautions be included in the product labeling, including boxed warnings;
−Removed: require that post-approval studies, including Phase IV clinical trials, be conducted to further assess a biologic’s efficacy and safety after approval;
+Added: require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a biologic’s efficacy and safety after approval;
or require testing and surveillance programs to monitor the product after commercialization.
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The Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) which amended the PHSA authorized the FDA to approve biosimilars under Section 351(k) of the PHSA.
−Removed: Under the BCPIA, a manufacturer may submit an application for licensure of a biologic product that is biosimilar to or interchangeable with a previously approved biological product or reference product.
+Added: Under the BPCIA, a manufacturer may submit an application for licensure of a biologic product that is biosimilar to or interchangeable with a previously approved biological product or reference product.
For the FDA to approve a biosimilar product, it must find that it is highly similar to the reference product notwithstanding minor differences in clinically inactive components and that there are no clinically meaningful differences between the reference product and proposed biosimilar product in safety, purity or potency.
A finding of interchangeability requires that a product is determined to be biosimilar to the reference product, and that the product can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.
−Removed: An application for a biosimilar product may not be submitted to the FDA until four years following approval of the reference product, and it may not be approved until 12 years thereafter.
+Added: An application for a biosimilar product may not be submitted to the FDA until four years following approval of the reference product, and it may not be approved until 12 years following approval of the reference product.
These exclusivity provisions only apply to biosimilar companies and not companies that rely on their own data and file a full BLA.
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Certain changes and supplements to an approved BLA, and subsequent applications filed by the same sponsor, manufacturer, licensor, predecessor in interest, or other related entity do not qualify for the twelve-year exclusivity period.
−Removed: Further, the twelve-year exclusivity market period in the U.S.
+Added: Further, the twelve-year exclusivity period in the U.S.
for biologics has been controversial and may be shortened in the future.
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This list includes product names, the date of licensure, and any periods of regulatory exclusivity.
−Removed: Additionally, under a newly enacted statute related to biological product patent transparency, following the exchange of patent information between the biosimilar and reference product sponsor, the reference product sponsor must also provide the exchanged patent information and patent expiry dates to the FDA.
+Added: Following the exchange of patent information between the biosimilar and reference product sponsor, the reference product sponsor must also provide the exchanged patent information and patent expiry dates to the FDA.
The FDA then publishes this information in the Purple Book.
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Orphan Drug Exclusivity
−Removed: Under the Orphan Drug Act of 1983, the FDA may designate a biological product as an orphan drug if it is intended to treat a rare disease or condition that affects fewer than 200,000 individuals in the United States, or more in cases in which there is no reasonable expectation that the cost of developing and making a biological product available in the United States for treatment of the disease or condition will be recovered from sales of the product.
+Added: Under the Orphan Drug Act of 1983, the FDA may designate a biological product as an orphan drug if it is intended to treat a rare disease or condition that affects fewer than 200,000 individuals in the U.S., or more in cases in which there is no reasonable expectation that the cost of developing and making a biological product available in the U.S.
+Added: for treatment of the disease or condition will be recovered from sales of the product.
Additionally, sponsors must present a plausible hypothesis for clinical superiority to obtain orphan drug designation if there is a product already approved by the FDA that is considered by the FDA to be the same as the already approved product and is intended for the same indication.
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Any of the FDA sameness determinations could impact our ability to receive approval for our product candidates and to obtain or retain orphan drug exclusivity.
−Removed: If a product with orphan designation receives the first FDA approval, it will be granted seven years of marketing exclusivity, which means that the FDA may not approve any other applications for the same product for the same indication for seven years, unless clinical superiority is demonstrated.
+Added: If a product with orphan designation receives the first FDA approval, it may be granted seven years of marketing exclusivity, which means that the FDA may not approve any other applications for the same product for the same indication for seven years, unless clinical superiority is demonstrated.
Competitors may receive approval of different products for the indication for which the orphan product has exclusivity and may obtain approval for the same product but for a different indication.
