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May 07, 2018

25 Up and Coming Gene Therapies

Investment, Incentives, and IP Drive Growth in Clinical Development

25 Up and Coming Gene Therapies

By far the most crowded therapeutic area is oncology, accounting for two-thirds or 1,254 of the 1,855 trials recorded by Informa Pharma Intelligence. The next-largest indication is cardiovascular with 214 trials (11.5%), followed by infectious disease (6.5%). [Getty Images]

  • Gene therapy’s numbers look promising. In a year full of biopharma mergers and acquisitions, one of the biggest deals has been Novartis’ planned $8.7 billion purchase of AveXis, whose lead candidate AVXS-101 has advanced into a pivotal trial following positive Phase I data published in November in The New England Journal of Medicine.

    Additional figures furnished to GEN by Informa show the extent of gene-therapy development: Informa Pharma Intelligence’s Trialtrove database records 729 gene therapies as having been developed, of which nearly two-thirds (461) were preclinical. Those therapies have been assessed in 1,855 clinical trials, most in early phases: 657 in Phase I, 509 in Phase I/II, and 455 in Phase II. As for later development, 89 have reached Phase III, 32 are in Phase II/III, and 28 in Phase IV.

    By far the most crowded therapeutic area is oncology, accounting for two-thirds or 1,254 of the 1,855 trials. The next-largest indication is cardiovascular with 214 trials (11.5%), followed by infectious disease (6.5%).

    Clinical activity is expected to increase, in part due to the FDA’s Regenerative Medicine Advanced Therapy (RMAT) designation, created through the 21st Century Cures Act. “There are a lot of incentives for sponsors who get RMAT, including early and frequent interactions with the FDA, as well as the ability to discuss early on any potential surrogate or intermediate endpoints in their clinical trials,” Amanda Micklus, principal analyst with Informa Pharma Intelligence, told GEN. “The RMAT designation potentially could really advance the progress of these therapies through the pipeline.”

    Patricia Reilly, Informa Pharma Intelligence vice president, Intelligence Alliances and Product Unification, highlighted another sign of growth: The number of gene-therapy developers has ballooned from the 69 counted in 2014 by the Alliance for Regenerative Medicine (ARM), to 255 today.

    Below is a list of 25 “up and coming” gene-therapy candidates that had reached Phase III and/or registrational trials as of the first quarter of 2018, based on figures from ARM, as well as ClinicalTrials.gov and/or company announcements. Each candidate is listed by name, sponsor(s), indication(s), mechanism, late-stage trials, and updates.

    Two gene-therapy candidates on ARM’s list not included here are TransVax™, whose co-developer Vical eliminated more than half its staff and halted development after it failed the Phase III HELIOS trial. The other is Amgen’s Imlygic® (talimogene laherparepvec), which is in trials for additional melanoma indications (NCT02263508 and NCT02211131) following initial approval in 2015.

  • Axalimogene filolisbac (ADXS11-001) and ADXS-DUAL

    Sponsor(s): Advaxis

    Indication: Metastatic cervical cancer

    Mechanism: Targeted immunotherapy based on a platform technology that uses live attenuated Listeria monocytogenes (Lm) bioengineered to secrete antigen/adjuvant fusion proteins. ADXS-DUAL is second-generation of axalimogene filolisbac.

    Trial(s) (Identifier): Study of ADXS11-001 in Subjects with High Risk Locally Advanced Cervical Cancer (AIM2CERV; NCT02853604; Phase III)

    Updates: Advaxis is assessing axalimogene filolisbac in combinations with Bristol-Myers Squibb’s Opdivo® (nivolumab) and AstraZeneca’s Imfinzi® (durvalumab). On March 12, Advaxis acknowledged the FDA’s clinical hold on a Phase I/II study of axalimogene filolisbac/Imfinzi after a patient died in February.

