Regulatory Roundup: Designations come through before year's end

By The Science Advisory Board staff writers

December 7, 2020 -- This week's Regulatory Roundup covers activities from November 30 to December 4 and is filled with breakthrough, orphan, and rare disease designations from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Several cancer, immunotherapy, and vaccine companies also submitted biologic license applications (BLA) to move their candidates forward.

3-antigen prophylactic hepatitis B vaccine, VBI Vaccines

VBI Vaccines has submitted a BLA to the FDA for the company's 3-antigen prophylactic hepatitis B vaccine for the prevention of the infection caused by all known serotypes of the hepatitis B virus in adults. The company previously announced the submission of a marketing authorization application to the EMA and it expects to submit regulatory approval applications to the U.K. Medicines and Healthcare Products Regulatory Agency and to Health Canada by the end of the first quarter of 2021. The vaccine is approved for use and is commercially available in Israel. The submissions are based on data from the Protect and Constant clinical trials.

ACE-1334, Acceleron Pharma

The FDA has granted orphan drug designation to Acceleron's ACE-1334 for the treatment of patients with system sclerosis. ACE-1334 is a transforming growth factor (TGF)-beta superfamily-based ligand trap designed to bind and inhibit TGF-beta 1 and 3 ligands but not TGF-beta 2. ACE-1334 has shown strong anti-fibrotic activity in multiple preclinical models, Acceleron recently completed an ascending dose phase I clinical trial in healthy volunteers. The company plans to begin a phase IB/II trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in 2021. SSc-ILD is a rare, progressive, autoimmune connective tissue disorder characterized by immune dysregulation. ACE-1334 has previously been granted fast track designation for SSc-ILD and orphan drug designation for systemic sclerosis by the FDA.

ACN00177, Aeglea BioTherapeutics

The FDA has granted rare pediatric disease designation to ACN00177 for the treatment of homocystinuria. ACN00177 is a novel recombinant human enzyme therapy designed to lower the total level of homocysteine in the plasma by degrading the amino acid homocysteine and the related homocystine dimer. Aeglea initiated a phase I/II clinical trial in the second quarter of 2020 to investigate ACN00177 for the treatment of homocystinuria. ACN00177 has previously received orphan drug designations in the U.S. and E.U.

Amivantamab, Janssen Pharmaceutical

Janssen Pharmaceutical submitted a BLA to the FDA for amivantamab for the treatment of patients with metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. Amivantamab is an investigational, fully human EGFR and mesenchymal epithelial transition factor (MET) bispecific antibody with immune cell-directing activity that targets tumors with activating and resistance EGFR and MET mutations and amplifications. In March 2020, the FDA granted amivantamab breakthrough therapy designation. The submission is based on data from a monotherapy arm of the phase I Chrysalis study.

The production and development of the antibody followed Janssen Biotech's licensing agreement with Genmab for use of its DuoBody technology platform.

Aspartylglucosaminuria, Neurogene

The EMA has granted orphan drug designation to Neurogene's adeno-associated viral (AAV) vector with an engineered transgene encoding the human AGA gene for patients diagnosed with aspartylglucosaminuria (AGU), an inherited rare, progressively debilitating neurodegenerative lysosomal storage disorder. Earlier in 2020, the FDA granted Neurogene orphan drug designation for its gene therapies (CLN5 and CLN7) targeting two subtypes of Batten disease.

AT-GAA, Amicus Therapeutics

Amicus Therapeutics has initiated the rolling BLA submission to the FDA for AT-GAA, an investigational two-component therapy for the treatment of late-onset Pompe disease (LOPD), an inherited lysosomal disorder caused by the deficiency of acid alpha-glucosidase (GAA). The therapy consists of the recombinant human GAA enzyme with optimized carbohydrate structures, particularly bis-phosphorylated mannose-6 phosphate (bis-M6P) glycans, to enhance uptake into cells, administered in conjunction with AT2221 (miglustat), a stabilizer of cipaglucosidase alfa. The company is conducting an ongoing phase III clinical study to assess the safety, efficacy, and tolerability of the treatment. Topline results are on track for the first quarter of 2021. The FDA has previously granted breakthrough therapy designation to AT-GAA for the treatment of LOPD based on clinical efficacy results from a phase I/II clinical study.

Dupilumab, Regeneron/Sanofi

The European Commission (EC) has extended the marketing authorization for dupilumab (Dupixent) in the E.U. to include children 6 to 11 years of age with severe atopic dermatitis who are candidates for systemic therapy. Dupixent is a fully human monoclonal antibody that inhibits the signaling of interleukin 4 (IL-4) and IL-13 proteins and was developed using Regeneron's VelocImmune technology. The EC's decision was based on data from a phase III efficacy and safety trial, demonstrating that dupixent blocks IL-4 and IL-13, which are key drivers of type II inflammation that plays a major role in atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis. Dupixent is approved in more than 60 countries around the world, including the E.U., U.S., and Japan.

EG-70, EnGene

The FDA has granted fast track designations to EnGene for EG-70, its lead investigational nonviral gene therapy for the treatment of patients with Bacille Calmette-Guerin-unresponsive nonmuscle invasive bladder cancer. The therapy is developed using the company's dually derived chitosan (DDX) platform, which can deliver DNA and RNA payloads with broad tissue and disease applications.