−Removed: Orphan product designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.
−Removed: The FDA has granted orphan drug designation to AMT-130 for the treatment of Huntington’s disease as well as for etranacogene dezaparvovec;
−Removed: meaning that they would receive orphan drug exclusivity if they are the first products approved for their respective indications.
+Added: Notably, a 2021 judicial decision, Catalyst Pharms., Inc.
+Added: Becerra, challenged and reversed an FDA decision on the scope of orphan product exclusivity for the drug, Firdapse .
+Added: Under this decision, orphan drug exclusivity for Firdapse blocked approval of another company’s application for the same drug for the entire disease or condition for which orphan drug designation was granted, not just the disease or condition for which approval was received.
+Added: In a January 2023 Federal Register notice, however, FDA stated that it intends to continue to apply its regulations tying the scope of orphan-drug exclusivity to the uses or indications for which a drug is approved.
+Added: The exact scope of orphan drug exclusivity will likely be an evolving area.
Pediatric Exclusivity
−Removed: Under the Pediatric Research Equity Act of 2003, pediatric exclusivity provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity in the US, including orphan exclusivity and exclusivity against biosimilars.
+Added: Under the Pediatric Research Equity Act of 2003, pediatric exclusivity provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity in the US, including orphan exclusivity and reference biologic exclusivity.
This six-month exclusivity may be granted if the FDA issues a written request to the sponsor for the pediatric study, the sponsor submits a final study report after receipt of the written request and meets the terms and timelines in the FDA’s written request.
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and 3) preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition.
−Removed: A RMAT must be made with the submission of an IND or as an amendment to an existing IND.
+Added: A RMAT designation request must be made with the submission of an IND or as an amendment to an existing IND.
FDA will determine if a product is eligible for RMAT designation within 60 days of submission.
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Moreover, clinical trial sponsors using investigational devices in their studies must comply with FDA’s investigational device exemption regulations.
−Removed: Once approved or cleared, the device component sponsor (or the combination product sponsor, if both components are covered by one application) must comply with the FDA’s post-market device requirements, including establishment registration, device listing, device labeling, unique device identifier, quality system regulation, medical device reporting, and reporting of corrections and removals requirements.
+Added: Once approved or cleared, the device component sponsor (or the combination product sponsor, if both components are covered by one application) must comply with the remaining FDA general controls, including establishment registration, device listing, device labeling, unique device identifier, quality system regulation, medical device reporting, and reporting of corrections and removals requirements.
If the safety or effectiveness of a biologic product is dependent on the results of a diagnostic, the FDA may require that the in vitro companion diagnostic device and biologic product be contemporaneously approved, with labeling that describes the use of the two products together.
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A premarket approval (“PMA”), application is required for high risk devices classified as Class III;
−Removed: a 510(k) premarket notification is required for moderate risk devices classified as Class II;
+Added: a 510(k) premarket notification is required for moderate risk devices classified as Class II A de novo request may be used for devices not previously classified by the FDA (and hence are automatically Class III) but are low or moderate risk (due to the application of special controls) and thus are classified as Class II.
and a de novo request may be used for novel devices not previously classified by the FDA that are low or moderate risk.
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A company can make only those claims relating to a product that are approved by the FDA.
−Removed: Physicians, in their independent professional medical judgment, may prescribe legally available products for unapproved indications that are not described in the product’s labeling and that differ from those tested and approved by the FDA.
+Added: Physicians, in their independent professional medical judgment, may prescribe legally available products for unapproved indications that are not described in the product’s labeling and that differ from those tested and that have been approved by the FDA.
Biopharmaceutical companies, however, are required to promote their products only for the approved indications and in accordance with the provisions of the approved label.
−Removed: The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability, including, but not limited to, criminal and civil penalties under the FDCA and False Claims Act, exclusion from participation in federal healthcare programs, mandatory compliance programs under corporate integrity agreements, suspension and debarment from government procurement and non-procurement programs, and refusal of orders under existing government contracts.