  • AMG0101 (AMG0103)

    Sponsor(s): AnGes, Shionogi (global license for dermal diseases), MEDRx, and Alfresa Pharma

    Indication(s): Atopic Dermatitis [Japan]; Chronic discogenic low back pain (DLBP) [U.S.]

    Mechanism: NF-kB Decoy Oligonucleotide, a specific inhibitor for NF-kB that acts as a switch to a gene cluster involved in the immune inflammatory response in the body. Administered via ointment in atopic dermatitis, and via injection in discogenic low back pain.

    Trial(s) (Identifier): Phase III study in atopic dermatitis (details unavailable); AMG0103 in Subjects with Chronic Discogenic Lumbar Back Pain (NCT03263611; Phase Ib)

    Updates: As of April 12, AnGes stated, the Phase III atopic dermatitis study was completed, and failed. On February 28, AnGes said the first patient was dosed in the Phase Ib study.

  • AMT-061

    Sponsor(s): uniQure

    Indication(s): Hemophilia B

    Mechanism: AMT-061 consists of an AAV5 viral vector carrying a gene cassette with the Padua variant of Factor IX (FIX-Padua).

    Trial(s) (Identifiers): Dose Confirmation Trial of AAV5-hFIXco-Padua (NCT03489291; Phase II)

    Updates: Phase II study not yet recruiting patients. uniQure announced plans to advance AMT-061 into a pivotal study on October 19, 2017.

  • AVXS-101

    Sponsor(s): AveXis (to be acquired by Novartis)

    Indication(s): Spinal muscular atrophy (SMA)

    Mechanism: A non-replicating adeno-associated virus 9 (AAV9) capsid is used to deliver a functional copy of a human SMN gene to the nucleus of the patient's own cells. The gene is meant to supplement the cell's production of the SMN protein, increasing that production to an adequate level.

    Trial(s) (Identifiers): Pre-Symptomatic Study of Intravenous AVXS-101 in Spinal Muscular Atrophy (SMA) for Patients With Multiple Copies of SMN2 (SPRINT; NCT03505099; Phase III); Single-Dose Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1 (STRIVE-EU; NCT03461289; Phase III); Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1 (STR1VE; NCT03306277; Phase III)

    Updates: On April 25, AveXis said the first patient was dosed in the Phase III SPRINT trial. A day earlier, AveXis released initial results from the STR1VE trial showing that all six patients were alive and event-free as of April 11—plus 24-month follow-up data from a Phase I trial of AVXS-101 in SMA Type 1 showing that all 15 patients were alive and without need for permanent ventilation.

  • CG0070

    Sponsor(s): Cold Genesys

    Indication(s): Non-muscle invasive bladder cancer (NMIBC); muscle invasive bladder cancer (MIBC)

    Mechanism: Oncolytic immunotherapy based on a modified common cold adenovirus backbone that contains a cancer-specific promoter and a GM-CSF transgene. CG0070 is designed to replicate inside the tumor cells, causing tumor cell lysis and immunogenic cell death.

    Trial(s) (Identifier): Safety and Efficacy of CG0070 Oncolytic Virus Regimen for High Grade NMIBC After BCG Failure (BOND2; NCT02365818; Phase II)

    Updates: Cold Genesys last year reported topline results from BOND2 that included a six-month Complete Response rate of 46.7%.

  • E10A

    Sponsor(s): Marsala Biotech, Guangzhou Dabo Biological Products

    Indication(s): Squamous cell carcinoma of the head and neck

    Mechanism: E10A uses the Endostatin gene to prevent angiogenesis and shut off the nutrient supply to tumors, starving the tumors and leading to tumor shrinkage. The gene is integrated into an adenoviral vector which is injected into the tumor. The vector infects the tumor cells, delivering the endostatin gene inside the cell.

    Trial(s) (Identifier): E10A for the Treatment of Squamous Cell Carcinoma of the Head and Neck (NCT02630264; Phase III)

    Updates: NCT02630264 status is unknown.