Eprenetapopt, Aprea Therapeutics

The FDA granted fast track designation for eprenetapopt, Aprea's small-molecule drug, for the treatment of TP53 mutant acute myeloid leukemia (AML). The p53 tumor suppressor gene is the most frequently mutated gene in human cancers, occurring in around 50% of all human tumors. Eprenetapopt restores the wildtype p53 conformation and function, thereby inducing programmed cell death in human cancer cells. Preclinical studies have demonstrated that eprenetapopt has anti-tumor activity against a wide variety of solid and hematological cancers. The company is conducting ongoing AML clinical trials and is expected to present data to the FDA in 2021. The company has previously received breakthrough therapy, orphan drug, and fast track designations for eprenetapopt in the treatment of TP53 mutant myelodysplastic syndromes.

Mitazalimab, Alligator Bioscience

The FDA has approved Alligator's investigational new drug (IND) application for the CD-40 targeting antibody mitazalimab. The agonistic antibody targets CD-40, a receptor in the dendritic cells of the immune system, which are the cells that detect enemies such as cancer cells. The approval is based on clinical trial data demonstrating the potent immune-activating properties and anti-tumor effects of mitazalimab. The company is planning an upcoming phase IB/II study in pancreatic cancer that will be starting soon in Europe. Alligator hopes that the IND will later lead to expansion of a previous phase I trial conducted by Janssen Biotech in the U.S.

Omalizumab, Genentech

The FDA approved Genentech's supplemental BLA for omalizumab (Xolair) for add-on maintenance treatment of nasal polyps in adult patients with inadequate response to nasal corticosteroids. The antibody is designed to target and block immunoglobulin E (IgE), a key driver of inflammation. The approval is based on results from the phase III Polyp 1 and Polyp 2 trials, which demonstrated improvement in polyp scores and in congestion compared to the placebo. The injectable biologic medicine is also FDA-approved for the treatment of certain patients with moderate to severe persistent allergic asthma (older than 6 years of age) and chronic idiopathic urticaria (older than 12 years of age).

PR006, Prevail Therapeutics

The EC has granted orphan designation for Prevail Therapeutics' PR006 for the treatment of GRN-associated frontotemporal dementia. PR006 is an investigational AAV-9 gene therapy delivery of the GRN gene, which encodes progranulin. The company expects to initiate a phase I/II trial of PR006 by the end of 2020 and anticipates providing biomarker and safety analysis on a subset of patients from the trial in 2021. PR006 has also been granted orphan drug and fast track designations by the FDA.

Remestemcel-L, Mesoblast Limited

The FDA has granted fast track designation for remestemcel-L in the treatment of acute respiratory distress syndrome (ARDS) due to COVID-19 infection. Remestemcel-L is an investigational therapy comprising culture-expanded mesenchymal stromal cells derived from the bone marrow of an unrelated donor, thought to have immunomodulatory properties that counteract cytokine storms. The designation was granted based on results from a pilot study of remestemcel-L under emergency compassionate use in ventilator-dependent COVID-19 ARDS patients. Under an FDA IND clearance, the company is conducting an ongoing randomized controlled phase III trial in up to 300 ventilator-dependent patients with moderate to severe COVID-19 ARDS.

Mesoblast recently entered into a license and collaboration agreement with Novartis for the development, manufacture, and commercialization of remestemcel-L.

TSHA-103, Taysha Gene Therapies

The FDA granted rare pediatric disease and orphan drug designations for TSHA-103, an AAV-9-based gene therapy in development, for SLC6A1-related epilepsy. SLC6A1 epilepsy is an autosomal dominant genetic disorder characterized by the loss of function of one copy of the SLC6A1 gene, with clinical manifestations of seizures, epilepsy, language impairment, and intellectual disability.

Ublituximab, TG Therapeutics

TG Therapeutics has initiated rolling submission of a BLA to the FDA for ublituximab, an investigational glycoengineered anti-CD20 monoclonal antibody, in combination with umbralisib, the company's investigational once-daily, oral, dual inhibitor of PI3K-delta and CK1-epsilon, as a treatment for patients with chronic lymphocytic leukemia (CLL). The submission is supported by data from a phase III clinical trial. The FDA previously approved fast track and orphan drug designations to the combination of ublituximab and umbralisib (U2) for the treatment of adult patients with CLL.

WP1066, Moleculin Biotech

The FDA has approved Moleculin's request for rare pediatric disease designation for WP1066, an immune/transcription modulator capable of inhibiting phoso-Stat3 and other oncogenic transcription factors, while also stimulating a natural immune response. The drug targets brain tumors (diffuse intrinsic pontine glioma and medulloblastoma), pancreatic cancer, and hematologic malignancies (atypical teratoid rhabdoid tumor). The designation will enable the company to receive a transferrable priority review voucher upon new drug approval for each of the three indications.

Zanidatamab, Zymeworks

The FDA has granted breakthrough therapy designation for Zymeworks' zanidatamab in patients previously treated for HER2 gene-amplified biliary tract cancer (BTC). The designation is based on data generated in BTC patients treated in a phase I trial. Zanidatamab is a bispecific antibody, developed using the company's Azymetric platform, which simultaneously binds two nonoverlapping epitopes of HER2. Earlier in 2020, the company initiated a phase IIB registration-enabling study of zanidatamab in patients with previously treated HER2 gene-amplified BTC. Depending on the results of this ongoing study, the company plans to submit a BLA as early as 2022. Zanidatamab has also received orphan drug designations treatment of biliary tract, gastric, and ovarian cancers from the FDA and for the treatment of gastric cancer from the EMA.

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