+Added: The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability, including, but not limited to, criminal fines and civil penalties under the FDCA and False Claims Act, exclusion from participation in federal healthcare programs, mandatory compliance programs under corporate integrity agreements, suspension and debarment from government procurement and non-procurement programs, and refusal of orders under existing government contracts.
In addition, the distribution of prescription biopharmaceutical samples is subject to the Prescription Drug Marketing Act (the “PDMA”), which regulates the distribution of samples at the federal level.
−Removed: Both the PDMA and state laws limit the distribution of prescription biopharmaceutical product.
−Removed: Certain reporting related to samples is also required and laws and regulations impose requirements to ensure accountability in distribution.
+Added: Both the PDMA and state laws limit the distribution of prescription biopharmaceutical products.
+Added: Certain reporting related to samples is also required under federal and state laws and regulations, some of which impose requirements to ensure accountability in distribution.
Free trial or starter prescriptions provided through pharmacies are also subject to regulations under the Medicaid Drug Rebate Program and potential liability under anti-kickback and false claims laws.
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Among the requirements of this legislation, sponsors are required to provide certain information regarding the products to individuals and entities to which product ownership is transferred, are required to label products with a product identifier, and are required to keep certain records regarding the product.
−Removed: The transfer of information to subsequent product owners by sponsors is also required to be done electronically.
+Added: The transfer of information to subsequent product owners by sponsors is also required to be done electronically and will be required to allow interoperable electronic product tracing at the package level by November 2023.
Sponsors must also verify that purchasers of the sponsors’ products are appropriately licensed.
−Removed: Further, under this legislation, manufactures have product investigation, quarantine, disposition, and notification responsibilities related to counterfeit, diverted, stolen, and intentionally adulterated products that would result in serious adverse health consequences or death to humans, as well as products that are the subject of fraudulent transactions or which are otherwise unfit for distribution such that they would be reasonably likely to result in serious health consequences or death.
+Added: Further, under this legislation, manufactures have product verification responsibilities, as well as investigation, quarantine, disposition, and notification responsibilities related to counterfeit, diverted, stolen, and intentionally adulterated products that would result in serious adverse health consequences or death to humans, as well as products that are the subject of fraudulent transactions or which are otherwise unfit for distribution such that they would be reasonably likely to result in serious health consequences or death.
Similar requirements additionally are also imposed through this legislation on other companies within the biopharmaceutical product supply chain, such as distributors and dispensers, as well as certain sponsor licensees and affiliates.
Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements before or after approval, may result in significant regulatory actions.
−Removed: Such actions may include refusal to approve pending applications, license or approval suspension or revocation, imposition of a clinical hold or termination of clinical trials, warning letters, untitled letters, cyber letters, modification of promotional materials or labeling, provision of corrective information, imposition of post-market requirements including the need for additional testing, imposition of distribution or other restrictions under a REMS, product recalls, product seizures or detentions, refusal to allow imports or exports, total or partial suspension of production or distribution, FDA debarment, injunctions, fines, consent decrees, corporate integrity agreements, suspension and debarment from government procurement and non-procurement programs, and refusal of orders under existing government contracts, exclusion from participation in federal and state healthcare programs, restitution, disgorgement, or civil or criminal penalties, including fines and imprisonment, and adverse publicity, among other adverse consequences.
+Added: Such actions may include refusal to approve pending applications, license or approval suspension or revocation, imposition of a clinical hold or termination of clinical trials, warning letters, untitled letters, cyber letters, modification of promotional materials or labeling, provision of corrective information, imposition of post-market requirements including the need for additional testing, imposition of distribution or other restrictions under a REMS, product recalls, product seizures or detentions, refusal to allow imports or exports, total or partial suspension of production or distribution, FDA debarment, injunctions, consent decrees, corporate integrity agreements, suspension and debarment from government procurement and non-procurement programs, refusal of orders under existing government contracts, exclusion from participation in federal and state healthcare programs, restitution, disgorgement, civil penalties, criminal prosecution, including fines and imprisonment, and adverse publicity, among other adverse consequences.