  • Generx® (alferminogene tadenovec, Ad5FGF-4)

    Sponsor(s): Angionetics, Huapont Life Sciences, Gene Biotherapeutics (formerly Taxus Cardium Pharmaceuticals Group)

    Indication(s): Angiogenic growth factor gene therapy for cardiac microvascular insufficiency in patients with myocardial ischemia and symptomatic chronic stable angina pectoris due to coronary microvascular dysfunction in association with advanced coronary artery disease.

    Mechanism: Generx consists of the human fibroblast growth factor-4 (FGF-4) gene, a CMV promoter sequence, and a signal peptide, encapsulated in a human serotype 5 adenovirus. Generx is delivered to the heart using Angionetic’s optimized cardiac catheter technique, binds to heart cells via the coxsackie adenovirus receptors, and transfects the cells with the FGF-4 gene.

    Trial(s) (Identifier): Ad5FGF-4 in Patients with Refractory Angina Due to Myocardial Ischemia (AFFIRM; NCT02928094; Phase III)

    Updates: NCT02928094 active but not yet recruiting patients as of January 10.

  • GSK2696274

    Sponsor(s): GlaxoSmithKline (GSK) and Ospedale (Hospital) San Raffaele–Telethon Institute for Gene Therapy (OSR-TIGET)

    Indication(s): Metachromatic Leukodystrophy (MLD)

    Mechanism: Autologous cluster of differentiation 34+ (CD34+) cells transduced with lentiviral vector containing human arylsulfatase A (ARSA) complementary deoxyribonucleic acid (cDNA)

    Trial(s) (Identifier): A Safety and Efficacy Study of Cryopreserved GSK2696274 for Treatment of Metachromatic Leukodystrophy (MLD; NCT03392987; Phase III)

    Updates: On April 12, GSK said it will hand off its rare disease gene therapy portfolio to Orchard Therapeutics in return for a 19.9% stake in the acquirer, undisclosed milestone payments, royalties, and a seat on Orchard’s board. The portfolio includes GSK269274, another late-stage clinical candidate GSK269275, and the European-approved gene therapy Strimvelis™.

  • GSK296275

    Sponsor(s): GlaxoSmithKline (GSK) and Ospedale (Hospital) San Raffaele-Telethon Institute for Gene Therapy (OSR-TIGET)

    Indication(s): Wiskott Aldrich syndrome (WAS)

    Mechanism: Genetically modified autologous hematopoietic stem cells that were collected from bone marrow and/or mobilized from peripheral blood and transduced with a lentiviral vector encoding for WAS.

    Trial(s) (Identifier): Gene Therapy for Wiskott-Aldrich Syndrome (TIGET-WAS; NCT01515462; Phase II)

    Updates: On April 12, GSK said it will hand off its rare disease gene therapy portfolio to Orchard Therapeutics in return for a 19.9% stake in the acquirer, undisclosed milestone payments, royalties, and a seat on Orchard’s board. The portfolio includes GSK269275, GSK269274, and the European-approved gene therapy Strimvelis™.

  • GS010

    Sponsor(s): GenSight Biologics

    Indication(s): Leber Hereditary Optic Neuropathy (LHON) caused by mutation of the ND4 gene

    Mechanism: AAV2 gene-therapy vector that encodes the human wild-type ND4 protein

    Trial(s) (Identifier): Efficacy Study of GS010 for the Treatment of Vision Loss up to 6 Months From Onset in LHON Due to the ND4 Mutation (RESCUE, NCT02652767; Phase III); Efficacy Study of GS010 for Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the ND4 Mutation (REVERSE, NCT02652780); Efficacy and Safety Study of Bilateral Intravitreal Injection of GS010 for the Treatment of Vision Loss up to 1 Year from Onset in LHON Due to the ND4 Mutation (REFLECT, NCT03293524; Phase III).

    Updates: On April 2, GenSight said the Phase III REVERSE trial missed its primary endpoint, as the 48-weeks improvement of +11 ETDRS letters in GS010-treated eyes was similar to that of untreated eyes across the study’s 37 subjects.

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