Additional controls for biologics
To help reduce the increased risk of the introduction of adventitious agents, the PHSA emphasizes the importance of manufacturing controls for products whose attributes cannot be precisely defined.
−Removed: The PHSA also provides authority to the FDA to immediately suspend licenses in situations where there exists a danger to public health, to prepare or procure products in the event of shortages and critical public health needs, and to authorize the creation and enforcement of regulations to prevent the introduction or spread of communicable diseases in the United States and between states.
+Added: The PHSA also provides authority to the FDA to immediately suspend licenses in situations where there exists a danger to public health, to prepare or procure products in the event of shortages and critical public health needs, and to authorize the creation and enforcement of regulations to prevent the introduction or spread of communicable diseases in the U.S.
+Added: and between states.
After a BLA is approved, the product may also be subject to official lot release as a condition of approval.
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The Patient Protection and Affordable Care Act, of 2010, as amended, (the “ACA”) modified the intent requirement under the Anti-Kickback Statute to a stricter standard, such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it to have committed a violation.
−Removed: In addition, the ACA also provided that a violation of the federal Anti-Kickback Statute is grounds for the government or a whistleblower to assert that a claim for payment of items or services resulting from such violation constitutes a per se false or fraudulent claim for purposes of the federal civil False Claims Act.
+Added: In addition, the ACA also provided that a violation of the federal Anti-Kickback Statute is grounds for the government or a whistleblower to assert that a claim for reimbursement submitted to a federal healthcare program for payment of items or services resulting from such violation constitutes a per se false or fraudulent claim for purposes of the federal civil False Claims Act.
The Department of Health and Human Services (“HHS”) recently promulgated a regulation with respect to the safe harbors that is effective in two phases.
First, the regulation excludes from the definition of “remuneration” limited categories of (a) Pharmacy Benefit Manager (“PBM”) rebates or other reductions in price to a plan sponsor under Medicare Part D or a Medicaid Managed Care Organization plan reflected in point-of-sale reductions in price and (b) PBM service fees.
−Removed: Second, the regulation expressly provides that rebates to plan sponsors under Medicare Part D either directly to the plan sponsor under Medicare Part D, or indirectly through a pharmacy benefit manager will not be protected under the anti-kickback discount safe harbor.
+Added: Second, the regulation expressly provides that rebates to plan sponsors under Medicare Part D, either directly to the plan sponsor under Medicare Part D or indirectly through a PBM, will not be protected under the Anti-Kickback Statute discount safe harbor.
Recent legislation delayed implementation of this portion of the rule until January 1, 2026, and further proposed legislation would permanently prohibit implementation of the rule beginning in 2026.
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Civil False Claims Act liability may further be imposed for known Medicare or Medicaid overpayments, for example, overpayments caused by understated rebate amounts, that are not refunded within 60 days of discovering the overpayment, even if the overpayment was not caused by a false or fraudulent act.
−Removed: In addition, conviction, or civil judgment for violating the FCA may result in exclusion from federal healthcare programs, suspension and debarment from government procurement and non-procurement programs, and refusal of orders under existing government contracts.
−Removed: The majority of states also have statutes or regulations similar to the federal anti-kickback law and false claims laws, which apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payer.
+Added: In addition, civil judgment for violating the FCA may result in exclusion from federal healthcare programs, suspension and debarment from government procurement and non-procurement programs, and refusal of orders under existing government contracts.
+Added: The majority of states also have statutes similar to the federal Anti-Kickback Statute and civil False Claims Act, which apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payer.
The government may further prosecute conduct constituting a false claim under the criminal False Claims Act.
The criminal False Claims Act prohibits the making or presenting of a claim to the government knowing such claim to be false, fictitious, or fraudulent and, unlike the civil False Claims Act, requires proof of intent to submit a false claim.
−Removed: The civil monetary penalties statute is another potential statute under which biopharmaceutical companies may be subject to enforcement.
+Added: The Civil Monetary Penalties Law is another potential statute under which biopharmaceutical companies may be subject to enforcement.
Among other things, the civil monetary penalties statue imposes fines against any person who is determined to have knowingly presented, or caused to be presented, claims to a federal healthcare program that the person knows, or should know, is for an item or service that was not provided as claimed or is false or fraudulent.
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Manufacturers of drugs, biologics and devices for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program (with certain exceptions) are required to annually report to CMS certain payments and other transfers of value made to or at the request of covered recipients, which are physicians (as defined under the Social Security Act), physician assistants, nurse practitioners, clinical nurse specialists, certified registered nurse anesthetists and certified nurse midwifes licensed in the U.S.
−Removed: teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family.
+Added: teaching hospitals, as well as ownership and investment interests held by physicians and members of their immediate family.
Payments made to principal investigators and research institutions at teaching hospitals for clinical trials are also included within this law.
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Further, we may be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business.
−Removed: HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, (“HITECH Act”), and their respective implementing regulations impose certain requirements on covered entities relating to the privacy, security, and transmission of protected health information.
+Added: HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, (“HITECH Act”), and their respective implementing regulations impose certain requirements on covered entities relating to the privacy, security, and transmission of certain individually identifiable health information known as protected health information.
Among other things, the HITECH Act, and its implementing regulations, made HIPAA’s security standards and certain privacy standards directly applicable to business associates, defined as persons or organizations, other than members of a covered entity’s workforce, that create, receive, maintain, or transmit protected health information on behalf of a covered entity for a function or activity regulated by HIPAA.
−Removed: The HITECH Act also strengthened the civil and criminal penalties that may be imposed against covered entities, business associates, and individuals, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.
−Removed: In addition, other federal and state laws, such as the California Consumer Privacy Act, may govern the privacy and security of health and other information in certain circumstances, many of which differ from each other in significant ways, thus complicating compliance efforts.
+Added: The HITECH Act also strengthened the civil and criminal sanctions that may be imposed against covered entities, business associates, and individuals, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.
+Added: In addition, other federal and state laws, such as the California Consumer Privacy Act, may govern the privacy and security of health and other information in certain circumstances, many of which differ from each other in significant ways and may not be preempted by HIPAA, thus complicating compliance efforts.
Many states have also adopted laws similar to each of the above federal laws, which may be broader in scope and apply to items or services reimbursed by any third-party payor, including commercial insurers.
Certain state laws also regulate sponsors’ use of prescriber-identifiable data.
−Removed: Certain states also require implementation of commercial compliance programs and compliance with the pharmaceutical industry’s voluntary compliance guidelines and the applicable compliance guidance promulgated by the federal government, or otherwise restrict payments or the provision of other items of value that may be made to healthcare providers and other potential referral sources;
+Added: Certain states also require implementation of commercial compliance programs and compliance with the pharmaceutical industry’s voluntary compliance guidelines and the applicable compliance program guidance promulgated by the federal government, or otherwise restrict payments or the provision of other items of value that may be made to healthcare providers and other potential referral sources;
impose restrictions on marketing practices;
−Removed: or require sponsors to track and report information related to payments, gifts, and other items of value to physicians and other healthcare providers.
+Added: or require sponsors to track and report information related to payments, gifts, and other items of value to physicians and other healthcare providers and entities.
Recently, states have enacted or are considering legislation intended to make drug prices more transparent and deter significant price increases that impose reporting requirements on biopharmaceutical companies.
These laws may affect our future sales, marketing, and other promotional activities by imposing administrative and compliance burdens.
−Removed: Such laws also typically impose significant civil monetary penalties for each instance of reporting noncompliance that can quickly aggregate into the millions of dollars.
−Removed: If our operations are found to be in violation of any of the laws or regulations described above or any other laws that apply to us, we may be subject to penalties or other enforcement actions, including criminal and significant civil monetary penalties, damages, fines, disgorgement, imprisonment, exclusion from participation in government healthcare programs, corporate integrity agreements, suspension and debarment from government procurement and non-procurement programs, and refusal of orders under existing government contracts, reputational harm, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our business.
+Added: Such laws also typically impose significant civil monetary penalties for each instance of reporting noncompliance that can quickly aggregate into the tens of millions of dollars.
+Added: If our operations are found to be in violation of any of the laws or regulations described above or any other laws that apply to us, we may be subject to penalties or other enforcement actions, including significant civil monetary penalties, damages, criminal fines, disgorgement, imprisonment, exclusion from participation in government healthcare programs, corporate integrity agreements, suspension and debarment from government procurement and non-procurement programs, refusal of orders under existing government contracts, reputational harm, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our business.
Foreign Corrupt Practices Act
−Removed: Foreign Corrupt Practices Act, to which we are subject, prohibits corporations and individuals from engaging in certain activities to obtain or retain business or to influence a person working in an official capacity.
+Added: Foreign Corrupt Practices Act, to which we are subject, imposes certain recordkeeping requirements and prohibits corporations and individuals from engaging in certain activities to obtain or retain business or to influence a person working in an official capacity.
It is illegal to pay, offer to pay or authorize the payment of anything of value to any foreign government official, government staff member, political party, or political candidate in an attempt to obtain or retain business or to otherwise influence a person working in an official capacity.
14 unchanged sentences
As a result, the marketability of any product which receives regulatory approval for commercial sale may suffer if the government and third-party payers choose to provide low coverage and reimbursement.
−Removed: In addition, an increasing emphasis on managed care in the United States has increased and will continue to increase the pressure on drug pricing.
+Added: In addition, an increasing emphasis on managed care in the U.S.
+Added: has increased and will continue to increase the pressure on drug pricing.
Decisions regarding whether to cover any of our products, the extent of coverage and amount of reimbursement to be provided are made on a plan-by-plan basis.
−Removed: Further, no uniform policy for coverage and reimbursement exists in the United States, and coverage and reimbursement can differ significantly from payor to payor.
+Added: Further, no uniform policy for coverage and reimbursement exists in the U.S., and coverage and reimbursement can differ significantly from payor to payor.
Coverage policies, third party reimbursement rates and drug pricing regulation may change at any time.
3 unchanged sentences
Regulation in the European Union
−Removed: Product development, the regulatory approval process and safety monitoring of medicinal products and their manufacturers in the European Union proceed broadly in the same way as they do in the United States.
+Added: Product development, the regulatory approval process and safety monitoring of medicinal products and their manufacturers in the European Union proceed broadly in the same way as they do in the U.S..
Therefore, many of the issues discussed above apply similarly in the context of the European Union.
In addition, drugs are subject to the extensive price and reimbursement regulations of the various EU member states.
−Removed: The Clinical Trial Regulation EU 536/2014 (“CTR”), which replaced the current Clinical Trials Directive 2001/20/EC, as amended (“CTD”), on January 31, 2022, provides a system for the approval of clinical trials in the European Union via (in the case of the CTD) implementation through national legislation of the member states.
+Added: The Clinical Trial Regulation EU 536/2014 (“CTR”), which replaced the Clinical Trials Directive 2001/20/EC, as amended (“CTD”), on January 31, 2022, provides a system for the approval of clinical trials in the European Union.
The CTR is directly applicable in all member states without the need for national implementation.
3 unchanged sentences
either following the directive for “Contained use” (Directive 2009/41/EC) or “deliberate release” (Directive 2001/18/EC).
−Removed: This results in some EU member states, the GMO application must be approved before the Clinical Trial Application (CTA) is submitted, in some after approval of the CTA and in some parallel.
+Added: As a consequence, in some EU member states the GMO application must be approved before the CTA is submitted, in some after approval of the CTA, and in some, in parallel.
The sponsor of a clinical trial, or its legal representative, must be based in the European Economic Area (“EEA”).
5 unchanged sentences
Marketing approvals under the European Union regulatory system may be obtained through a centralized or decentralized procedure.
−Removed: The centralized procedure results in the grant of a single marketing authorization that is valid for all—currently 28—EU member states.
+Added: The centralized procedure results in the grant of a single marketing authorization that is valid for all 27 EU member states.
Pursuant to Regulation (EC) No 726/2004, as amended, the centralized procedure is mandatory for drugs developed by means of specified biotechnological processes, and advanced therapy medicinal products as defined in Regulation (EC) No 1394/2007, as amended.
1 unchanged sentence
Because of our focus on gene therapies, which fall within the category of advanced therapy medicinal products (“ATMPs”) and orphan indications, our products and product candidates will need to go through the centralized procedure.
−Removed: In the MAA the applicant must properly and sufficiently demonstrate the quality, safety, and efficacy of the drug.
−Removed: Guidance on the factors that the EMA will consider in relation to the development and evaluation of ATMPs have been issued and include, among other things, the preclinical studies required to characterize ATMPs;
+Added: In the marketing authorization application (“MAA”) the applicant must properly and sufficiently demonstrate the quality, safety, and efficacy of the drug.
+Added: Guidance on the factors that the EMA will consider in relation to the development and evaluation of ATMPs have been issued and include, among other things, the nonclinical studies required to characterize ATMPs;
the manufacturing and control information that should be submitted in a MAA;
83 unchanged sentences
Human Capital Resources
−Removed: As of December 31, 2021, we had a total of 463 employees, 250 of whom are based in The Netherlands, 206 in the United States of America, and seven in other European countries.
+Added: As of December 31, 2022, we had a total of 501 employees, 290 of whom are based in The Netherlands, 199 in the U.S., and 12 in other European countries.
As of December 31, 2022, 110 of our employees had an M.D.
10 unchanged sentences
● Focus relentlessly on quality.
+Added: Our people are a critical component in our continued success.
+Added: We strive to maximize the potential of our human capital resources by creating a respectful, rewarding and inclusive work environment that enables our employees to further our values.
Development of our culture is reflected as part of our annual corporate goals.
We invest in numerous learning opportunities focused on individual, management and team development and other initiatives to support our employees and build our culture.
−Removed: In 2021 we initiated activities to coordinate our various ongoing activities and initiatives within an environmental, social and governance (“ESG”) framework.
+Added: In 2021 and 2022, we initiated activities to coordinate our various ongoing activities and initiatives within an environmental, social and governance (“ESG”) framework.
Corporate Information
8 unchanged sentences
Our headquarters are in Amsterdam, the Netherlands, and its registered office is located at Paasheuvelweg 25, Amsterdam 1105 BP, the Netherlands and its telephone number is +31 20 240 6000.
−Removed: From our initial public offering until December 31, 2018, we were an emerging growth company, as defined in the Jumpstart Our Business Startups Act of 2012.
−Removed: On the last business day of our second quarter in fiscal year 2018 the aggregate worldwide market value of ordinary shares held by our non-affiliate shareholders exceeded $700.0 million.
−Removed: As a result, as of December 31, 2018, we were considered a large accelerated filer and as a consequence lost our status as an emerging growth company.
Our website address is www.uniqure.com.
1 unchanged sentence
Also available through our website’s “Investors & Newsroom:
−Removed: Corporate Governance” page are charters for the Audit, Compensation and Nominations and Corporate Governance committees of our board of directors and our Code of Business Conduct and Ethics.
+Added: Corporate Governance” page are charters for the Audit, Compensation and Nominations and Corporate Governance committees of our board of directors (the “Board”) and our Code of Business Conduct and Ethics.
We are not including the information on our website as a part of, nor incorporating it by reference into, this report.
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.